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Conformer-specific IR spectroscopy of laser-desorbed sulfonamide drugs:
Tautomeric and conformational preferences of sulfanilamide and its derivatives Thomas Uhlemann, Sebastian Seidel, Christian Müller 72nd ISMS, University of Illinois at Urbana-Champaign
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RUHR-UNIVERSITÄT BOCHUM
Sulfonamides Sulfanilamide: The progenitor of the sulfonamide drug family Antibiotic 1935 Gerhard Domagk 1942 1955 Hypo- glycemic Nobel Prize in Physiology or Medicine 1939 “for the discovery of the antibacterial effects of prontosil” Diuretic 1949 1957 Antihypertensive J. Drews, Science, 2000, 287, 1960.
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RUHR-UNIVERSITÄT BOCHUM
Single-Conformation Infrared Spectroscopy Determining conformational structures Mass-selected UV spectrum through resonantly enhanced two-photon ionization. Conformation-specific UV spectra through IR/UV–UV hole-burning spectroscopy. Conformation-specific IR spectra through IR– UV double-resonance spectroscopy. or Conformation-specific Raman spectra through stimulated Raman–UV double-resonance spectroscopy.
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Laser desorption setup Vaporization of nonvolatile or thermolabile compounds desorption laser pulsed valve graphite rod sample probe & load lock assembly translation & rotation stage M. Taherkhani et al., Rev. Sci. Instrum., 2010, 81,
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Sulfonamides studied Sulfonamide drugs with bacteriostatic activity
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Sulfonamides studied Conformational preference upon microhydration: Sulfonamide–(H2O)1
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Sulfonamides and the sulfonamide group Topics for single-conformation studies Conformational preferences and flexibility Tautomeric preferences Types, strengths, and nature of noncovalent intra- and intermolecular interactions
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Sulfanilamide Conformers: Sulfonamide and anilinic NH2 inversion coordinates sulfonamide NH2 eclipsed anilinic NH2 up anilinic NH2 down sulfonamide NH2 staggered M05-2X/ G(3df,3pd)
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Sulfanilamide Single-conformation UV and IR spectra
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide Single-conformation UV and IR spectra One conformer present in the molecular beam. Same as has been found in an matrix isolation study. S1←S0 electronic origin red-shifted by only −138 cm−1 from the electronic origin of aniline. Scaled harmonic frequencies calculated at the M05-2X/ G(3df,3pd) level of theory A. Borba et al., J. Phys. Chem. A, 2013, 117, 704 T. Uhlemann et al., Phys. Chem. Chem. Phys., 2017, 19,
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Sulfanilamide 2D-PES‘s for interconversion between conformers Inversion Rotation xsulf xanil M05-2X/6-311G(3df,3pd)
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Sulfanilamide Potential energy curves for conformational isomerization
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide Potential energy curves for conformational isomerization From the zero-point level wave functions 2:2’:1:1’ conformer probabilities of 47%:30%:14%:9% can be estimated. The anilinic NH2 group can be regarded as quasi-planar. Potential energy curves calculated at the M05-2X/ G(3df,3pd) level of theory T. Uhlemann et al., Phys. Chem. Chem. Phys., 2017, 19, .
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Sulfanilamide–H2O Single-conformation UV and IR spectra
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide–H2O Single-conformation UV and IR spectra One isomer present in the molecular beam. S1←S0 electronic origin blue-shifted by +71 cm−1 from the electronic origin of the monomer. Scaled harmonic frequencies calculated at the M05-2X/ G(3df,3pd) level of theory
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Sulfanilamide–H2O Assignment of the single-conformation IR spectrum
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide–H2O Assignment of the single-conformation IR spectrum Lowest-energy SA–H2O structures calculated at the M05-2X/ G(3df,3pd) level of theory The symmetric and asymmetric sulfonamide NH2 vibrations are red- shifted by −56 cm−1 and −12 cm−1 relative to those of the SA monomer.
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Sulfanilamide–H2O Assignment of the single-conformation IR spectrum
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide–H2O Assignment of the single-conformation IR spectrum Lowest-energy SA–H2O structures calculated at the M05-2X/ G(3df,3pd) level of theory The symmetric and asymmetric sulfonamide NH2 vibrations are red- shifted by −56 cm−1 and −12 cm−1 relative to those of the SA monomer.
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RUHR-UNIVERSITÄT BOCHUM
Sulfanilamide–H2O Quantum Theory of Atoms in Molecules (QTAIM) analysis M05-2X/ G(3df,3pd) Molecular graph Virial graph Espinosa-Molins-Lecomte prescription: 𝐸 HB = 1 2 𝑉( 𝐫 BCP ) E. Espinosa et al., Chem. Phys. Lett., 1998, 285, 170. OH···O NH···O CH···O −6.55 −4.02 −1.50 kcal/mol −12.07 kcal/mol Ecompl = −11.26 kcal/mol
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RUHR-UNIVERSITÄT BOCHUM
Interacting Quantum Atoms (IQA) An energy decomposition method based on QTAIM atoms Binding energy between two atoms/functional groups/molecules A and B with the atomic/functional group/molecular deformation energies and the total interaction energy between two atoms/ functional groups/molecules cl xc X corr – classical exchange-correlation exchange correlation M.A. Blanco, A. Martín Pendás, E. Francisco, J. Chem. Theory Comput., 2005, 1, 1096. AIMAll, Todd A. Keith, TK Gristmill Software, Overland Parks KS, USA, 2016.
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EML hydrogen bond energy
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide–H2O Interacting Quantum Atoms (IQA) analysis (kcal/mol) EML hydrogen bond energy EHB = −12.90 kcal/mol Ecompl = −11.56 kcal/mol Complexation energy M06-2X/ G(3df,3pd)
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EML hydrogen bond energy
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide–H2O Interacting Quantum Atoms (IQA) analysis (kcal/mol) EML hydrogen bond energy EHB = −12.90 kcal/mol Ecompl = −11.56 kcal/mol Complexation energy M06-2X/ G(3df,3pd)
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EML hydrogen bond energy
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide–H2O Interacting Quantum Atoms (IQA) analysis (kcal/mol) EML hydrogen bond energy EHB = −12.90 kcal/mol Ecompl = −11.56 kcal/mol Complexation energy The hydrogen bonds the sulfonamide group engages in upon water complexation are dominated by the short-range exchange-correlation contribution.
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Sulfanilamide dimer Single-conformation UV and IR spectra
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide dimer Single-conformation UV and IR spectra One isomer present in the molecular beam. S2←S0 electronic origin blue-shifted by +152 cm−1 from the electronic origin of the monomer. Scaled harmonic frequencies calculated at the M05-2X/ G(3df,3pd) level of theory
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Sulfanilamide dimer Assignment of the single-conformation IR spectrum
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide dimer Assignment of the single-conformation IR spectrum Lowest-energy SA dimer structures calculated at the M05-2X/ G(3df,3pd) level of theory
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Sulfanilamide dimer Assignment of the single-conformation IR spectrum
RUHR-UNIVERSITÄT BOCHUM Sulfanilamide dimer Assignment of the single-conformation IR spectrum Lowest-energy SA dimer structures calculated at the M05-2X/ G(3df,3pd) level of theory
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Sulfanilamide dimer Assignment of the single-conformation IR spectrum
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Sulfamethoxazole & Sulfisoxazole Single-conformation UV and IR spectra Sulfamethoxazole Sulfisoxazole M05-2X/6-31+G(d)
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Sulfamethoxazole–H2O & Sulfisoxazole–H2O Single-conformation UV and IR spectra Sulfamethoxazole Sulfisoxazole M05-2X/6-31+G(d)
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Sulfamethizole & Sulfamethizole–H2O Single-conformation UV and IR spectra M05-2X/6-31+G(d)
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Acknowledgements Deutsche Forschungsgemeinschaft Christian W. Müller Sebastian Seidel “This work is supported by the Cluster of Excellence RESOLV (EXC 1069) funded by the Deutsche Forschungsgemeinschaft”
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