NMR studies of coupled low- and high-barrier hydrogen bonds in pyridoxal-5′-phosphate model systems in polar solution

Shasad Sharif, Gleb S. Denisov, Michael D. Toney, Hans Heinrich Limbach

Research output: Contribution to journalArticle

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Abstract

The 1H and 15N NMR spectra of several 15N-labeled pyridoxal-5′-phosphate model systems have been measured at low temperature in various aprotic and protic solvents of different polarity, i.e., dichloromethane-d2, acetonitrile-d3, tetrahydrofuran-d8, freon mixture CDF3/CDClF2, and methanol. In particular, the 15N-labeled 5′-triisopropyl- silyl ether of N-(pyridoxylidene)-tolylamine (1a), N-(pyridoxylidene)- methylamine (2a), and the Schiff base with 15N-2-methylaspartic acid (3a) and their complexes with proton donors such as triphenylmethanol, phenol, and carboxylic acids of increasing strength were studied. With the use of hydrogen bond correlation techniques, the 1H/15N chemical shift and scalar coupling data could be associated with the geometries of the intermolecular O1H1N1 (pyridine nitrogen) and the intramolecular O2H2N2 (Schiff base) hydrogen bonds. Whereas O1H1N1 is characterized by a series of asymmetric low-barrier hydrogen bonds, the proton in O2H2N2 faces a barrier for proton transfer of medium height. When the substituent on the Schiff base nitrogen is an aromatic ring, the shift of the proton in O1H1N1 from oxygen to nitrogen has little effect on the position of the proton in the O2H2N2 hydrogen bond. By contrast, when the substituent on the Schiff base nitrogen is a methyl group, a proton shift from O to N in O1H1N1 drives the tautomeric equilibrium in O2H2N2 from the neutral O2-H2⋯N2 to the zwitterionic O2-⋯H2- N2+ form. This coupling is lost in aqueous solution where the intramolecular O2H2N2 hydrogen bond is broken by solute-solvent interactions. However, in methanol, which mimics hydrogen bonds to the Schiff base in the enzyme active site, the coupling is preserved. Therefore, the reactivity of Schiff base intermediates in pyridoxal-5′-phosphate enzymes can likely be tuned to the requirements of the reaction being catalyzed by differential protonation of the pyridine nitrogen.

Original languageEnglish (US)
Pages (from-to)6313-6327
Number of pages15
JournalJournal of the American Chemical Society
Volume129
Issue number19
DOIs
StatePublished - May 16 2007

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Pyridoxal Phosphate
Schiff Bases
Protons
Hydrogen
Hydrogen bonds
Phosphates
Nuclear magnetic resonance
Nitrogen
Pyridine
Methanol
Enzymes
Chlorofluorocarbons
Proton transfer
Methylene Chloride
Protonation
Dichloromethane
Chemical shift
Carboxylic Acids
Phenol
Acetonitrile

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

NMR studies of coupled low- and high-barrier hydrogen bonds in pyridoxal-5′-phosphate model systems in polar solution. / Sharif, Shasad; Denisov, Gleb S.; Toney, Michael D.; Limbach, Hans Heinrich.

In: Journal of the American Chemical Society, Vol. 129, No. 19, 16.05.2007, p. 6313-6327.

Research output: Contribution to journalArticle

Sharif, Shasad ; Denisov, Gleb S. ; Toney, Michael D. ; Limbach, Hans Heinrich. / NMR studies of coupled low- and high-barrier hydrogen bonds in pyridoxal-5′-phosphate model systems in polar solution. In: Journal of the American Chemical Society. 2007 ; Vol. 129, No. 19. pp. 6313-6327.
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title = "NMR studies of coupled low- and high-barrier hydrogen bonds in pyridoxal-5′-phosphate model systems in polar solution",
abstract = "The 1H and 15N NMR spectra of several 15N-labeled pyridoxal-5′-phosphate model systems have been measured at low temperature in various aprotic and protic solvents of different polarity, i.e., dichloromethane-d2, acetonitrile-d3, tetrahydrofuran-d8, freon mixture CDF3/CDClF2, and methanol. In particular, the 15N-labeled 5′-triisopropyl- silyl ether of N-(pyridoxylidene)-tolylamine (1a), N-(pyridoxylidene)- methylamine (2a), and the Schiff base with 15N-2-methylaspartic acid (3a) and their complexes with proton donors such as triphenylmethanol, phenol, and carboxylic acids of increasing strength were studied. With the use of hydrogen bond correlation techniques, the 1H/15N chemical shift and scalar coupling data could be associated with the geometries of the intermolecular O1H1N1 (pyridine nitrogen) and the intramolecular O2H2N2 (Schiff base) hydrogen bonds. Whereas O1H1N1 is characterized by a series of asymmetric low-barrier hydrogen bonds, the proton in O2H2N2 faces a barrier for proton transfer of medium height. When the substituent on the Schiff base nitrogen is an aromatic ring, the shift of the proton in O1H1N1 from oxygen to nitrogen has little effect on the position of the proton in the O2H2N2 hydrogen bond. By contrast, when the substituent on the Schiff base nitrogen is a methyl group, a proton shift from O to N in O1H1N1 drives the tautomeric equilibrium in O2H2N2 from the neutral O2-H2⋯N2 to the zwitterionic O2-⋯H2- N2+ form. This coupling is lost in aqueous solution where the intramolecular O2H2N2 hydrogen bond is broken by solute-solvent interactions. However, in methanol, which mimics hydrogen bonds to the Schiff base in the enzyme active site, the coupling is preserved. Therefore, the reactivity of Schiff base intermediates in pyridoxal-5′-phosphate enzymes can likely be tuned to the requirements of the reaction being catalyzed by differential protonation of the pyridine nitrogen.",
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T1 - NMR studies of coupled low- and high-barrier hydrogen bonds in pyridoxal-5′-phosphate model systems in polar solution

AU - Sharif, Shasad

AU - Denisov, Gleb S.

AU - Toney, Michael D.

AU - Limbach, Hans Heinrich

PY - 2007/5/16

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N2 - The 1H and 15N NMR spectra of several 15N-labeled pyridoxal-5′-phosphate model systems have been measured at low temperature in various aprotic and protic solvents of different polarity, i.e., dichloromethane-d2, acetonitrile-d3, tetrahydrofuran-d8, freon mixture CDF3/CDClF2, and methanol. In particular, the 15N-labeled 5′-triisopropyl- silyl ether of N-(pyridoxylidene)-tolylamine (1a), N-(pyridoxylidene)- methylamine (2a), and the Schiff base with 15N-2-methylaspartic acid (3a) and their complexes with proton donors such as triphenylmethanol, phenol, and carboxylic acids of increasing strength were studied. With the use of hydrogen bond correlation techniques, the 1H/15N chemical shift and scalar coupling data could be associated with the geometries of the intermolecular O1H1N1 (pyridine nitrogen) and the intramolecular O2H2N2 (Schiff base) hydrogen bonds. Whereas O1H1N1 is characterized by a series of asymmetric low-barrier hydrogen bonds, the proton in O2H2N2 faces a barrier for proton transfer of medium height. When the substituent on the Schiff base nitrogen is an aromatic ring, the shift of the proton in O1H1N1 from oxygen to nitrogen has little effect on the position of the proton in the O2H2N2 hydrogen bond. By contrast, when the substituent on the Schiff base nitrogen is a methyl group, a proton shift from O to N in O1H1N1 drives the tautomeric equilibrium in O2H2N2 from the neutral O2-H2⋯N2 to the zwitterionic O2-⋯H2- N2+ form. This coupling is lost in aqueous solution where the intramolecular O2H2N2 hydrogen bond is broken by solute-solvent interactions. However, in methanol, which mimics hydrogen bonds to the Schiff base in the enzyme active site, the coupling is preserved. Therefore, the reactivity of Schiff base intermediates in pyridoxal-5′-phosphate enzymes can likely be tuned to the requirements of the reaction being catalyzed by differential protonation of the pyridine nitrogen.

AB - The 1H and 15N NMR spectra of several 15N-labeled pyridoxal-5′-phosphate model systems have been measured at low temperature in various aprotic and protic solvents of different polarity, i.e., dichloromethane-d2, acetonitrile-d3, tetrahydrofuran-d8, freon mixture CDF3/CDClF2, and methanol. In particular, the 15N-labeled 5′-triisopropyl- silyl ether of N-(pyridoxylidene)-tolylamine (1a), N-(pyridoxylidene)- methylamine (2a), and the Schiff base with 15N-2-methylaspartic acid (3a) and their complexes with proton donors such as triphenylmethanol, phenol, and carboxylic acids of increasing strength were studied. With the use of hydrogen bond correlation techniques, the 1H/15N chemical shift and scalar coupling data could be associated with the geometries of the intermolecular O1H1N1 (pyridine nitrogen) and the intramolecular O2H2N2 (Schiff base) hydrogen bonds. Whereas O1H1N1 is characterized by a series of asymmetric low-barrier hydrogen bonds, the proton in O2H2N2 faces a barrier for proton transfer of medium height. When the substituent on the Schiff base nitrogen is an aromatic ring, the shift of the proton in O1H1N1 from oxygen to nitrogen has little effect on the position of the proton in the O2H2N2 hydrogen bond. By contrast, when the substituent on the Schiff base nitrogen is a methyl group, a proton shift from O to N in O1H1N1 drives the tautomeric equilibrium in O2H2N2 from the neutral O2-H2⋯N2 to the zwitterionic O2-⋯H2- N2+ form. This coupling is lost in aqueous solution where the intramolecular O2H2N2 hydrogen bond is broken by solute-solvent interactions. However, in methanol, which mimics hydrogen bonds to the Schiff base in the enzyme active site, the coupling is preserved. Therefore, the reactivity of Schiff base intermediates in pyridoxal-5′-phosphate enzymes can likely be tuned to the requirements of the reaction being catalyzed by differential protonation of the pyridine nitrogen.

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