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  • 1.
    Acharya, Parag
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Studies on the Non-covalent Interactions (Stereoelectronics, Stacking and Hydrogen Bonding) in the Self-assembly of DNA and RNA2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on ten publications (Papers I-X). The phosphodiester backbone makes DNA or RNA to behave as polyelectrolyte, the pentose sugar gives the flexibility, and the aglycones promote the self-assembly or the ligand-binding process. The hydrogen bonding, stacking, stereoelectronics and hydration are few of the important non-covalent forces dictating the self-assembly of DNA/RNA. The pH-dependent thermodynamics clearly show (Papers I and II) that a change of the electronic character of aglycone modulates the conformation of the sugar moiety by the tunable interplay of stereoelectronic anomeric and gauche effects, which are further transmitted to steer the sugar-phosphate backbone conformation in a cooperative manner. 3'-anthraniloyl adenosine (a mimic of 3'-teminal CCAOH of the aminoacyl-tRNAPhe) binds to EF-Tu*GTP in preference over 2'-anthraniloyl adenosine, thereby showing (Paper III) that the 2’-endo sugar conformation is a more suitable mimic of the transition state geometry than the 3’-endo conformation in discriminating between correctly and incorrectly charged aminoacyl-tRNAPhe by EF-Tu during protein synthesis. The presence of 2'-OH in RNA distinguishes it from DNA both functionally as well as structurally. This work (Paper IV) provides straightforward NMR evidence to show that the 2'-OH is intramolecularly hydrogen bonded with the vicinal 3'-oxygen, and the exposure of the 3'-phosphate of the ribonucleotides to the bulk water determines the availability of the bound water around the vicinal 2'-OH, which then can play various functional role through inter- or intramolecular interactions. The pH-dependent 1H NMR study with nicotinamide derivatives demonstrates (Paper V) that the cascade of intramolecular cation (pyridinium)-π(phenyl)-CH(methyl) interaction in edge-to-face geometry is responsible for perturbing the pKa of the pyridine-nitrogen as well as for the modulation of the aromatic character of the neighboring phenyl moiety, which is also supported by the T1 relaxation studies and ab initio calculations. It has been found (Papers VI-IX) that the variable intramolecular electrostatic interaction between electronically coupled nearest neighbor nucleobases (steered by their respective microenvironments) can modulate their respective pseudoaromatic characters. The net result of this pseudoaromatic cross-modulation is the creation of a unique set of aglycones in an oligo or polynucleotide, whose physico-chemical properties are completely dependent upon the propensity and geometry of the nearest neighbor interactions (extended genetic code). The propagation of the interplay of these electrostatic interactions across the hexameric ssDNA chain is considerably less favoured (effectively up to the fourth nucleobase) compared to that of the isosequential ssRNA (up to the sixth nucleobase). The dissection of the relative strength of basepairing and stacking in a duplex shows that stability of DNA-DNA duplex weakens over the corresponding RNA-RNA duplexes with the increasing content of A-T/U base pairs, while the strength of stacking of A-T rich DNA-DNA duplex increases in comparison with A-U rich sequence in RNA-RNA duplexes (Paper X).

    List of papers
    1. The Transmission of the Electronic Character of Guanin-9-yl Drives the Sugar-phosphate Backbone Torsions in Guanosine 3',5'-bisphosphate.
    Open this publication in new window or tab >>The Transmission of the Electronic Character of Guanin-9-yl Drives the Sugar-phosphate Backbone Torsions in Guanosine 3',5'-bisphosphate.
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    1999 In: Angew. Chem. Int. Ed., Vol. 38, no 24, p. 3645-3650Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91143 (URN)
    Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
    2. The RNA Molecular Wire: The pH-Dependent Change in Electronic Character of Adenine-9-yl is Transmitted to Drive the Sugar-Phosphate Backbone Torsions in Adenosine 3', 5'-bisphosphate
    Open this publication in new window or tab >>The RNA Molecular Wire: The pH-Dependent Change in Electronic Character of Adenine-9-yl is Transmitted to Drive the Sugar-Phosphate Backbone Torsions in Adenosine 3', 5'-bisphosphate
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    2000 In: J. Phys. Org. Chem., Vol. 13, p. 300-305Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91144 (URN)
    Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
    3. The Strength of the 3'-gauche effect Dictates the Structure of 3'-anthraniloyladenosine and its 5'-phosphate, Two Analogues of the 3'-end of Aminoacyl tRNA
    Open this publication in new window or tab >>The Strength of the 3'-gauche effect Dictates the Structure of 3'-anthraniloyladenosine and its 5'-phosphate, Two Analogues of the 3'-end of Aminoacyl tRNA
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    1999 In: J. Chem. Soc. Perkin 2, p. 1531-1536Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91145 (URN)
    Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
    4. The Hydrogen Bonding and Hydration of 2'-OH in Adenosine and Adenosine 3'-ethylphosphate
    Open this publication in new window or tab >>The Hydrogen Bonding and Hydration of 2'-OH in Adenosine and Adenosine 3'-ethylphosphate
    2002 In: J. Org. Chem., Vol. 67, no 6, p. 1852-1865Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91146 (URN)
    Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
    5. A Repertoire of Pyridinium-Phenyl-Methyl Cross-Talk through a Cascade of Intramolecular Electrostatic Interactions
    Open this publication in new window or tab >>A Repertoire of Pyridinium-Phenyl-Methyl Cross-Talk through a Cascade of Intramolecular Electrostatic Interactions
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    2003 In: J. Org. Chem., Vol. 68, no 4, p. 1529-1538Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91147 (URN)
    Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
    6. Cross-Modulation of Physicochemical Character of Aglycones in Dinucleoside (3'→5') monophosphates by the Nearest Neighbor Interaction in the Stacked State
    Open this publication in new window or tab >>Cross-Modulation of Physicochemical Character of Aglycones in Dinucleoside (3'→5') monophosphates by the Nearest Neighbor Interaction in the Stacked State
    2002 In: J. Am. Chem. Soc., Vol. 124, no 46, p. 13722-13730Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91148 (URN)
    Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
    7. Tandem Electrostatic Effect From the First to the Third Aglycon in the Trimeric RNA Owing to the Nearest-neighbor Stacking
    Open this publication in new window or tab >>Tandem Electrostatic Effect From the First to the Third Aglycon in the Trimeric RNA Owing to the Nearest-neighbor Stacking
    2003 In: J. Am. Chem. Soc., Vol. 125, no 8, p. 2094-2100Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91149 (URN)
    Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
    8. Cross-Modulation of the pKa of Nucleobases in a Single-Stranded Hexameric-RNA Due to Tandem Electrostatic Nearest-Neighbor Interactions
    Open this publication in new window or tab >>Cross-Modulation of the pKa of Nucleobases in a Single-Stranded Hexameric-RNA Due to Tandem Electrostatic Nearest-Neighbor Interactions
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    2003 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 125, no 33, p. 9948-9961Article in journal (Refereed) Published
    Abstract [en]

    The pH titration studies (pH 6.7-12.1) in a series of dimeric, trimeric, tetrameric, pentameric, and hexameric oligo-RNA molecules [GpA (2a), GpC (3a), GpApC (5), GpA(1)pA(2)pC (6), GpA(1)pA(2)pA(3)pC (7), GpA(1)pA(2)pA(3)pA(4)pC (8)] have shown that the pK(a) of N(1)-H of 9-guaninyl could be measured not only from its own deltaH8G, but also from the aromatic marker protons of other constituent nucleobases. The relative chemical shift differences [Deltadelta((N)(-)(D))] between the protons in various nucleotide residues in the oligo-RNAs at the neutral (N) and deprotonated (D) states of the guanine moiety show that the generation of the 5'-(9-guanylate ion) in oligo-RNAs 2-8 reduces the stability of the stacked helical RNA conformation owing to the destabilizing anion(G(-))-pi/dipole(Im(delta)(-)) interaction. This destabilizing effect in the deprotonated RNA is, however, opposed by the electrostatically attractive atom-pisigma (major) as well as the anion(G(-))-pi/dipole(Py(delta)(+)) (minor) interactions. Our studies have demonstrated that the electrostatically repulsive anion(G(-))-pi/dipole(Im(delta)(-)) interaction propagates from the first to the third nucleobase quite strongly in the oligo-RNAs 6-8, causing destacking of the helix, and then its effect is gradually reduced, although it is clearly NMR detectable along the RNA chain. Thus, such specific generation of a charge at a single nucleobase moiety allows us to explore the relative strength of stacking within a single-stranded helix. The pK(a) of 5'-Gp residue from its own deltaH8G in the hexameric RNA 8 is found to be 9.76 +/- 0.01; it, however, varies from 9.65 +/- 0.01 to 10.5 +/- 0.07 along the RNA chain as measured from the other marker protons (H2, H8, H5, and H6) of 9-adeninyl and 1-cytosinyl residues. This nucleobase-dependent modulation of pK(a)s (DeltapK(a) +/- 0.9) of 9-guaninyl obtained from other nucleobases in the hexameric RNA 8 represents a difference of ca. 5.1 kJ mol(-)(1), which has been attributed to the variable strength of electrostatic interactions between the electron densities of the involved atoms in the offset stacked nucleobases as well as with that of the phosphates. The chemical implication of this variable pK(a) for guanin-9-yl deprotonation as obtained from all other marker protons of each nucleotide residue within a ssRNA molecule is that it enables us to experimentally understand the variation of the electronic microenvironment around each constituent nucleobase along the RNA chain in a stepwise manner with very high accuracy without having to make any assumption. This means that the pseudoaromaticity of neighboring 9-adeninyl and next-neighbor nucleobases within a polyanionic sugar-phosphate backbone of a ssRNA can vary from one case to another due to cross-modulation of an electronically coupled pi system by a neighboring nucleobase. This modulation may depend on the sequence context, spatial proximity of the negatively charged phosphates, as well as whether the offset stacking is ON or OFF. The net outcome of this electrostatic interaction between the neighbors is creation of new sequence-dependent hybrid nucleobases in an oligo- or polynucleotide whose properties are unlike the monomeric counterpart, which may have considerable biological implications.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-91150 (URN)10.1021/ja034651h (DOI)12914458 (PubMedID)
    Available from: 2003-11-26 Created: 2003-11-26 Last updated: 2017-12-14Bibliographically approved
    9. The Nucleobases in Single-stranded DNA are Better Stacked and Yet Their Pseudoaromatic Characters are More Poorly Cross-modulated Than in the RNA Counterparts Due to Variable Tandem Nearest-neighbour Electrostatic Interactions
    Open this publication in new window or tab >>The Nucleobases in Single-stranded DNA are Better Stacked and Yet Their Pseudoaromatic Characters are More Poorly Cross-modulated Than in the RNA Counterparts Due to Variable Tandem Nearest-neighbour Electrostatic Interactions
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    In: J. Am. Chem. Soc.Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91151 (URN)
    Available from: 2003-11-26 Created: 2003-11-26Bibliographically approved
    10. Measurement of nucleobase pKa values in model mononucleotides shows RNA-RNA duplexes to be more stable than DNA-DNA duplexes
    Open this publication in new window or tab >>Measurement of nucleobase pKa values in model mononucleotides shows RNA-RNA duplexes to be more stable than DNA-DNA duplexes
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    2004 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 126, no 9, p. 2862-2869Article in journal (Refereed) Published
    Abstract [en]

    To understand why the RNA-RNA duplexes in general has a higher thermodynamic stability over the corresponding DNA-DNA duplexes, we have measured the pK(a) values of both nucleoside 3',5'-bis-ethyl phosphates [Etp(d/rN)pEt] and nucleoside 3'-ethyl phosphates [(d/rN)pEt] (N = A, G, C, or T/U), modeling as donors and acceptors of base pairs in duplexes. While the 3',5'-bis-phosphates, Etp(d/rN)pEt, mimic the internucleotidic monomeric units of DNA and RNA, in which the stacking contribution is completely absent, the 3'-ethyl phosphates, (d/rN)pEt, mimic the nucleotide at the 5'-end. The pK(a) values of the nucleobase in each of these model nucleoside phosphates have been determined with low pK(a) error (sigma = +/-0.01 to 0.02) by (1)H NMR (at 500 MHz) with 20-33 different pH measurements for each compound. This study has led us to show the following: (1) All monomeric DNA nucleobases are more basic than the corresponding RNA nucleobases in their respective Etp(d/rN)pEt and (d/rN)pEt. (2) The pK(a) values of the monomeric nucleotide blocks as well as Delta pK(a) values between the donor and acceptor can be used to understand the relative base-pairing strength in the oligomeric duplexes in the RNA and DNA series. (3) The Delta G*(pKa) of the donor and acceptor of the base pair in duplexes enables a qualitative dissection of the relative strength of the base-pairing and stacking in the RNA-RNA over the DNA-DNA duplexes. (4) It is also found that the relative contribution of base-pairing strength and nucleobase stacking in RNA-RNA over DNA-DNA is mutually compensating as the % A-T/U content increases or decreases. This interdependency of stacking and hydrogen bonding can be potentially important in the molecular design of the base-pair mimics to expand the alphabet of the genetic code.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-91152 (URN)10.1021/ja0386546 (DOI)14995203 (PubMedID)
    Available from: 2003-11-26 Created: 2003-11-26 Last updated: 2017-12-14Bibliographically approved
  • 2.
    Alvi, Muhammad Rouf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Low-coordinate Organosilicon Chemistry: Fundamentals, Excursions Outside the Field, and Potential Applications2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis reports on unsaturated silicon compounds, as well as excursions from these into germanium chemistry, single molecule electronics, and silyl protective group chemistry. Both experimental and computational investigations were performed.

    Potassium germenolates were synthesized through reactions of tris(timethylsilyl) substituted acyl- and carbamylgermanes with potassium tert-butoxide. The potassium germenolates calculated by density functional theory have pyramidal structures at the Ge atoms, similar to the Si in the corresponding potassium silenolates, indicating negative charge on germanium rather than on oxygen. Germenolates also display germyl anion-like reactivity instead of germene-like reactivity as they are alkylated at Ge and initiate anionic polymerization of dienes rather than form [4+2] cycloadducts. The NMR chemical shifts reveal more negative charge at Ge in germenolates than at Si in analogous silenolates.

    Computations indicate that silabenzenes and silapyridines are reachable via [1,3]-silyl shifts from cyclic conjugated acylsilanes. Differently sized substituents were considered to prevent dimerizations, and 1-triisopropylsilyl-2-triisopropylsiloxy-6-tert-butylsilabenzene is a good synthetic target. Computations also show that silaphenolates are species with negative charge primarily localized at oxygen atom. Their planar structures, bond lengths, and NICS values reveal significant influence of aromaticity. Electrostatic repulsion should increase their stability, however, steric bulk is also important.

    Furthermore, it was found computationally that [1,3]-silyl shift from an acylsilane to a silene can function as a molecular switch reaction. Conductance calculations support this proposition.  

    Finally, tris(trimethylsilyl)silylmethaneamide (hypersilylamide) together with catalytic amounts of triflic acid were found to be efficient for protection of a range of alkyl and aryl alcohols and thiols in good to excellent yields. The protocol can be used to protect the less hindered OH group of a diol and has a broad functional group tolerance. A catalytic cycle is proposed. Hypersilyl protected alcohols and thiols are deprotected efficiently under photolytic conditions.

    List of papers
    1. Remarkably Stable Silicon Analogues of Amide Enolates: Synthesis, Structural Characterization, and Reactivity Studies
    Open this publication in new window or tab >>Remarkably Stable Silicon Analogues of Amide Enolates: Synthesis, Structural Characterization, and Reactivity Studies
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Potassium 2-N,N-dialkylamino-1,1-bis(trimethylsilyl)silen-2-olates (or amide silenolates, silicon analogues of amide enolates) were synthesized through reaction of N,N-dialkyl-tris(trimethylsilyl)silylmethaneamides with potassium tert-butoxide, and these 2-N,N-dialkylaminosilen-2-olates display remarkable thermal stabilities (e.g., merely 37% decomposition after 8 h at 90 ºC).  The crystal structure of one of the potassium 2-N,N-dialkylaminosilen-2-olates, without potassium ion chelating agent, reveals a more pyramidal configuration around the Si atom than found in previously reported silenolates, indicating a strong localization of the negative charge to this atom. The reactivities of the potassium 2-N,N-dialkylaminosilen-2-olates are in part similar to those of previous lithium and potassium silenolates as they are alkylated with MeI at Si. However, they do not react with dienes to yield [4+2] cycloadducts, the customary adducts of silenolates and reverse polarized silenes, but instead initiate anionic diene polymerization.  Consequently, they display silyl anion-like rather than silene-like reactivities. Finally, we find that potassium 2-aminosilen-2-olates with N,N-diphenylamino instead of N,N-dialkylamino substitution decompose rapidly to potassium diphenylamide, carbon monoxide, and silylenes. Clearly, if the substituent at the 2-position of a silenolate is able to accept and stabilize negative charge, such as NPh2, then this silenolate will be prone to decompose.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169783 (URN)
    Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2012-04-19
    2. Formation and Fundamental Properties of Potassium Germen-2-olates
    Open this publication in new window or tab >>Formation and Fundamental Properties of Potassium Germen-2-olates
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Potassium 1,1-bis(trimethylsilyl)germen-2-olates (2a - 2d) with different substituents at the carbon atom were generated in good yields through the treatment of the correspondingly substituted tris(trimethylsilyl)acyl- and tris(trimethylsilyl)carbamyl-germanes (1a - 1d) with potassium tert-butoxide at room temperature in dry THF. Comparisons between the 29Si and 13C NMR chemical shifts of the germenolates and the analogous silenolates (4a4d) were performed. The recorded 13C and 29Si NMR chemical shifts of the potassium germenolates were also compared to those obtained from GIAO-B3LYP/6-31+G(d)//B3LYP/LANL2DZp calculations. The chemical reactivities of potassium germenolates were compared with silenolates. In this regard, the reactions of 2a - 2d were performed with methyliodide at -40 oC and the germanium methylated products (5a - 5c) were obtained in yields of 54 - 77 %. The reactions of these germenolates with 1,3-butadiene at low temperatures, however, lead to polymerization of dienes (2,3-dimethyl-1,3-butadiene, isoprene, and 1,3-pentadiene) revealing a reactivity resemblance to aminosilenolates, species which in return are comparable to silyl anions in reactivity.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169795 (URN)
    Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2012-04-19
    3. Computational Investigation of Brook-Type Silabenzenes and Their Possible Formation through [1,3]-Si -> O Silyl Shifts
    Open this publication in new window or tab >>Computational Investigation of Brook-Type Silabenzenes and Their Possible Formation through [1,3]-Si -> O Silyl Shifts
    2013 (English)In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, no 1, p. 16-28Article in journal (Refereed) Published
    Abstract [en]

    Quantum chemical calculations with the M062X hybrid meta density functional theory method were performed in order to examine formation of Brook-type silabenzenes 4a 4l, silapyridines 6a 6d, and five-membered ring silaheteroaromatics 8a8d through [1,3]-trimethylsilyl (TMS) and [1,3]-tri(isopropyl)silyl (TIPS) shifts from a tetrahedral silicon atom to an adjacent carbonyl oxygen of cyclic conjugated acylsilane precursors. All Brook-type silabenzenes and silapyridines, having a 2-trialkylsiloxy substituent, are at lower relative energies than their precursors, whereas silaheteroaromatics 8a 8d are found at slightly higher energies. The free energies of activation for the thermal [1,3]-TMS shifts range from 29 to 44 kcal/mol, with the lowest for a Brook-type silapyridine and the highest for a silafuran. The geometries of the Brook-type silabenzenes, silapyridines, silafuran and silathiophene indicate aromatic character, but the silapyrroles are nonaromatic. At M062X/6-311+G(d)//M062X/6-31G(d) level all Brook-type silabenzene dimers studied herein are more stable than two silabenzenes, also for a silabenzene with bulky TIPS, OTIPS and tert-butyl substituents (4l). Yet, comparisons of the B3LYP/6-31G(d) dimerization energies of 4l with that of the isolable 1-Tbt-silabenzene (Tbt = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl) of Tokitoh [J. Chin. Chem. Soc. 2008, 55, 487] indicate that 4l will also be a monomeric silabenzene, and thus, a suitable synthetic target.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169784 (URN)10.1021/om300023s (DOI)000313606200005 ()
    Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2017-12-07Bibliographically approved
    4. Silaphenolates and Silaphenylthiolates: Two Unexplored Unsaturated Silicon Compound Classes Influenced by Aromaticity
    Open this publication in new window or tab >>Silaphenolates and Silaphenylthiolates: Two Unexplored Unsaturated Silicon Compound Classes Influenced by Aromaticity
    2012 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 17, no 1, p. 369-389Article in journal (Refereed) Published
    Abstract [en]

    Monosilicon analogs of phenolates and phenylthiolates are studied by quantum chemical calculations. Three different silaphenolates and three different silaphenylthiolates are possible; the ortho-, meta-, and para-isomers. For the silaphenolates, the meta- isomer is the thermodynamically most stable, regardless if the substituent R at Si is H, t-Bu or SiMe3. However, with R = H and SiMe3 the energy differences between the three isomers are small, whereas with R = t-Bu the meta- isomer is similar to 5 kcal/mol more stable than the ortho- isomer. For the silaphenylthiolates the ortho- isomer is of lowest energy, although with R = H the ortho- and meta- isomers are isoenergetic. The calculated nucleus independent chemical shifts (NICS) indicate that the silaphenolates and silaphenylthiolates are influenced by aromaticity, but they are less aromatic than the parent silabenzene. The geometries and charge distributions suggest that all silaphenolates and silaphenylthiolates to substantial degrees are described by resonance structures with an exocyclic C=O double bond and a silapentadienyl anionic segment. Indeed, they resemble the all-carbon phenolate and phenylthiolate. Silaphenylthiolates are less bond alternate and have slightly more negative NICS values than analogous silaphenolates, suggesting that this compound class is a bit more aromatic. Dimerization of the silaphenolates and silaphenylthiolates is hampered due to intramolecular Coulomb repulsion in the dimers, and silaphenolates with a moderately bulky SiMe3 group as substituent at Si should prefer the monomeric form.

    Keywords
    silicon, aromaticity, quantum chemical calculations
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-166896 (URN)10.3390/molecules17010369 (DOI)000299535700025 ()
    Available from: 2012-01-16 Created: 2012-01-16 Last updated: 2017-12-08Bibliographically approved
    5. The [1,3]-Si→O Silyl Shift from a Nonconducting Acylsilane to a Conducting Brook-Silene as Basis for a Molecular Switch
    Open this publication in new window or tab >>The [1,3]-Si→O Silyl Shift from a Nonconducting Acylsilane to a Conducting Brook-Silene as Basis for a Molecular Switch
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    By usage of density functional theory (DFT) calculations we explored if the [1,3]-silyl shift leading from an acylsilane with two p-conjugated substituents to a silene (a Si=C double bonded compound) can be used as a basis for a molecular conductance switch. In such a switch, the acylsilane, with a tetrahedral saturated silicon atom disrupting the conjugation through the molecule, acts as the OFF state, whereas the silene with a conjugated path running through the complete molecule represents the ON state. Our requirements are (i) the silenes should be slightly higher in relative energy than the acylsilane so as to promote a thermal backrearragment, (ii) the barrier for the backtransfer of the silyl group should be 25-30 kcal/mol, (iii) the ON/OFF conductance ratio should be high, and (iv) the switch should be realistic. According to our calculations using non-equilibrium Green’s function theory, a 1,2-bis(4-thiophenylethynyl)silene has a conductance which is 270 times higher than that of the corresponding acylsilane at zero bias voltage. However, at a voltage of +1 V the ON/OFF ratio decreases to ~40.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169782 (URN)
    Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2012-04-19
    6. Highly Efficient and Convenient Acid Catalyzed Hypersilyl Protection of Alcohols and Thiols by Tris(trimethylsilyl)silyl-N,N-dimethylmethaneamide
    Open this publication in new window or tab >>Highly Efficient and Convenient Acid Catalyzed Hypersilyl Protection of Alcohols and Thiols by Tris(trimethylsilyl)silyl-N,N-dimethylmethaneamide
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    2012 (English)Article in journal (Other academic) Submitted
    Abstract [en]

    Tris(trimethylsilyl)silyl-N,N-dimethylmethaneamide, herein named hypersilylamide, is a convenient and efficient source of the hypersilyl group in the first widely applicable acid catalyzed protocol for silyl group protection of primary, secondary, tertiary alkyl as well as aryl alcohols and thiols in high yields. The sole by-product is N,N-dimethylformamide (DMF) and a range of solvents can be used, including DMF. A high selectivity in the protection of diols can be achieved, also for diols with very small differences in the steric demands at the two hydroxyl groups. Moreover, in the protection of equivalent alcohol and thiol sites the protection of the alcohol is faster, allowing for selective protection in high yields. Quantum chemical calculations at the M062X hybrid meta density functional theory level give insights on the mechanism for the catalytic process. Finally, the hypersilyl group is easily removed from all protected alcohols and thiols examined herein by irradiation at 254 nm.

    National Category
    Organic Chemistry Inorganic Chemistry
    Research subject
    Chemistry with specialization in Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169781 (URN)
    Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2013-03-07Bibliographically approved
    7. Scope and Limitations of an Acid Catalyzed Protocol for Hypersilyl Protection of Alcohols
    Open this publication in new window or tab >>Scope and Limitations of an Acid Catalyzed Protocol for Hypersilyl Protection of Alcohols
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    A highly efficient and convenient triflic acid (TfOH) catalyzed protocol for the protection of various functionalized alcohols in CH2Cl2 at ambient temperature using tris(trimethylsilyl)silyl-N,N-dimethyl-methaneamide (hypersilylamide) 1 as the protecting reagent is developed. Herein, results on the scope and limitations of this protocol for a number of functionalized alcohols are presented. This method was found to be effective for the selective protection of less hindered OH groups in different classes of diols containing both pri/tert, sec/tert, or aromatic/aliphatic hydroxyl groups. In general, our protocol exhibited excellent functional group tolerance in the protection of alcohols containing alkoxy, keto, amino, as well as halo substituents in good to excellent yields.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169780 (URN)
    Available from: 2012-03-06 Created: 2012-03-06 Last updated: 2012-04-19
  • 3.
    Andersson, Claes-Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Physical Organic Chemistry.
    Chemistry of Carbon Nanostructures: Functionalization of Carbon Nanotubes and Synthesis of Organometallic Fullerene Derivatives2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on two main parts. The first part concerns purification and functionalization of carbon nanotubes (papers I-III), and the second part is related to the synthesis of organometallic fullerene derivatives (papers IV-VII):

    Two oxidative methods involving aqueous nitric acid were compared with respect to their capability to introduce carboxylic groups into single walled carbon nanotubes, and several literature methods for esterification and amidation of these groups have been evaluated with focus on efficiency and reproducibility in forming covalently functionalized products soluble in organic media. Amidation proceeding via a SWNT-(COCl)n intermediate yielded the expected covalent product, whereas carboxylate salt formation dominated with other attempted methods. Esterification was achieved via the acyl chloride method and via alkylation of SWNT-(COO)n, the latter being the more efficient method.

    A new, reagent-free method for purification of single- and multi walled carbon nanotubes has been developed. Microwave treatment dissociates non-nanotube carbon and disperses it into an organic solvent, resulting in very pure carbon nanotubes within a few minutes of heating, without the involvement of acidic/oxidative reagents. According to thermogravimetric analysis, Raman and IR spectroscopy, as well as SEM, the process yields nanotubes with a low degree of defects.

    A non-covalent approach has been employed to prepare nanotubes functionalized with glycosides. Derivatives of galactose and lactose were covalently linked to a pyrene moiety and the thus formed pyrene-glycosides were non-covalently attached to single- and multi walled carbon nanotubes by π-π interactions. Fluorescence titrations have been used to quantify the formed supramolecular assemblies, which for SWNTs exhibits increased water solubility.

    A fulleropyrrolidine-(tricarbonyl)chromium complex was synthesized and fully characterized. IR spectroelectrochemistry was used to probe the redox state of the fullerene and provided evidence for electronic communication between the two electroacive moieties. A C60-ferrocene-C60 triad system was synthesized and characterized. Cyclic voltammetry and fluorescence studies suggested electronic communication between ferrocene and the two fullerenes. Finally, the synthesis and initial characterization of short fullerene-ferrocene oligomers are presented.

    List of papers
    1. Reproducibility and efficiency of carbon nanotube end-group generation and functionalization
    Open this publication in new window or tab >>Reproducibility and efficiency of carbon nanotube end-group generation and functionalization
    2009 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 26, p. 4421-4428Article in journal (Refereed) Published
    Abstract [en]

    In a systematic fashion, several methods for esterification and  amidation of single-walled carbon nanotubes have been evaluated with   focus on efficiency and reproducibility in forming covalently   functionalized products soluble in organic media. The outcome of   transformations was determined using IR, Raman and NMR spectroscopy and   by thermogravimetric analysis (TGA). Amidation proceeding via a   SWNT-(COCl)(n) intermediate yielded the expected covalent product,  whereas carboxylate salt formation dominated with other attempted   methods. Esterification was achieved via the acyl chloride method and   via alkylation of SWNT-(COO-)(n), the latter being the more efficient   method. A non-covalent solubilizing interaction was obtained for RNH2   but not for ROH (R = octadecyl), proving that the most important   non-covalent interaction between oxidatively cleaned SWNTs and   octadecylamine is a salt formation. The outcome of the secondary   functionalization of carboxyl units is highly reproducible for   experiments carried out on the same batch of SWNT-(COOH)(n). Normalization of the outcome of the secondary functionalization to the   composition of the different batches of starting materials reveals an overall high reproducibility of the secondary function alizations. The   differences in outcome related to different commercial SWNT batches   from the same synthetic procedure is negligible compared to that   resulting from differences in overall carboxyl content after the   primary HNO3 oxidative cleaning step. Hence, the composition of   purified SWNT starting materials always needs to be assessed, in particular before drawing any conclusions concerning differences in   outcome from reaction systems involving different sources of SWNT  material.

    Keywords
    Nanotubes, Nanotechnology, Functionalization, Esterification, Amidation
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-112369 (URN)10.1002/ejoc.200900534 (DOI)000270014700006 ()
    Available from: 2010-01-13 Created: 2010-01-13 Last updated: 2017-12-12Bibliographically approved
    2. The reagent-free, microwave-assisted purification of carbon nanotubes
    Open this publication in new window or tab >>The reagent-free, microwave-assisted purification of carbon nanotubes
    Show others...
    2010 (English)In: New Journal of Chemistry, ISSN 1144-0546, E-ISSN 1369-9261, Vol. 34, no 10, p. 2275-2280Article in journal (Refereed) Published
    Abstract [en]

    We have developed a microwave-assisted, reagent-free method for the efficient primary purification of MW and SW carbon nanotubes that is extremely fast compared to previously reported processes. The treatment dissociates and disperses non-nanotube carbon in an organic solvent to yield very pure carbon nanotubes within a few minutes of heating and a simple filtration, without the involvement of acidic/oxidative reagents. According to thermogravimetric analysis, Raman and IR spectroscopy, as well as scanning and transmission electron microscopy, the process yields pure nanotubes with a low degree of defects.

    National Category
    Chemical Sciences Inorganic Chemistry Engineering and Technology
    Research subject
    Chemistry with specialization in Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-134674 (URN)10.1039/c0nj00087f (DOI)000282219600029 ()
    Available from: 2010-12-01 Created: 2010-11-30 Last updated: 2018-06-04Bibliographically approved
    3. Reversible Non-Covalent Derivatisation of Carbon Nanotubes with Glycosides
    Open this publication in new window or tab >>Reversible Non-Covalent Derivatisation of Carbon Nanotubes with Glycosides
    2009 (English)In: Soft Matter, ISSN 1744-683X, Vol. 5, no 14, p. 2713-2716Article in journal (Refereed) Published
    Abstract [en]

    SWNTs and MWNTs have been non-covalently functionalized with glycosides   in a reversible manner, and fluorescence titrations have been used to   quantify the formed supramolecular assemblies which for SWNTs exhibits   increased water solubility.

    Keywords
    carbon nanotube
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-112366 (URN)10.1039/ B907791J (DOI)000268783500006 ()
    Available from: 2010-01-13 Created: 2010-01-13 Last updated: 2011-11-04Bibliographically approved
    4. Synthesis and IR Spectroelectrochemical Studies of a [60]Fulleropyrrolidine-(tricarbonyl)chromium Complex: Probing C-60 Redox States by IR Spectroscopy
    Open this publication in new window or tab >>Synthesis and IR Spectroelectrochemical Studies of a [60]Fulleropyrrolidine-(tricarbonyl)chromium Complex: Probing C-60 Redox States by IR Spectroscopy
    2011 (English)In: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, no 11, p. 1744-1749Article in journal (Refereed) Published
    Abstract [en]

    The synthesis of a new fulleropyrrolidine-(tricarbonyl)chromium complex: 1-methyl-2-(4-methoxyphenyl)-3,4-[60]fulleropyrrolidine-(tricarbonyl)chromium is described together with its characterization by IR, NMR and cyclic voltammetry. IR spectro-electrochemistry has been used to probe the redox level of the fullerene derivative via the relative position of the vibrational bands of the CO ligands, which are sensitive to the electronic state of the complex. Other strategies to incorporate a tricarbonylchromium moiety to fullerene C60 are also briefly discussed and evaluated.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2011
    Keywords
    Fullerenes, Chromium, IR spectroscopy, Cyclic voltammetry, Redox chemistry, Electrochemistry
    National Category
    Chemical Sciences
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-148456 (URN)10.1002/ejic.201100011 (DOI)000289354900008 ()
    Available from: 2011-03-07 Created: 2011-03-07 Last updated: 2017-12-11
    5. Synthesis and characterization of a ferrocene-linked bis-fullerene[60] dumbbell
    Open this publication in new window or tab >>Synthesis and characterization of a ferrocene-linked bis-fullerene[60] dumbbell
    2012 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 41, no 8, p. 2374-2381Article in journal (Refereed) Published
    Abstract [en]

    A new [60]fullerene dumbbell consisting of two fulleropyrrolidines connected to a central ferrocene unit by amide linkages has been prepared and fully characterized by elemental analysis, 1H NMR, UV/Vis, fluorescence and mass spectrometry. The electrochemical properties as determined by cyclic voltammetry show ground state electronic communication between the ferrocene and the fullerene units. In addition, the preparaton of a ferrocene building block for an alternative linking approach is presented.

    Keywords
    Fullerenes, Ferrocene, Dumbbell, Cyclic voltammetry
    National Category
    Organic Chemistry Inorganic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry; Chemistry with specialization in Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-158905 (URN)10.1039/C2DT12097F (DOI)000300186100022 ()
    Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2017-12-08Bibliographically approved
    6. Short ferrocene-[60]fulleropyrrolidine oligomers. A preliminary account on synthetic studies
    Open this publication in new window or tab >>Short ferrocene-[60]fulleropyrrolidine oligomers. A preliminary account on synthetic studies
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    A synthetic strategy towards short fullerene based organometallic oligomers is reported. The synthetic approach is based on the secondary functionalization of N-unsubstituted fulleropyrrolidines with ferrocene dicarboxylic acid chloride. Preliminary characterization by mass spectrometry, UV/Vis and NMR suggest a trimer or tetramer structure.

    Keywords
    Fullerenes / Oligomers / Ferrocene
    National Category
    Organic Chemistry
    Research subject
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-159308 (URN)
    Note
    preliminärt manuskriptAvailable from: 2011-09-27 Created: 2011-09-27 Last updated: 2011-11-04
    7.   Appendix: Experimental details for tricarbonyl chromium complexes
    Open this publication in new window or tab >>  Appendix: Experimental details for tricarbonyl chromium complexes
    2011 (English)Other (Other academic)
    Place, publisher, year, pages
    Uppsala: Acta Universitatis Upsaliensis, 2011
    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-159309 (URN)
    Available from: 2011-09-27 Created: 2011-09-27 Last updated: 2011-11-04
  • 4.
    Arefalk, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    New Methods for the Synthesis of 3-Substituted 1-Indanones: A Palladium-Catalyzed Approach2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In medicinal chemistry, there is a constant need for new preparative methods, both to make the synthesis process more effective, and to increase the accessibility to a wide variety of compounds. A number of different approaches can be used to attain these goals. Transition metal catalysis is generally performed under mild conditions, providing both regio- and chemoselective reactions. Thus, it offers an attractive means of preparation of complex drug candidates. Two additional methodologies used to increase the preparative efficiency are one-pot protocols and controlled microwave heating. One-pot and multi-component reactions are less time consuming than step-by-step reactions, and microwave heating has been used to considerably shorten the reaction times.

    This thesis describes a new palladium-catalyzed, one-pot reaction producing racemic acetal-protected 3-hydroxy-1-indanones from ethylene glycol vinyl ether and triflates of salicylic aldehydes. The triflates were prepared using controlled microwave heating. The reaction sequence starts with a regioselective internal Heck coupling, followed by an annulation cascade. By including secondary amines in the reaction mixture, the reaction was further developed into a three-component reaction delivering racemic acetal-protected 3-amino-1-indanones. This new method was utilized for the synthesis of primary, secondary and tertiary aminoindanones. Finally, by using enantiopure t-butyl sulfinyl imines, derived from salicylic aldehyde triflates and ethylene glycol vinyl ether as starting materials in a closely related type of palladium coupling–annulation sequence, a stereoselective protocol providing enantiomerically pure 3-amino-1-indanones was developed. To demonstrate an application in medicinal chemistry, the enantiopure 3-amino-1-indanones were incorporated as P2 and/or P2´ substituents into active HIV-1 protease inhibitors.

    List of papers
    1. Fast Synthesis of Aryl Triflates with Controlled Microwave Heating
    Open this publication in new window or tab >>Fast Synthesis of Aryl Triflates with Controlled Microwave Heating
    2002 (English)In: Organic Letters, ISSN 1523-7060, Vol. 4, no 7, p. 1231-1233Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93597 (URN)
    Available from: 2005-10-20 Created: 2005-10-20 Last updated: 2013-07-04Bibliographically approved
    2. Protected Indanones by a Heck-Aldol Annulation Reaction
    Open this publication in new window or tab >>Protected Indanones by a Heck-Aldol Annulation Reaction
    2002 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 67, no 16, p. 5854-5856Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93598 (URN)
    Available from: 2005-10-20 Created: 2005-10-20 Last updated: 2013-07-04Bibliographically approved
    3. Masked 3-Aminoindan-1-ones by a Palladium-Catalyzed Three-Component Annulation Reaction
    Open this publication in new window or tab >>Masked 3-Aminoindan-1-ones by a Palladium-Catalyzed Three-Component Annulation Reaction
    2005 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 70, no 3, p. 938-942Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93599 (URN)
    Available from: 2005-10-20 Created: 2005-10-20 Last updated: 2013-07-04Bibliographically approved
    4. Stereoselective Synthesis of 3-Aminoindan-1-ones and Subsequent Incorporation into HIV-1 Protease Inhibitors
    Open this publication in new window or tab >>Stereoselective Synthesis of 3-Aminoindan-1-ones and Subsequent Incorporation into HIV-1 Protease Inhibitors
    2006 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 71, no 3, p. 1265-1268Article in journal (Refereed) Published
    Abstract [en]

    A new method for the stereoselective synthesis of 3-aminoindan-1-ones from triflates of salicylic sulfinyl imines and ethylene glycol vinyl ether has been developed. The reaction sequence starts with a regioselective Heck reaction followed by stereoselective Lewis acid mediated annulation. Acidic cleavage of the sulfinamides produced pure (R)- and (S)-3-aminoindan-1-ones, which were successfully isolated and incorporated into active HIV-1 protease inhibitors.

    Keywords
    HIV Protease Inhibitors/*chemical synthesis/chemistry/*pharmacology, Imines/chemistry, Indans/chemical synthesis/*chemistry/*pharmacology, Molecular Structure, Stereoisomerism, Sulfones/chemistry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93600 (URN)16438552 (PubMedID)
    Available from: 2005-10-20 Created: 2005-10-20 Last updated: 2017-12-14Bibliographically approved
  • 5.
    Arkhypchuk, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Novel Approaches to Phosphorus-containing Heterocycles and Cumulenes2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fast development in all areas of life and science over the last 50 years demands versatile, energy efficient and cheap materials with specific but easily tuneable properties which can be used for example in organic light emitting diodes (OLEDs), thin-film transistors, photovoltaic cells, etc. This thesis is devoted to the development of novel synthetic approaches to molecules with potential applications in the field of molecular electronics.  The acquisition of a detailed mechanistic understanding of the newly developed reactions is central to the work presented in this thesis.

    The first chapter is dedicated to the development of a new procedure for the preparation of phospha-Wittig-Horner (pWH) reagents, i.e. a reagents that has been known to convert carbonyl compounds into compounds with P=C double bonds. Each step of the synthetic sequence, i.e. preparation of the starting P,P-dichlorophosphines, their phosphorylation using the Michaelis-Arbuzov protocol, coordination to the metal centre and final hydrolysis, are presented in detail. A possible route to uncoordinated pWH reagents is also discussed.

    The second chapter focuses on the reactivity of the pWH reagents with acetone under different reaction conditions. The results show how changes in the ratio of starting material vs. base as well as reaction time or structure of the pWH reagent can influence the reaction outcome and the stability of the obtained products. The possibility to prepare unusual phosphaalkenes with unsaturated P-substituents is presented.

    The third chapter of the thesis is dedicated to the reactivity of pWH reagents towards symmetric and asymmetric ketones which contain one or two acetylene units. The proposed mechanisms of the reactions are studied by means of in situ FTIR spectroscopy as well as theoretical calculations. Physical-chemical properties of oxaphospholes, cumulenes and bisphospholes are presented.

    The last chapter is dedicated to reactivity studies of pWH reagents towards ketenes, and the exploration of a reliable route to 1-phosphaallenes. Detailed mechanistic studies of the pWH reaction that are based on the isolation and crystallographic characterization of unique reaction intermediates are presented. The reactivity of phosphaallenes towards nucleophiles such as water and methanol are examined.

    In summary, this thesis presents synthetic routes to novel phosphorus-containing molecules, together with detailed studies of the reaction mechanisms of the observed transformations.

    List of papers
    1. Revisiting the Phospha-Wittig - Horner Reaction
    Open this publication in new window or tab >>Revisiting the Phospha-Wittig - Horner Reaction
    2012 (English)In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 31, no 3, p. 1118-1126Article in journal (Refereed) Published
    Abstract [en]

    P,P-Dichlorophosphines 2a-c (RPCl2, R = Ph (a), t-Bu (b), 2,4,6-Me3Ph (c)) and P,P-dibromophosphines 4d,e (RPBr2, R = (i-Pr)(3)SiC C (d) and H2C=CH (e)) react with triethylphosphite under Michaelis-Arbuzov conditions to give phosphinodiphosphonates 3a-e in quantitative yields. After complexation to W(CO)(5) and treatment with CH3ONa, phospha-Wittig-Horner reagents 9a,b are obtained on a multigram scale in good overall yield. Phospha-Wittig-Horner reagents with unsaturated, substituents at P-III (10d,e) can be prepared in analogous procedures; however, their prevail in an unusual ylide form that allows conjugation between the lone pair and the acetylene and vinyl pi-systems, respectively. Phosphinophosphonate 9a has been characterized by X-ray crystallography and is shown to react smoothly with acetone within minutes. The resulting W(CO)(5)-coordinated phosphaalkene is shown to dimerize to a 1,2-diphosphitane or to undergo a 1,3-proton shift depending on the reaction conditions. In addition, a one-pot synthetic sequence starting from W(CO)(5)-coordinated phosphinodiphosphonates 5d,e has been developed to engage compounds with vinyl and acetylene substituents in phospha-Wittig-Horner reactions.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-170346 (URN)10.1021/om201158k (DOI)000300116100046 ()
    Available from: 2012-03-12 Created: 2012-03-12 Last updated: 2017-12-07Bibliographically approved
    2. Cascade Reactions Forming Highly Substituted, Conjugated Phospholes and 1,2-Oxaphospholes
    Open this publication in new window or tab >>Cascade Reactions Forming Highly Substituted, Conjugated Phospholes and 1,2-Oxaphospholes
    2012 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 51, no 31, p. 7776-7780Article in journal (Refereed) Published
    Abstract [en]

    The reaction of a phospha-Wittig–Horner reagent with diacetylenic ketones (see scheme) results in a cascade of reactions that can lead to both an oxaphosphole-terminated cumulene system and an alkene-bridged bis-phosphole. The reaction outcome is determined by the nature of the acetylene termini, with phenyl groups stabilizing a carbene intermediate that dimerizes to give the bis-phosphole product.

    Keywords
    acetylenes, conjugation, cumulenes, phospha-Wittig, reaction mechanisms
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-182042 (URN)10.1002/anie.201202153 (DOI)000306757900029 ()
    Available from: 2012-10-05 Created: 2012-10-02 Last updated: 2017-12-07Bibliographically approved
    3. Phosphorus Heterocylces from Phosphinophosphonates and α,β-Unsaturated Ketones
    Open this publication in new window or tab >>Phosphorus Heterocylces from Phosphinophosphonates and α,β-Unsaturated Ketones
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-198753 (URN)
    Available from: 2013-04-25 Created: 2013-04-24 Last updated: 2013-08-30
    4. Mechanism of the Phospha-Wittig-Horner Reaction
    Open this publication in new window or tab >>Mechanism of the Phospha-Wittig-Horner Reaction
    2013 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 52, no 25, p. 6484-6487Article in journal (Refereed) Published
    Keywords
    ketenes; phosphaallenes; phospha-Wittig-Horner reaction; reaction mechanisms
    National Category
    Organic Chemistry Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-198754 (URN)10.1002/anie.201301469 (DOI)000320378800024 ()
    Available from: 2013-04-25 Created: 2013-04-24 Last updated: 2017-12-06Bibliographically approved
  • 6.
    Axelsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Development of HIV-1 Protease Inhibitors and Palladium-Catalyzed Synthesis of Aryl Ketones and N-Allylbenzamides2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The use of palladium-catalyzed reactions to introduce new carbon-carbon bonds is a fundamental synthetic strategy that has been widely embraced due to its high chemo- and regioselectivity and functional group tolerance. In this context, Pd(0)-catalyzed aminocarbonylations using Mo(CO)6 instead of toxic and gaseous CO and with allylamine as the nucleophile were investigated. The aminocarbonylated product dominated over the Mizoroki-Heck product, and (hetero)aryl iodides, bromides and chlorides gave N-allylbenzamides in good yields.

    In this thesis improvements to an existing protocol for the Pd(II)-catalyzed synthesis of aryl ketones from five benzoic acids and a variety of nitriles are also presented. Addition of TFA improved the yields and employing THF as solvent enabled the use of solid nitriles, and the aryl ketones were isolated in good yields.

    The pandemic of HIV infection is one of the greatest public health issues of our time and approximately 35.3 million people worldwide are living with HIV. There are currently many drugs on the market targeting various parts of the viral reproduction cycle, but the problems of resistance warrant the search for new drugs. HIV-1 protease makes the virus mature into infectious particles. In this thesis a new type of HIV-1 protease inhibitor (PI) is presented, based on two of the PIs on the market, atazanavir and indinavir, but it has a tertiary alcohol, as well as a two-carbon tether between the quaternary carbon and the hydrazide β-nitrogen. A total of 25 new inhibitors were designed, synthesized and biologically evaluated, the best compound had an EC50 value of 3 nM.

    Based on this series a project aimed at synthesizing macrocycles spanning the P1-P3 area was initiated. Macrocycles often tend to have an improved affinity and metabolic profile compared to their linear analogs. Introduction of a handle in the para position of the P1 benzyl group proved difficult, despite efforts to synthesize intermediates containing either a bromo-, hydroxy-, methoxy-, silyl-group protected hydroxy- or an alkyne-group. The lactone intermediate was abandoned in favor of an alternative synthetic route and initial studies were found to be promising. This new approach requires further investigation before the target macrocycles can be synthesized. 

    List of papers
    1. Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up
    Open this publication in new window or tab >>Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up
    2008 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 39, p. 5625-5628Article in journal (Refereed) Published
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of various (hetero)aryl halides with allylamine using Mo(CO)(6) as a solid, in situ CO source, were explored. Microwave-enhanced conditions proved to be highly useful in promoting the conversions in a mere 10-20 min with various (hetero)aryl iodides, bromides and chlorides. The scale-up of a microwave-enhanced aminocarbonylation to 25 mmol scale was performed successfully. (C) 2008 Elsevier Ltd. All rights reserved.

    Keywords
    carbonylation, microwave, palladium, aryl chloride, scale-up
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-104304 (URN)10.1016/j.tetlet.2008.07.053 (DOI)000259309700018 ()0040-4039 (ISBN)
    Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
    2. An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles
    Open this publication in new window or tab >>An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles
    Show others...
    2014 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 55, no 15, p. 2376-2380Article in journal (Refereed) Published
    Abstract [en]

    A palladium(II)-catalyzed decarboxylative protocol for the synthesis of aryl ketones has been developed. The addition of TFA was shown to improve the reaction yield and employing THF as solvent enabled the use of solid nitriles and in only a small excess. Using this method, five different benzoic acids reacted with a wide range of nitriles to produce 29 diverse (hetero)aryl ketone derivatives in up to 94% yield.

    National Category
    Organic Chemistry Engineering and Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-211660 (URN)10.1016/j.tetlet.2014.02.109 (DOI)000334977100012 ()
    Funder
    Knut and Alice Wallenberg Foundation
    Available from: 2013-11-27 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
    3. HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells
    Open this publication in new window or tab >>HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells
    Show others...
    2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 2, p. 607-615Article in journal (Refereed) Published
    Abstract [en]

    By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-137907 (URN)10.1021/jm901165g (DOI)000273672100007 ()
    Available from: 2010-12-17 Created: 2010-12-16 Last updated: 2018-01-12Bibliographically approved
  • 7.
    Ayub, Rabia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström.
    Excited State Aromaticity and Antiaromaticity: Fundamental Studies and Applications2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The central theme of this thesis is the ability to tune various molecular properties by controlling and utilizing aromaticity and antiaromaticity in the lowest electronically excited states. This investigation is based on qualitative theory, quantum chemical (QC) calculations and experimental work.

    Baird's rule tells that the π-electron count for aromaticity and antiaromaticity is reversed in the ππ* triplet (T1) state when compared to Hückel's rule for the singlet ground state. The excited state aromatic character of [4n]annulenes is probed by usage of two structural moieties, the cyclopropyl (cPr) group and the silacyclobutene (SCB) ring. The results of QC calculations and photoreactivity experiments showed that the cPr group and the SCB ring remained closed when attached to or fused with [4n]annulenes so as to preserve T1 aromatic stabilization. In contrast, both moieties ring-opened when attached to or fused with [4n+2]annulenes as a means for alleviation of T1 antiaromaticity. These two structural moieties are shown to indicate T1 aromatic character of [4n]annulenes except in a limited number of cases.

    The T1 antiaromatic character of compounds with 4n+2 π-electrons was utilized for photo(hydro)silylations and photohydrogenations. QC calculations showed that due to T1 antiaromaticity, benzene is able to abstract hydrogen atoms from trialkylsilanes. The photoreactions occurred under mild conditions for benzene and certain polycyclic aromatic hydrocarbons. In contrast, COT was found to be unreactive under similar conditions.

    It is further revealed that various properties of molecules can be tailored by rational design using Baird’s rule. Three modes of connectivity (linear, bent, and cyclic) of polycyclic conjugated hydrocarbons (PCH) were explored by DFT calculations. When the PCHs contain a central [4n]unit and 4nπ-electron perimeter, bent isomers have lower triplet state energies than linear ones due to increased T1 aromaticity in the bent isomers. With regard to the cyclic connectivity, macrocyclic compounds are designed by modifying the C20 monocycle through incorporation of monocyclic units (all-carbon as well as heterocyclic) and the impact of macrocyclic T1 aromaticity upon insertion of different units is examined through QC calculations. The results provide insights on excited state aromaticity in macrocyclic systems.

    List of papers
    1. Cyclopropyl group: An excited state aromaticity indicator?
    Open this publication in new window or tab >>Cyclopropyl group: An excited state aromaticity indicator?
    2017 (English)In: Chemistry - A European Journal, Vol. 23, p. 13684-13695Article in journal (Refereed) Published
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-332139 (URN)10.1002/chem.201701404 (DOI)
    Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2017-10-27
    2. The silacyclobutene ring: An indicator of triplet state Baird-aromaticity
    Open this publication in new window or tab >>The silacyclobutene ring: An indicator of triplet state Baird-aromaticity
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-332402 (URN)
    Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2017-10-27
    3. Metal-free photochemical silylations and transfer hydrogenations of benzenoid hydrocarbons and graphene
    Open this publication in new window or tab >>Metal-free photochemical silylations and transfer hydrogenations of benzenoid hydrocarbons and graphene
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    2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723Article in journal (Refereed) Published
    Abstract [en]

    The first hydrogenation step of benzene, which is endergonic in the electronic ground state (S0), becomes exergonic in the first triplet state (T1). This is in line with Baird’s rule, which tells that benzene is antiaromatic and destabilized in its T1 state and also in its first singlet excited state (S1), opposite to S0, where it is aromatic and remarkably unreactive. Here we utilized this feature to show that benzene and several polycyclic aromatic hydrocarbons (PAHs) to various extents undergo metal-free photochemical (hydro)silylations and transfer-hydrogenations at mild conditions, with the highest yield for naphthalene (photosilylation: 21%). Quantum chemical computations reveal that T1-state benzene is excellent at H-atom abstraction, while COT, aromatic in the T1 and S1 states according to Baird’s rule, is unreactive. Remarkably, also CVD-graphene on SiO2 is efficiently transfer-photohydrogenated using formic acid/water mixtures together with white light or solar irradiation under metal-free conditions.

    National Category
    Chemical Sciences Chemical Engineering
    Identifiers
    urn:nbn:se:uu:diva-303639 (URN)10.1038/ncomms12962 (DOI)000385553900001 ()27708336 (PubMedID)
    Funder
    Wenner-Gren FoundationsSwedish Research CouncilKnut and Alice Wallenberg FoundationÅForsk (Ångpanneföreningen's Foundation for Research and Development)Magnus Bergvall Foundation
    Available from: 2016-09-21 Created: 2016-09-21 Last updated: 2018-04-23Bibliographically approved
    4. Can Baird's and Clar's Rules Combined Explain Triplet State Energies of Polycyclic Conjugated Hydrocarbons with Fused 4n pi- and (4n+2)pi-Rings?
    Open this publication in new window or tab >>Can Baird's and Clar's Rules Combined Explain Triplet State Energies of Polycyclic Conjugated Hydrocarbons with Fused 4n pi- and (4n+2)pi-Rings?
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    2017 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, no 12, p. 6327-6340Article in journal (Refereed) Published
    Abstract [en]

    Compounds that can be labeled as "aromatic chameleons" are pi-conjugated compounds that are able to adjust their pi-electron distributions so as to comply with the different rules of aromaticity in different electronic states. We used quantum chemical calculations to explore how the fusion of benzene rings onto aromatic chameleonic units represented by biphenylene, dibenbzocyclooctatetraene, and dibenzo[a,e]pentalene modifies the first triplet excited states (T-1) of the compounds. Decreases in T-1 energies are observed when going from isomers with linear connectivity of the fused benzene rings to those with cis- or transbent connectivities. The T-1 energies decreased down to those of the parent (isolated) 4n pi-electron units. Simultaneously, we observe an increased influence of triplet State aromaticity of the central 4n ring as given by Baird's rule and evidenced by geometric, magnetic, and electron density based aromaticity indices (HOMA, NICS-XY, ACID, and FLU). Because of an influence of,triplet state aromaticity in the central 4n pi-electron units,, the most stabilized, compounds, retain the triplet excitation in Baird pi-quartets or octets, enabling the outer benzene rings to adapt closed-shell singlet Clar pi-sextet character. Interestingly, the T-1 energies go down as the total number of aromatic cycles within a molecule in the T-1 state increases.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2017
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-329665 (URN)10.1021/acs.joc.7b00906 (DOI)000403854500031 ()28535673 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2017-10-27Bibliographically approved
    5. Relating the triplet state Baird-aromaticity of the monocycle to that of the macrocycle
    Open this publication in new window or tab >>Relating the triplet state Baird-aromaticity of the monocycle to that of the macrocycle
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-332403 (URN)
    Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2017-10-27
  • 8.
    Balliu, Aleksandra
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Exploring molecular interactions between polypeptide conjugates and protein targets: Manipulating affinity by chemical modifications2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis molecular interactions between polypeptide conjugates and protein targets were investigated. Polypeptides were derivatized with small organic molecules, peptides and oligonucleotides. New strategies were developed with the aim to increase affinities for proteins of biological interest.

    A 42-residue polypeptide (4-C15L8) conjugated to a small organic molecule 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoic acid (PP1), was shown to bind glycogen phosphorylase a (GPa) in the presence of zinc ions. Under the assumption that hydrophobic interactions dominated the binding energy, the hydrophobic residues of 4-C15L8-PP1 were systematically replaced in order to study their contribution to the affinity enhancement. The replacement of the Nle, Ile and Leu residues by Ala amino acids reduced affinities. The introduction of non-natural L-2-aminooctanoic acid (Aoc) residues into the peptide sequence enhanced the binding affinity for GPa. A decreased KD of 27nM was obtained when Nle5, Ile9 and Leu12 were replaced by Aoc residues, in comparison to the KD value of 280nM obtained for the unmodified 4-C15L8-PP1. It is evident that there are non-obvious hydrophobic binding sites on the surfaces of proteins that could be identified by introducing the more hydrophobic and conformationally flexible Aoc residues. The downsizing of the 42-mer peptide to an 11-mer and the incorporation of three Aoc residues gave rise to a KD of 550 nM, comparable to that of  4-C15L8-PP1 suggesting that bioactive peptides can be downsized by the introduction of Aoc.

    Aiming to improve in vivo stability, the affinity for human serum albumin (HSA) of hydrophobic, positively and negatively charged polypeptide-PP1 conjugates was evaluated. Increased hydrophobicity due to the introduction of Aoc residues did not significantly increase the affinity for HSA. No binding was observed in the case of the most negatively charged polypeptides whereas the slightly negatively and positively charged polypeptides conjugated to PP1 bound HSA with affinities that increased with the positive charge. It was found that polypeptide-PP1 conjugates target the zinc binding site of the HSA. Affinity enhancement was obtained due to the incorporation of PP1 and increased by charge to charge interactions between the positively charged amino acids of the polypeptide and the negatively charged residues of HSA, in close proximity to the HSA zinc binding site. The survival times of the peptide-PP1 conjugates in human serum were extended as a result of binding to HSA. Zn2+ ion chelating agents can be incorporated in potential peptide therapeutics with a short plasma half-life, without increasing their molecular weights.

    List of papers
    1. Exploring Non-obvious Hydrophobic Binding Pockets on Protein Surfaces: Increasing Affinities in Peptide–Protein Interactions
    Open this publication in new window or tab >>Exploring Non-obvious Hydrophobic Binding Pockets on Protein Surfaces: Increasing Affinities in Peptide–Protein Interactions
    2017 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 14, p. 1396-1407Article in journal (Refereed) Published
    Abstract [en]

    A 42-residue polypeptide conjugated to a small-molecule organic ligand capable of targeting the phosphorylated side chain of Ser15 was shown to bind glycogen phosphorylase a (GPa) with a KD value of 280 nm. The replacement of hydrophobic amino acids by Ala reduced affinities, whereas the incorporation of l-2-aminooctanoic acid (Aoc) increased them. Replacing Nle5, Ile9 and Leu12 by Aoc reduced the KD value from 280 to 27 nm. “Downsizing” the 42-mer to an undecamer gave rise to an affinity for GPa an order of magnitude lower, but the undecamer in which Nle5, Ile9 and Leu12 were replaced by Aoc showed a KD value of 550 nm, comparable with that of the parent 42-mer. The use of Aoc residues offers a convenient route to increased affinity in protein recognition as well as a strategy for the “downsizing” of peptides essentially without loss of affinity. The results show that hydrophobic binding sites can be found on protein surfaces by comparing the affinities of polypeptide conjugates in which Aoc residues replace Nle, Ile, Leu or Phe with those of their unmodified counterparts. Polypeptide conjugates thus provide valuable opportunities for the optimization of peptides and small organic compounds in biotechnology and biomedicine.

    Keywords
    affinity enhancement, aminooctanoic acid, hydrophobic amino acids, peptide conjugation, peptides
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-326803 (URN)10.1002/cbic.201700048 (DOI)000405726100009 ()28432776 (PubMedID)
    Available from: 2017-07-31 Created: 2017-07-31 Last updated: 2017-11-02Bibliographically approved
    2. Conjugation of a Dipicolyl Chelate to Polypeptide Conjugates Increases Binding Affinities for Human Serum Albumin and Survival Times in Human Serum
    Open this publication in new window or tab >>Conjugation of a Dipicolyl Chelate to Polypeptide Conjugates Increases Binding Affinities for Human Serum Albumin and Survival Times in Human Serum
    2017 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 14, p. 1408-1414Article in journal (Refereed) Published
    Abstract [en]

    The affinity for human serum albumin (HSA) of a series of 2–5 kDa peptides covalently linked to 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoic acid, a dipicolyl chelator with micromolar affinity for Zn2+, was found by surface plasmon resonance to increase in the presence of 1 μm ZnCl2 at physiological pH. The dependence on polypeptide hydrophobicity was found to be minor, thus suggesting that the conjugates bound to the metal-binding site and not to the fatty-acid-binding site. The affinity of the conjugates increased strongly with the positive charge of the polypeptides, thus implicating the negatively charged protein surface surrounding the metal-binding site. The survival times of the peptides in human serum were extended as a consequence of stronger binding to HSA, thus suggesting that Zn2+-chelating agents might provide a general route to increased survival time of peptides in serum in therapeutic and diagnostic applications without significantly increasing their molecular weights.

    Keywords
    affinity, biosensor, human serum albumin, peptides, zinc-binding site
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-326838 (URN)10.1002/cbic.201700049 (DOI)000405726100010 ()28301711 (PubMedID)
    Available from: 2017-07-31 Created: 2017-07-31 Last updated: 2017-11-02Bibliographically approved
  • 9.
    Barletta, Julien
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    [11C]Carbon Monoxide in Rhodium-/Palladium-Mediated Carbonylation Reactions2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Methods for the 11C-labeling of carbonyl compounds applicable in the preparation of radiotracers for Positron Emission Tomography (PET) are described. To this end [11C]carbon monoxide at low concentration was used in transition metal- mediated reactions.

    Stille couplings were employed in the synthesis of [carbonyl-11C]ketones from methyl and aryl halides with [11C]carbon monoxide. The synthesized [carbonyl-11C]ketones were obtained from the corresponding organostannanes with analytical radiochemical yields up to 98%.

    A number of synthetic routes were designed using [11C]carbon monoxide and rhodium complexes. Nitrene intermediates were generated from azides and reacted via a rhodium-mediated carbonylation reaction as a general synthetic route to [carbonyl-11C]isocyanates, versatile precursors. [carbonyl-11C]Isocyanate reacted via nucleophilic attack of an amine to form N,N’-diphenyl[11C]urea in 82% analytical radiochemical yield, ethyl phenyl[11C]carbamate was synthesized by the same route, using ethanol as the nucleophile, in 70% radiochemical yield. [11C]Isocyanate was also able to react in a [2+3] cycloaddition with ethylene oxide to form 3-phenyl[carbonyl-11C]oxazolidin-2-one in over 80% analytical radiochemical yield. This method was applied to the synthesis of a potential efflux system tracer [11C]hydroxyurea in 38% isolated radiochemical yield and the derivative 1-hydroxy-3-phenyl[11C]urea in 35% isolated radiochemical yield. Carbene intermediates, generated from diazo compounds, were reacted with [11C]carbon monoxide in the rhodium-mediated synthesis of [carbonyl-11C]ketenes. [carbonyl-11C]Ketene intermediates were utilised in the synthesis of diethyl[carbonyl-11C]malonate, from ethyl diazoacetate and ethanol. The product was obtained with a 20% isolated radiochemical yield. Alkylation of diethyl[carbonyl-11C]malonate, with ethyliodide and tetrabutylammonium fluoride, was successfully accomplished and diethyl diethyl[carbonyl-11C]malonate was synthesized in 50% analytical radiochemical yield. Several (carbonyl-13C)compounds were also synthesized using the described methods as a way of characterizing the position of the label using 13C-NMR.

    List of papers
    1. Synthesis of 11C-labelled N,N’-diphenylurea and ethyl phenylcarbamate by rhodium-promoted carbonylation reaction via [11C]-isocyanatobenzene using phenyl azide and [11C]carbon monoxide
    Open this publication in new window or tab >>Synthesis of 11C-labelled N,N’-diphenylurea and ethyl phenylcarbamate by rhodium-promoted carbonylation reaction via [11C]-isocyanatobenzene using phenyl azide and [11C]carbon monoxide
    Show others...
    2004 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 2, no 21, p. 3063-3066Article in journal (Refereed) Published
    Abstract [en]

    The reaction with phenyl azide and [11C]carbon monoxide to give N,N'-diphenyl[11C]urea and ethyl phenyl[11C]carbamate has been studied with the aim of development of a new methodology for carbonylation using [11C]carbon monoxide with high specific radioactivity. The synthesis of 11C-labelled N,N'-diphenylurea from phenyl azide and [11C]carbon monoxide, with 1,2-bis(diphenylphosphino)ethane-bound Rh(I) complex at 120 degrees C at a pressure of 35 MPa in the presence of aniline was accomplished in 82% trapping efficiency and 82% conversion yield. This approach was also useful for the synthesis of ethyl phenyl[11C]carbamate with lithium ethoxide as a nucleophilic reagent giving 90% trapping efficiency and 76% conversion yield. These reactions can be considered to proceed via a [11C]isocyanate or a [11C]isocyanate-coordinated Rh complex to give the corresponding 11C-products. This protocol provides the chemical basis for the synthesis of [11C]urea and [11C]carbamate derived from [11C]isocyanates.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-94170 (URN)10.1039/B409294E (DOI)15505707 (PubMedID)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    2. Palladium-mediated 11C-carbonylative cross coupling of alkyl / aryl iodides with organostannanes. An efficient synthesis of un-symmetrical alkyl - aryl [carbonyl-11C]ketones
    Open this publication in new window or tab >>Palladium-mediated 11C-carbonylative cross coupling of alkyl / aryl iodides with organostannanes. An efficient synthesis of un-symmetrical alkyl - aryl [carbonyl-11C]ketones
    2005 In: Eur.J. Org. Chem., p. 2374-2378Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94171 (URN)
    Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
    3. Synthesis of [11C-carbonyl]hydroxyureas by a rhodium-mediated carbonylation reaction using [11C]carbon monoxide
    Open this publication in new window or tab >>Synthesis of [11C-carbonyl]hydroxyureas by a rhodium-mediated carbonylation reaction using [11C]carbon monoxide
    2006 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 5, p. 429-436Article in journal (Refereed) Published
    Abstract [en]

    [11C]Hydroxyurea has been successfully labelled using [11C]carbon monoxide at low concentration. The decay-corrected radiochemical yield was 38±3%, and the trapping efficiency of [11C]carbon monoxide in the order of 90±5%. This synthesis was performed by a rhodium-mediated carbonylation reaction starting with azidotrimethylsilane and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]2) and 1,2-bis(diphenylphosphino)ethane (dppe). (13C)Hydroxyurea was synthesized using this method and the position of the labelling was confirmed by 13C-NMR. In order to perform accurate LC–MS identification, the derivative 1-hydroxy-3-phenyl[11C]urea was synthesized in a 35±4% decay-corrected radiochemical yield. After 13 µA h bombardment and 21 min synthesis, 1.6 GBq of pure 1-hydroxy-3-phenyl[11C]urea was collected starting from 6.75 GBq of [11C]carbon monoxide and the specific radioactivity of this compound was in the order of 686 GBq/µmol (3.47 nmol total mass). [11C]Hydroxyurea could be used in conjunction with PET to evaluate the uptake of this anticancer agent into tumour tissue in individual patients.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-94172 (URN)10.1002/jlcr.1062 (DOI)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    4. Synthesis of diethyl [carbonyl-C-11]malonate from [C-11]carbon monoxide by rhodium-promoted carbonylation and its application as a reaction intermediate
    Open this publication in new window or tab >>Synthesis of diethyl [carbonyl-C-11]malonate from [C-11]carbon monoxide by rhodium-promoted carbonylation and its application as a reaction intermediate
    2006 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 9, p. 801-809Article in journal (Refereed) Published
    Abstract [en]

    Rhodium-mediated carbonylation reaction was applied to synthesize diethyl [carbonyl-C-11]malonate using [C-11]carbon monoxide at low concentration. The synthesis was performed starting with ethyl diazoacetate, ethanol and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(l) dimer ([Rh(cod)Cl](2)) and 1,2-bis(diphenylphosphino)ethane (dppe), and the reaction is assumed to proceed via a ketene intermediate. The isolated radiochemical yield was 20% (75% analytical radiochemical yield) and the trapping efficiency of [C-11]carbon monoxide in the order of 85%. The specific radioactivity of this compound was measured at 127 GBq/mu mol (7.28 nmol total mass) after 8 mu Ah bombardment and 35 min synthesis. The corresponding C-13-labelled compound was synthesized using (C-13)carbon monoxide to confirm the position of the carbonyl-labelled atom by C-13-NMR. Diethyl [carbonyl-C-11]malonate was further used in subsequent alkylation step using ethyl iodide and tetrabutylammonium fluoride to obtain diethyl diethyl [carbonyl-C-11]malonate in 50% analytical radiochemical yield.

    Keywords
    diethyl [carbonyl-C-11]malonate, [C-11]carbon monoxide, rhodium-mediated carbonylation reaction, ketene
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94173 (URN)10.1002/jlcr.1098 (DOI)000240473200005 ()
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    5. Synthesis of [11C]oxazolidinone via rhodium-mediated carbon-yaltion reaction using [11C]carbon monoxide and [11C]isocyanate intermediate
    Open this publication in new window or tab >>Synthesis of [11C]oxazolidinone via rhodium-mediated carbon-yaltion reaction using [11C]carbon monoxide and [11C]isocyanate intermediate
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94174 (URN)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2010-01-13Bibliographically approved
  • 10.
    Barman, Jharna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Targeting RNA by the Antisense Approach and a Close Look at RNA Cleavage Reaction2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis summarizes the results of studies on two aspects of nucleic acids. Chemically modified antisense oligonucleotides (AONs) have been evaluated with regards to their suitability for mRNA targeting in an antisense approach (Paper I – III). The chemically modified nucleotidic units 2'-O-Me-T, 2'-O-MOE-T, oxetane-T, LNA-T, azetidine-T, aza-ENA-T, carbocyclic-ENA-T and carbocyclic-LNA-T were incorporated into 15-mer AONs and targeted against a 15-mer RNA chosen from the coding region of SV-40 large T antigen. The comparative study showed that a single modified nucleotide in the AON with North-East locked sugar (oxetane-T and azetidine-T) lowered the affinity for the complementary RNA whereas North locked sugars (LNA-T, aza-ENA-T, carbocyclic-ENA-T, and carbocyclic-LNA-T) significantly improved the affinity. A comparative RNase H digestion study showed that modifications of the same type (North-East type or North type) in different sequences gave rise to similar cleavage patterns. Determination of the Michaelis-Menten parameters by kinetic experiments showed that the modified AONs recruit RNase H resulting in enhanced turnover numbers (kcat) although with weaker enzyme-substrate binding (1/Km) compared to the unmodified AON. The modified AONs were also evaluated with regards to resistance towards snake venom phosphodiesterase and human serum to estimate their stability toward exonucleases. The aza-ENA-T and carbocyclic-ENA-T modified AONs showed improved stability compared to all other modified AONs. In general, the modified AONs with North type nucleotides (except LNA-T) were found to be superior to the North-East type as they showed improved target affinity, comparable RNase H recruitment capability and improved exonuclease stability.

    The second aspect studied in this thesis is based on physicochemical studies of short RNA molecules utilizing NMR based pH titration and alkaline hydrolysis reactions (Paper IV – V). The NMR based (1H and 31P) pH titration studies revealed the effect of guaninyl ion formation, propagated electrostatically through a single stranded chain in a sequence dependent manner. The non-identical electronic character of the internucleotidic phosphodiesters was further verified by alkaline hydrolysis experiments. The internucleotidic phosphodiesters, which were influenced by guaninyl ion formation, were hydrolyzed at a faster rate than those sequences where such guaninyl ion formation was prevented by replacing G with N1-Me-G.

    List of papers
    1. Comparison of the RNase H Cleavage Kinetics and Blood Serum Stability of the North-Conformationally Constrained and 2‘-Alkoxy Modified Oligonucleotides
    Open this publication in new window or tab >>Comparison of the RNase H Cleavage Kinetics and Blood Serum Stability of the North-Conformationally Constrained and 2‘-Alkoxy Modified Oligonucleotides
    2007 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 19, p. 5635-5646Article in journal (Refereed) Published
    Abstract [en]

    The RNase H cleavage potential of the RNA strand basepaired with the complementary antisense oligonucleotides (AONs) containing NorthEast conformationally constrained 1‘,2‘-methylene-bridged (azetidine-T and oxetane-T) nucleosides, North-constrained 2‘,4‘-ethylene-bridged (aza-ENA-T) nucleoside, and 2‘-alkoxy modified nucleosides (2‘-O-Me-T and 2‘-O-MOE-T modifications) have been evaluated and compared under identical conditions. When compared to the native AON, the aza-ENA-T modified AON/RNA hybrid duplexes showed an increase of melting temperature (ΔTm = 2.5−4 °C per modification), depending on the positions of the modified residues. The azetidine-T modified AONs showed a drop of 4−5.5 °C per modification with respect to the native AON/RNA hybrid, whereas the isosequential oxetane-T modified counterpart, showed a drop of 5−6 °C per modification. The 2‘-O-Me-T and 2‘-O-MOE-T modifications, on the other hand, showed an increased of Tm by 0.5 °C per modification in their AON/RNA hybrids. All of the partially modified AON/RNA hybrid duplexes were found to be good substrates for the RNase H mediated cleavage. The Km and Vmax values obtained from the RNA concentration-dependent kinetics of RNase H promoted cleavage reaction for all AON/RNA duplexes with identical modification site were compared with those of the reference native AON/RNA hybrid duplex. The catalytic activities (Kcat) of RNase H were found to be greater (1.4−2.6-fold) for all modified AON/RNA hybrids compared to those for the native AON/RNA duplex. However, the RNase H binding affinity (1/Km) showed a decrease (1.7−8.3-fold) for all modified AON/RNA hybrids. This resulted in less effective (1.1−3.2-fold) enzyme activity (Kcat/Km) for all modified AON/RNA duplexes with respect to the native counterpart. A stretch of five to seven nucleotides in the RNA strand (from the site of modifications in the complementary modified AON strand) was found to be resistant to RNase H digestion (giving a footprint) in the modified AON/RNA duplex. Thus, (i) the AON modification with azetidine-T created a resistant region of five to six nucleotides, (ii) modification with 2‘-O-Me-T created a resistant stretch of six nucleotides, (iii) modification with aza-ENA-T created a resistant region of five to seven nucleotide residues, whereas (iv) modification with 2‘-O-MOE-T created a resistant stretch of seven nucleotide residues. This shows the variable effect of the microstructure perturbation in the modified AON/RNA heteroduplex depending upon the chemical nature as well as the site of modifications in the AON strand. On the other hand, the enhanced blood serum as well as the 3‘-exonuclease stability (using snake venom phosphodiesterase, SVPDE) showed the effect of the tight conformational constraint in the AON with aza-ENA-T modifications in that the 3‘-exonuclease preferentially hydrolyzed the 3‘-phosphodiester bond one nucleotide away (n + 1) from the modification site (n) compared to all other modified AONs, which were 3‘-exonuclease cleaved at the 3‘-phosphodiester of the modification site (n). The aza-ENA-T modification in the AONs made the 5‘-residual oligonucleotides (including the n + 1 nucleotide) highly resistant in the blood serum (remaining after 48 h) compared to the native AON (fully degraded in 2 h). On the other hand, the 5‘-residual oligonucleotides (including the n nucleotide) in azetidine-T, 2‘-O-Me-T, and 2‘-O-MOE-T modified AONs were more stable compared to that of the native counterpart but more easily degradable than that of aza-ENA-T containing AONs.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96312 (URN)10.1021/bi0620205 (DOI)000246283600002 ()17411072 (PubMedID)
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14
    2. Conformationally Constrained 2'-N,4'-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides
    Open this publication in new window or tab >>Conformationally Constrained 2'-N,4'-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides
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    2006 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 47, p. 15173-15187Article in journal (Refereed) Published
    Abstract [en]

    The 2'-deoxy-2'-N,4'-C-ethylene-bridged thymidine (aza-ENA-T) has been synthesized using a key cyclization step involving 2'-ara-trifluoromethylsufonyl-4'-cyanomethylene 11 to give a pair of 3',5'-bis-OBn- protected diastereomerically pure aza-ENA-Ts (12a and 12b) with the fused piperidino skeleton in the chair conformation, whereas the pentofuranosyl moiety is locked in the North-type conformation (7 < P < 27 degrees, 44 degrees < phi(m) < 52 degrees). The origin of the chirality of two diastereomerically pure aza-ENA-Ts was found to be due to the endocyclic chiral 2'-nitrogen, which has axial N-H in 12b and equatorial N-H in 12a. The latter is thermodynamically preferred, while the former is kinetically preferred with E-a 25.4 kcal mol(-1), which is thus far the highest observed inversion barrier at pyramidal N-H in the bicyclic amines. The 5'-O-DMTr-aza-ENA-T-3'-phosphoramidite was employed for solid-phase synthesis to give four different singly modified 15-mer antisense oligonucleotides (AONs). Their AON/RNA duplexes showed a T m increase of 2.5-4 degrees C per modification, depending upon the modification site in the AON. The relative rates of the RNase H1 cleavage of the aza-ENA-T-modified AON/RNA heteroduplexes were very comparable to that of the native counterpart, but the RNA cleavage sites of the modified AON/RNA were found to be very different. The aza-ENA-T modifications also made the AONs very resistant to 3' degradation (stable over 48 h) in the blood serum compared to the unmodified AON (fully degraded in 4 h). Thus, the aza-ENA-T modification in the AON fulfilled three important antisense criteria, compared to the native: (i) improved RNA target affinity, (ii) comparable RNase H cleavage rate, and (iii) higher blood serum stability.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-96272 (URN)10.1021/ja0634977 (DOI)000242216100046 ()17117869 (PubMedID)
    Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14
    3. Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies
    Open this publication in new window or tab >>Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies
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    2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 26, p. 8362-8379Article in journal (Refereed) Published
    Abstract [en]

    Two unusual reactions involving the 5-hexenyl or the 6-heptenyl radical cyclization of a distant double bond at C4' and the radical center at C2' of the ribofuranose ring of thymidine have been used as key steps to synthesize North-type conformationally constrained cis-fused bicyclic five-membered and six-membered carbocyclic analogues of LNA (carbocyclic-LNA-T) and ENA (carbocyclic-ENA-T) in high yields. Their structures have been confirmed unambiguously by long range iH-13C NMR correlation (HMBC), TOCSY, COSY, and NOE experiments. The carbocyclic-LNA-T and carbocyclic-ENA-T were subsequently incorporated into the antisense oligonucleotides (AONs) to show that they enhance the Tm of the modified AON/RNA heteroduplexes by 3.5-5 °C and 1.5 °C/modification for carbocyclic-LNA-T and carbocyclic-ENA-T, respectively. Whereas the relative RNase H cleavage rates with carbocyclic-LNA-T, carbocyclic-ENA-T, aza-ENA-T, and LNA-T modified AON/RNA duplexes were found to be very similar to that of the native counterpart, irrespective of the type and the site modification in the AON strand, a single incorporation of carbocyclic-LNA and carbocyclic-ENA into AONs leads to very much more enhanced nuclease stability in the blood serum (stable >48 h) as compared to that of the native (fully degraded <3 h) and the LNA-modified AONs (fully degraded <9 h) and aza-ENA (≈85% stable in 48 h). Clearly, remarkably enhanced lifetimes of these carbocyclic-modified AONs in the blood serum may produce the highly desired pharmacokinetic properties because of their unique stability and consequently a net reduction of the required dosage. This unique quality as well as their efficient use as the AON in the RNase H-promoted cleavage of the target RNA makes our carbocyclic-LNA and carbocyclic-ENA modifications excellent candidates as potential antisense therapeutic agents.

    National Category
    Biological Sciences Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96273 (URN)10.1021/ja071106y (DOI)000247563700050 ()17552524 (PubMedID)
    Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14Bibliographically approved
    4. Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
    Open this publication in new window or tab >>Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
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    2004 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 126, no 28, p. 8674-8681Article in journal (Refereed) Published
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96321 (URN)10.1021/ja048484c (DOI)
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14Bibliographically approved
    5. Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds
    Open this publication in new window or tab >>Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds
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    2006 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 5, p. 928-941Article in journal (Refereed) Published
    Abstract [en]

    We here show that the electronic properties and the chemical reactivities of the internucleotidic phosphates in the heptameric ssRNAs are dissimilar in a sequence-specific manner because of their non-identical microenvironments, in contrast with the corresponding isosequential ssDNAs. This has been evidenced by monitoring the delta H8(G) shifts upon pH-dependent ionization (pK(a1)) of the central 9-guaninyl (G) to the 9-guanylate ion (G(-)), and its electrostatic effect on each of the internucleotidic phosphate anions, as measured from the resultant delta P-31 shifts (pKa(2)) in the isosequential heptameric ssRNAs vis-`a-vis ssDNAs: [d/r( 5'-Cp(1)Ap(2)Q(1)p(3)Gp(4)Q(2)p(5)Ap(6)C-3'): Q(1) = Q(2) = A (5a/5b) or C (8a/8b), Q(1) = A, Q(2) = C (6a/6b), Q(1) = C, Q(2) = A (7a/7b)]. These oligos with single ionizable G in the centre are chosen because of the fact that the pseudoaromatic character of G can be easily modulated in a pH-dependent manner by its transformation to G(-) (the 2'-OH to 2-O- ionization effect is not detectable below pH 11.6 as evident from the N1-Me-G analog), thereby modulating/titrating the nature of the electrostatic interactions of G to G- with the phosphates, which therefore constitute simple models to interrogate how the variable pseudoaromatic characters of nucleobases under different sequence context (J. Am. Chem. Soc., 2004, 126, 8674-8681) can actually influence the reactivity of the internucleotide phosphates as a result of modulation of sequence context-specific electrostatic interactions. In order to better understand the impact of the electrostatic effect of the G to G- on the tunability of the electronic character of internucleotidic phosphates in the heptameric ssRNAs 5b, 6b, 7b and 8b, we have also performed their alkaline hydrolysis at pH 12.5 at 20 degrees C, and have identified the preferences of the cleavage sites at various phosphates, which are p(2), p(3) and p(4) (Fig. 3). The results of these alkaline hydrolysis studies have been compared with the hydrolysis of analogous N1-Me-G heptameric ssRNA sequences 5c, 7c and 8c under identical conditions in order to establish the role of the electrostatic effect of the 9-guanylate ion (and the 2'-OH to 2-O- ionization) on the internucleotidic phosphate. It turned out that the relative alkaline hydrolysis rate at those particular phosphates ( p2, p3 and p(4)) in the N1-Me-G heptamers was reduced from 16-78% compared to those in the native counterparts [Fig. 4, and ESI 2 (Fig. S11)]. Thus, these physico-chemical studies have shown that those p2, p3 and p4 phosphates in the native heptameric RNAs, which show pK(a2) as well as more deshielding ( owing to weaker P-31 screening) in the alkaline pH compared to those at the neutral pH, are more prone to the alkaline hydrolysis because of their relatively enhanced electrophilic character resulting from weaker P-31 screening. This screening effect originates as a result of the systematic charge repulsion effect between the electron cloud in the outermost orbitals of phosphorus and the central guanylate ion, leading to delocalization of the phosphorus pp charge into its d pi orbitals. It is thus likely that, just as in the non-enzymatic hydrolysis, the enzymatic hydrolysis of a specific phosphate in RNA by general base-catalyss in RNA-cleaving proteins (RNase A, RNA phosphodiesterase or nuclease) can potentially be electrostatically influenced by tuning the transient charge on the nucleobase in the steric proximity or as a result of specific sequence context owing to nearest-neighbor interactions.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-96322 (URN)10.1039/B516733G (DOI)000235992700023 ()
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14Bibliographically approved
  • 11.
    Belfrage, Anna Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: Targeting Different Genotypes and Drug-Resistant Variants2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes.

    The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities.

    Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd-catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres.

    List of papers
    1. Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
    Open this publication in new window or tab >>Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
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    2010 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 20, no 14, p. 4004-4011Article in journal (Refereed) Published
    Abstract [en]

    Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. (C) 2010 Elsevier Ltd. All rights reserved.

    Keywords
    HCV, NS3/4A protease, Inhibitors, P2 substituent, Quinazoline, Replicon assay, In vitro, DMPK, In vivo PK
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-136039 (URN)10.1016/j.bmcl.2010.05.029 (DOI)000279258800001 ()
    Available from: 2010-12-09 Created: 2010-12-09 Last updated: 2018-01-12Bibliographically approved
    2. Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
    Open this publication in new window or tab >>Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
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    2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 5, p. 1790-1801Article in journal (Refereed) Published
    Abstract [en]

    Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

    National Category
    Medicinal Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-172003 (URN)10.1021/jm301887f (DOI)000333005800011 ()
    Available from: 2012-03-31 Created: 2012-03-31 Last updated: 2018-01-12Bibliographically approved
    3. Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Open this publication in new window or tab >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
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    2016 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, p. 2603-2620Article in journal (Refereed) Published
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

    Keywords
    Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
    Funder
    Swedish Research Council, D0571301
    Available from: 2015-02-08 Created: 2015-02-08 Last updated: 2017-12-04Bibliographically approved
    4. Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
    Open this publication in new window or tab >>Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
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    2015 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 5, p. 978-986Article in journal (Refereed) Published
    Abstract [en]

    The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.

    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243254 (URN)10.1002/ejoc.201403405 (DOI)000349391700009 ()
    Available from: 2015-02-06 Created: 2015-02-06 Last updated: 2017-12-04Bibliographically approved
    5. Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
    Open this publication in new window or tab >>Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
    (English)Manuscript (preprint) (Other academic)
    Keywords
    palladium
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry; Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243257 (URN)
    Available from: 2015-02-06 Created: 2015-02-06 Last updated: 2015-03-11
  • 12.
    Berlin, Stefan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Construction of Five-Membered Heterocyclic Compounds via Radical Cyclization2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes how radical cyclization chemistry can be applied for the construction of heterocyclic compounds.

    In the first part, a series of electron deficient α-phenylselenenylalkenes were prepared via a PhSeCl-addition/HCl-elimination sequence. Allyl- and propargylamines readily underwent conjugate addition to these species to produce pyrrolidines or dihydropyrrol derivatives, after triethylborane initiated reductive radical cyclization in the presence of tris(trimethylsilyl)silane.

    The second part describes a convergent synthesis of the pineal hormone melatonin. The indole nucleus is secured via a tris(trimethylsilyl)silane mediated 5-exo radical cyclization. The protocol provides convenient and simple access to compounds useful for studies of biological activity and structure activity relationships.

    The third part describes construction of substituted tetrahydrofuran-3-ones and pyrrolidin-3-ones. Regioselective ring-opening of epoxides or aziridines with benzeneselenolate/tellurolate, followed by Michael addition to electron deficient alkynes afforded the corresponding O/N-vinylated compounds. The tetrahydrofuran-3-ones and pyrrolidin-3-ones were secured via radical carbonylation/reductive cyclization using pressurized carbon monoxide (80 atm).

    The fourth part is concerned with the effect of an N-protecting group on the cyclization of 2-substituted-3-aza-5-hexenyl radicals. Relative energies for reactants and transition states were determined using density functional calculations. Reactant and transition state conformers leading to cis-product were lower in energy than those leading to trans-product. The results can be explained by the unfavorable 1,2-strain present in chair-equatorial and boat-equatorial conformers.

    List of papers
    1. A Radical Cyclization Route to Pyrrolidines Based on Conjugate Addition to Electron Deficient Phenylselenenylalkenes
    Open this publication in new window or tab >>A Radical Cyclization Route to Pyrrolidines Based on Conjugate Addition to Electron Deficient Phenylselenenylalkenes
    2000 In: Tetrahedron Letters, Vol. 41, no 19, p. 3701-3704Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90418 (URN)
    Available from: 2003-05-12 Created: 2003-05-12Bibliographically approved
    2. Efficient Route to the Pineal Hormone Melatonin by Radical-Based Indole Synthesis
    Open this publication in new window or tab >>Efficient Route to the Pineal Hormone Melatonin by Radical-Based Indole Synthesis
    2003 (English)In: Synthetic Communications, ISSN 0039-7911, E-ISSN 1532-2432, Vol. 33, no 20, p. 3631-3641Article in journal (Refereed) Published
    Abstract [en]

    The hormone melatonin, which is known to have a range of important biological effects, has been prepared in a high-yielding route that features formation of the indole nucleus by radical cyclization. Mediation of the radical cyclization by tristrimethylsilylsilane (TTMSS) is more efficient than by N-ethylpiperidine hypophosphite.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-90419 (URN)10.1081/SCC-120024751 (DOI)
    Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2017-12-14Bibliographically approved
    3. Construction of Tetrahydrofuran-3-ones from Readily Available Organochalcogen Precursors via Radical Carbonylation/Reductive Cyclization
    Open this publication in new window or tab >>Construction of Tetrahydrofuran-3-ones from Readily Available Organochalcogen Precursors via Radical Carbonylation/Reductive Cyclization
    2002 In: Organic Letters, Vol. 4, p. 3-6Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90420 (URN)
    Available from: 2003-05-12 Created: 2003-05-12Bibliographically approved
    4. Radical Carbonylation/Reductive Cyclization for the Construction of Tetrahydrofuran-3-ones and Pyrrolidin3-0nes
    Open this publication in new window or tab >>Radical Carbonylation/Reductive Cyclization for the Construction of Tetrahydrofuran-3-ones and Pyrrolidin3-0nes
    In: Journal of Organic ChemistryArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90421 (URN)
    Available from: 2003-05-12 Created: 2003-05-12Bibliographically approved
    5. On the origin of cis selectivity in the cyclization of N-protected 2-substituted 3-aza-5-hexenyl radicals: a density functional study
    Open this publication in new window or tab >>On the origin of cis selectivity in the cyclization of N-protected 2-substituted 3-aza-5-hexenyl radicals: a density functional study
    Show others...
    2004 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, no 5, p. 1487-1491Article in journal (Refereed) Published
    Abstract [en]

    Cyclization of the N-dimethylphosphinoyl-2-methyl-3-aza-5-hexenyl radical has been studied at the UB3LYP/6-31+G(d)//UB3LYP/6-31G(d) hybrid density functional level. The corresponding radical precursor has been synthesized and found to give cis/trans ratios of up to 10/1 in reductive radical cyclizations. The relative energies of reactant and transition state conformers were determined. In discord with the Beckwith-Houk model, it has been found that chair-axial transition states, which lead to cis products, are lowest in energy, rationalizing the observed experimental diastereoselectivity.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-90422 (URN)10.1021/jo030294h (DOI)14987001 (PubMedID)
    Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2017-12-14Bibliographically approved
  • 13.
    Beşev, Magnus
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Organic Chemistry.
    Radical Cyclization Approaches to Pyrrolidines2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Five-membered rings are readily prepared by 5-exo-trig radical cyclization. This thesis is concerned with novel methodology for pyrrolidine synthesis. We have synthesised selenium containing radical precursors from aziridines and α-phenylseleno ketones, and cyclized them to 2,4- and 3,4-disubstituted pyrrolidines. A few examples of 5-exo-dig cyclization were also demonstrated. In another study we investigated the capacity of the nitrogen protecting group to direct diastereoselectivity in the formation of 2,4-disubstituted pyrrolidines. The diphenylphosphinoyl protecting group directed cyclization to occur in a highly cis-selective manner. When cyclizations were performed at 17 oC, cis/trans-ratios as high as 24/1 were obtained. In contrast, cyclization of the unprotected pyrrolidine precursor afforded the trans-diastereomer as the major product (cis/trans = 1/3.3 – 1/20). We also examined the use of a hydroxyl auxiliary for controlling diastereoselectivity in radical cyclization. The required selenium containing radical precursors were synthesised from 2-cyanoaziridines by addition of organometallic reagents, reduction of the resulting aziridine ketone, and benzeneselenol ring-opening of the aziridine. Cyclization at 17 oC produced 2,4-disubstituted pyrrolidines substantially enriched in the trans-isomer (cis/trans = 1/9 – 1/12). Novel radical cyclization approaches to thiazolines and pyrrolines were also tried.

    The thesis also describes attempts to improve the Hassner aziridine synthesis by employing stannous chloride as a functional group tolerant reducing agent.

  • 14.
    Cadu, Alban
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Noble Metal Catalysed Reductions and Rearrangements2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The focus of this thesis has been organometallic catalysis applied to compounds containing heteroatoms which are usually poisonous to metal catalysts, by channelling their innate reactivity advantageously. The studies described in this thesis concentrate, in the first part, on iridium catalysed asymmetric hydrogenation (papers I and II) and in the second part, on gold catalysed internal rearrangements (papers III and IV). In each case, two classes of compounds are studied: pyridinium salts or sulphurous compounds. The asymmetric hydrogenation of pyridinium compounds was performed with 2% loading of N,P-ligated Ir catalyst with I2 additive (paper I) to achieve moderate to good enantiomeric excess (up to 98%). In paper II, olefinic sulphones were hydrogenated with an efficient 0.5% catalytic loading. In most cases full conversion was obtained and with good to excellent ees (up to 99%). The products of these reductions are chiral compounds, which could constitute further chemical building blocks. Palladium and gold were used sequentially in paper III, in order to perform a “Click” thiol-yne reaction followed by a semi-Pinacol rearrangement, leading to isolated yields of up to 98%. In paper IV The gold catalysed rearrangement of alkyl-pyridinium diynes was conducted, with a number of substrates providing >90% NMR yield. A highly selective hydrogenation was performed with a heterogeneous palladium catalyst to yield single diastereomer products. This methodology consists of up to three steps, with two catalysts in one pot.

    List of papers
    1. Iridium-Catalyzed Asymmetric Hydrogenation of Substituted Pyridines
    Open this publication in new window or tab >>Iridium-Catalyzed Asymmetric Hydrogenation of Substituted Pyridines
    2013 (English)In: Asian Journal of Organic Chemistry, ISSN 2193-5807, Vol. 2, no 12, p. 1061-1065Article in journal (Refereed) Published
    Abstract [en]

    Asymmetric hydrogenation of ortho-substituted pyridines catalyzed by N,P-ligated iridium is demonstrated. To facilitate this reaction, the aromaticity of the pyridines was weakened by forming N-iminopyridium ylides. The reactions give very high conversions, and after a single recrystallization, excellent ee of up to 98 % was obtained. This method lends itself to the synthesis of chiral piperidine building blocks.

    Keywords
    hydrogenation, iridium, N-iminopyridium ylides, pyridines, selective catalysis
    National Category
    Organic Chemistry Inorganic Chemistry
    Research subject
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-212412 (URN)10.1002/ajoc.201300160 (DOI)000328218000008 ()
    Available from: 2013-12-10 Created: 2013-12-10 Last updated: 2017-01-25Bibliographically approved
    2. An Enantioselective Approach to the Preparation of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation
    Open this publication in new window or tab >>An Enantioselective Approach to the Preparation of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation
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    2014 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 136, no 47, p. 16557-16562Article in journal (Refereed) Published
    Abstract [en]

    Several chiral sulfonyl compounds were prepared using the iridium catalyzed asymmetric hydrogenation reaction. Vinylic, allylic and homoallylic sulfone substitutions were investigated, and high enantioselectivity is maintained regardless of the location of the olefin with respect to the sulfone. Impressive stereoselectivity was obtained for dialkyl substitutions, which typically are challenging substrates in the hydrogenation. As expected, the more bulky Z-substrates were hydrogenated slower than the corresponding E isomers, and in slightly lower enantioselectivity.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2014
    National Category
    Organic Chemistry
    Research subject
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-236862 (URN)10.1021/ja5079877 (DOI)000345720500016 ()25300238 (PubMedID)
    Available from: 2014-11-24 Created: 2014-11-24 Last updated: 2017-12-05Bibliographically approved
    3. One-Pot Synthesis of Keto Thioethers by Palladium/Gold-Catalyzed Click and Pinacol Reactions
    Open this publication in new window or tab >>One-Pot Synthesis of Keto Thioethers by Palladium/Gold-Catalyzed Click and Pinacol Reactions
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    2014 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 16, no 21, p. 5556-5559Article in journal (Refereed) Published
    Abstract [en]

    An atom-efficient synthesis of keto thioethers was devised via tandem gold/palladium catalysis. The reaction proceeds through a regioselective thiol attack at the β-position of the alcohol, followed by an alkyl, aryl, or benzyl 1,2-shift. Both acyclic and cyclic systems were studied, in the latter case leading to the ring expansion of cyclic substrates.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2014
    Keywords
    Gold, Palladium, thioether, catalysis, synthesis
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-236857 (URN)10.1021/ol502553p (DOI)000344635200013 ()25325145 (PubMedID)
    Available from: 2014-11-24 Created: 2014-11-24 Last updated: 2017-12-05Bibliographically approved
    4. Dual Gold (I) Catalysed Cyclisation of Dialkynyl Pyridinium salts
    Open this publication in new window or tab >>Dual Gold (I) Catalysed Cyclisation of Dialkynyl Pyridinium salts
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Novel dialkynyl pyridines were synthesised and protected as alkyl salts for dual gold (I) catalysed cycloisomerisation. Different alkyl groups and counter ions were screened for the salts, with benzyl and PF6- providing the best results. The cyclisation led to NMR yields of >95% being obtained for a number of substrates. Step-wise hydrogenation of products could be carried out in one-pot by Pd/C, with selective reduction of the double bonds, followed by deprotection of the Bn group.

    Keywords
    chemistry
    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-272369 (URN)
    Available from: 2016-01-13 Created: 2016-01-13 Last updated: 2016-02-12Bibliographically approved
  • 15.
    Cedervall, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström.
    Magnetic Materials for Cool Applications: Relations between Structure and Magnetism in Rare Earth Free Alloys2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    New and more efficient magnetic materials for energy applications are a big necessity for sustainable future. Whether the application is energy conversion or refrigeration, materials based on sustainable elements should be used, which discards all rare earth elements. For energy conversion, permanent magnets with high magnetisation and working temperature are needed whereas for refrigeration, the entropy difference between the non-magnetised and magnetised states should be large. For this reason, magnetic materials have been synthesised with high temperature methods and structurally and magnetically characterised with the aim of making a material with potential for large scale applications. To really determine the cause of the physical properties the connections between structure (crystalline and magnetic) and, mainly, the magnetic properties have been studied thoroughly.

    The materials that have been studied have all been iron based and exhibit properties with potential for the applications in mind. The first system, for permanent magnet applications, was Fe5SiB2. It was found to be unsuitable for a permanent magnet, however, an interesting magnetic behaviour was studied at low temperatures. The magnetic behaviour arose from a change in the magnetic structure which was solved by using neutron diffraction. Substitutions with phosphorus (Fe5Si1-xPxB2) and cobalt (Fe1-xCox)5PB2 were then performed to improve the permanent magnet potential. While the permanent magnetic potential was not improved with cobalt substitutions the magnetic transition temperature could be greatly controlled, a real benefit for magnetic refrigeration. For this purpose AlFe2B2 was also studied, and there it was found, conclusively, that the material undergoes a second order transition, making it unsuitable for magnetic cooling. However, the magnetic structure was solved with two different methods and was found to be ferromagnetic with all magnetic moments aligned along the crystallographic a-direction. Lastly, the origin of magnetic cooling was studied in Fe2P, and can be linked to the interactions between the magnetic and atomic vibrations.

    List of papers
    1. Magnetostructural transition in Fe5SiB2 observed with neutron diffraction
    Open this publication in new window or tab >>Magnetostructural transition in Fe5SiB2 observed with neutron diffraction
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    2016 (English)In: Journal of Solid State Chemistry, ISSN 0022-4596, E-ISSN 1095-726X, Vol. 235, p. 113-118Article in journal (Refereed) Published
    Abstract [en]

    The crystal and magnetic structure of Fe5SiB2 has been studied by a combination of X-ray and neutron diffraction. Also, the magnetocrystalline anisotropy energy constant has been estimated from magnetisation measurements. High quality samples have been prepared using high temperature synthesis and subsequent heat treatment protocols. The crystal structure is tetragonal within the space group I4/mcm and the compound behaves ferromagnetically with a Curie temperature of 760 K. At 172 K a spin reorientation occurs in the compound and the magnetic moments go from aligning along the c-axis (high T) down to the ab-plane (low T). The magnetocrystalline anisotropy energy constant has been estimated to 03 MJ/m(3) at 300 K.

    National Category
    Inorganic Chemistry Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-267572 (URN)10.1016/j.jssc.2015.12.016 (DOI)000370467900017 ()
    Funder
    Swedish Research Council
    Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2017-12-01Bibliographically approved
    2. Magnetic properties of the Fe5SiB2−Fe5PB2 system
    Open this publication in new window or tab >>Magnetic properties of the Fe5SiB2−Fe5PB2 system
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    2017 (English)In: Physical Review B, ISSN 2469-9950, E-ISSN 2469-9969, Vol. 96, no 9, article id 094433Article in journal (Refereed) Published
    Abstract [en]

    The magnetic properties of the compound Fe5Si1−xPxB2 have been studied, with a focus on the Curie temperature TC, saturation magnetization MS, and magnetocrystalline anisotropy. Field and temperature dependent magnetization measurements were used to determine TC(x) and MS(x). The saturation magnetization at 10 K (300 K) is found to monotonically decrease from 1.11MA/m (1.03MA/m) to 0.97MA/m (0.87MA/m), as x increases from 0 to 1. The Curie temperature is determined to be 810 and 615 K in Fe5SiB2 and Fe5PB2, respectively. The highest TC is observed for x=0.1, while it decreases monotonically for larger x. The Curie temperatures have also been theoretically determined to be 700 and 660 K for Fe5SiB2 and Fe5PB2, respectively, using a combination of density functional theory and Monte Carlo simulations. The magnitude of the effective magnetocrystalline anisotropy was extracted using the law of approach to saturation, revealing an increase with increasing phosphorus concentration. Low-field magnetization vs temperature results for x=0,0.1,0.2 indicate that there is a transition from easy-axis to easy-plane anisotropy with decreasing temperature.

    Place, publisher, year, edition, pages
    American Physical Society, 2017
    Keywords
    Magnetism, Ferromagnetism, First-principle calculations, Magnetic interactions, Magnetic order parameter, Magnetic phase transition
    National Category
    Condensed Matter Physics Engineering and Technology
    Research subject
    Physics
    Identifiers
    urn:nbn:se:uu:diva-330463 (URN)10.1103/PhysRevB.96.094433 (DOI)000411975700001 ()
    Funder
    Swedish Research CouncilGöran Gustafsson Foundation for Research in Natural Sciences and MedicineKnut and Alice Wallenberg Foundation, 2013.0020, 2012.0031EU, Horizon 2020
    Available from: 2017-09-29 Created: 2017-09-29 Last updated: 2017-12-20Bibliographically approved
    3. Influence of cobalt substitution on the magnetic properties of Fe5PB2
    Open this publication in new window or tab >>Influence of cobalt substitution on the magnetic properties of Fe5PB2
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    2018 (English)In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 57, no 2, p. 777-784Article in journal (Refereed) Published
    Abstract [en]

    In this study the effects of cobalt substitutions in Fe5PB2 have been studied. An increased cobalt content reduces the magnetic exchange interactions. This has been concluded from a large, linear decrease in both the Curie temperature as well as the saturated magnetic moment. At high cobalt concentrations, cobalt prefers to order at the M(2) position in the crystal structure. A tunable Curie transition like this shows some prerequisites for magnetic cooling applications.

    The substitutional effects of cobalt in (Fe1–xCox)5PB2 have been studied with respect to crystalline structure and chemical order with X-ray diffraction and Mössbauer spectroscopy. The magnetic properties have been determined from magnetic measurements, and density functional theory calculations have been performed for the magnetic properties of both the end compounds, as well as the chemically disordered intermediate compounds. The crystal structure of (Fe1–xCox)5PB2 is tetragonal (space group I4/mcm) with two different metal sites, with a preference for cobalt atoms in the M(2) position (4c) at higher cobalt contents. The substitution also affects the magnetic properties with a decrease of the Curie temperature (TC) with increasing cobalt content, from 622 to 152 K for Fe5PB2 and (Fe0.3Co0.7)5PB2, respectively. Thus, the Curie temperature is dependent on composition, and it is possible to tune TC to a temperature near room temperature, which is one prerequisite for magnetic cooling materials.

    National Category
    Inorganic Chemistry Condensed Matter Physics Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-331758 (URN)10.1021/acs.inorgchem.7b02663 (DOI)000422810900030 ()29298054 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Energy AgencyEuropean Regional Development Fund (ERDF)
    Available from: 2017-10-19 Created: 2017-10-19 Last updated: 2018-10-19Bibliographically approved
    4. Magnetic structure of the magnetocaloric compound AlFe2B2
    Open this publication in new window or tab >>Magnetic structure of the magnetocaloric compound AlFe2B2
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    2016 (English)In: Journal of Alloys and Compounds, ISSN 0925-8388, E-ISSN 1873-4669, Vol. 654, p. 784-791Article in journal (Refereed) Published
    Abstract [en]

    The crystal and magnetic structures of AlFe2B2 have been studied with a combination of X-ray and neutron diffraction and electronic structure calculations. The magnetic and magnetocaloric properties have been investigated by magnetisation measurements. The samples have been produced using high temperature synthesis and subsequent heat treatments. The compound crystallises in the orthorhombic crystal system Cmmm and it orders ferromagnetically at 285 K through a second order phase transition. At temperatures below the magnetic transition the magnetic moments align along the crystallographic a-axis. The magnetic entropy change from 0 to 800 kA/m was found to be - 1.3 J/K kg at the magnetic transition temperature.

    National Category
    Inorganic Chemistry Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-267573 (URN)10.1016/j.jallcom.2015.12.111 (DOI)000369061700101 ()
    Funder
    Swedish Research Council
    Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2017-12-01Bibliographically approved
    5. Mössbauer study of the magnetocaloric compound AlFe2B2
    Open this publication in new window or tab >>Mössbauer study of the magnetocaloric compound AlFe2B2
    2016 (English)In: Hyperfine Interactions, ISSN 0304-3843, E-ISSN 1572-9540, Vol. 237, article id 47Article in journal (Refereed) Published
    Abstract [en]

    Mössbauer spectroscopy in the ferromagnetic AlFe2B2 reveals Tc=299 K and shows good agreement with magnetic measurements. The crystals are plate-shaped. The flakes are found from X-ray diffraction to be in the crystallographic ac-plane in the orthorhombic system. The axes of the principle electric field gradient tensor are, by symmetry, colinear with the crystal a-, b- and c-axes. By using information about the quadrupole splitting and line asymmetry in the paramagnetic regime together with the quadrupole shift of the resonance lines in the ferromagnetic regime the magnetic hyperfine field direction is found to be in the ab-plane having an angle =40° to the b-axis.

    National Category
    Inorganic Chemistry
    Research subject
    Chemistry with specialization in Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-312463 (URN)10.1007/s10751-016-1223-7 (DOI)000372730100020 ()
    Conference
    International Conference on the Applications of the Mössbauer Effect (ICAME 2015), 13-18 September 2015, Hamburg, Germany
    Available from: 2017-01-10 Created: 2017-01-10 Last updated: 2018-04-09Bibliographically approved
    6. Magnetic and mechanical effects of Mn substitutions in AlFe2B2
    Open this publication in new window or tab >>Magnetic and mechanical effects of Mn substitutions in AlFe2B2