1. 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

2. 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.

3. 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.

4. RUHR-UNIVERSITÄT BOCHUM
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,

5. RUHR-UNIVERSITÄT BOCHUM
Sulfonamides studied
Sulfonamide drugs with bacteriostatic activity

6. RUHR-UNIVERSITÄT BOCHUM
Sulfonamides studied
Conformational preference upon microhydration: Sulfonamide–(H2O)1

7. RUHR-UNIVERSITÄT BOCHUM
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

8. RUHR-UNIVERSITÄT BOCHUM
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)

9. 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,

10. RUHR-UNIVERSITÄT BOCHUM
Sulfanilamide
2D-PES‘s for interconversion between conformers
Inversion
Rotation
xsulf
xanil
M05-2X/6-311G(3df,3pd)

11. 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, .

12. 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

13. 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.

14. 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.

15. 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

16. 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.

17. 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)

18. 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)

19. 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.

20. 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

21. 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

22. 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

23. RUHR-UNIVERSITÄT BOCHUM
Sulfanilamide dimer
Assignment of the single-conformation IR spectrum

24. RUHR-UNIVERSITÄT BOCHUM
Sulfamethoxazole & Sulfisoxazole
Single-conformation UV and IR spectra
Sulfamethoxazole
Sulfisoxazole
M05-2X/6-31+G(d)

25. RUHR-UNIVERSITÄT BOCHUM
Sulfamethoxazole–H2O & Sulfisoxazole–H2O
Single-conformation UV and IR spectra
Sulfamethoxazole
Sulfisoxazole
M05-2X/6-31+G(d)

26. RUHR-UNIVERSITÄT BOCHUM
Sulfamethizole & Sulfamethizole–H2O
Single-conformation UV and IR spectra
M05-2X/6-31+G(d)

27. RUHR-UNIVERSITÄT BOCHUM
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”