NMR CRYSTALLOGRAPHY: NMR CRYSTALLOGRAPHY: The new application of combined theoretical The new application of combined theoretical

and spectroscopic approach for structural and spectroscopic approach for structural description in the solid statedescription in the solid state

Anife Ahmedova, Miroslava Nedyalkova, Mariana MitewaUniversity of Sofia

Vladislav AntonovInstitute for Nuclear Research and Nuclear Energy

NMR NMR CRYSTALLOGRAPHYCRYSTALLOGRAPHY

NMR experimentsin the solid state

Single-crystal or powder diffraction

CALCULATIONS

To define a space group, conformational changesor even structural parameters

Application to structural biology, organic and pharmaceutical chemistry,

inorganic and materials chemistry

Commonly studiedrelation

Structural data

Spectroscopic and/or biological experiments

Theoretical calculations

Frequently ignoreddetails !!!

Solid state (crystal or powder)

solution

Gas phase

What are hydantoinsandWhy hydantoins

•Hydantoin derivatives are well known for their medical applications, e.g. as:•antiepileptic drugs [D. Janz, Der Nervenarzt 21 (1950) 113; T. C. Butler, W. J. Waddell, J. Pharm. Exp.

Therapeut. 110 (1954) 120.] Phenytoin, Mephenytoin•Antiproliferative activity [C. S. A. Kumar, et al., Inv. New Drugs 27 (2009) 131;

C.V. Kavitha, et al., Biochem. Pharmacol. 77 (2009) 348.]•inhibition of aldosoreductase [R. Sarges, R. C. Schnur, J. L. Belletire, M. J. Peterson, J. Med. Chem. 31

(1988) 230.]•and potential application for treatment of HIV-1 infections [D. Kim, et al., Bioorg. Med.

Chem. Lett. 11 (2001) 3099.; D. Kim, et al., Bioorg. Med. Chem. Lett. 11 (2001) 3103.].

NN

Y

XR2

R1

H

H1

2

345

X, Y = O or Simidazolidineimidazolidine--2,42,4--dionedione(by IUPAC)(by IUPAC)

Metal-ion coordination ability,Biological activity,

BUTCorrect structure – for correct conclusions !!!!

Hydantoins vs thio-hydantoins

NH

HN S

S

CX8 01

NH

HNS

S

CX10002n = 2 - 5; 3 - 6

Structure of the studied Spiro-dithio-hydantoins

N

N

S

S

H

H(CH2)n

1

2

345

The crystal structure of the non-coordinated dithio-hydantoinsis available

However,none of their metal complexes could be crystallized

Biologicalactivity

Spectroscopicproperties

Biologicalactivity

structureSpectroscopicproperties

structure

Focus on the 13C NMR shifts of C2-, C4- and C5-carbon

atoms in the hydantoin ring

13C NM shielding constants (GIAO-B3LYP/6-31G**)Of the free ligands vs of the complexes

13C CPMAS NMR spectraOf the free ligands vs of the complexes

Gas-phase optimized structures (B3LYP/6-31G**)Of the free ligands vs models of the complexes

suggestThe best model structure of the complexes

1 A. Ahmedova, P. Marinova, K. Paradowska, M. Marinov, I. Wawer, M. Mitewa, Polyhedron 29 (2010) 1639-1645.2 A. Ahmedova, P. Marinova, K. Paradowska, N. Stoyanov, I. Wawer, M. Mitewa, Inorg. Chim. Acta 363 (2010) 3919-3925.

Infinite H-bond network in the crystal structures of compounds 2 – 6

All C2=S2 groupsare involved in 2 inter-molecular H bondings

C4=S4 groups do not form inter-molecular H bonds

All N-H groups participate in inter-molecular H bonds

INTERMOLECULAR INTERACTIONS AND THE CONSEQUENCES

Expected stronger H bonds in the solid state than in solutionand

Elongation of the corresponding bondsand

Less shielding of the corresponding C atoms

!!! Pay attention to the non-innocent role of the solvent

13C CPMAS NMR spectrum

13C NMR shifts in ppm in solid state and in DMSO

1

2

345

N

N

S

S

H

H6

78

9

1011 12

213.1 180.2 81.5

cy8

35.9 – 25.1

13C NMR shifts in DMSO

212.7 179.6 78.4 34.9 – 20.8

1

2

345

N

N

S

S

H

H

678

910 11

13C CPMAS NMR spectrum

211.8

cy7

40.2 – 22.9177.6

213.5 179.6 40.1 – 22.1

13C NMR shifts in ppm in solid state and in DMSO

13C NMR shifts in DMSO

79.1

81.1

1

2

345

N

N

S

S

H

H6

7

89

10

13C CPMAS NMR spectrumcy6

13C NMR shifts in ppm in solid state and in DMSO

13C NMR shifts in DMSO

209.2 178.8 79.540.2 - 23.0

211.8 180.0 77.1 36.7 – 20.8

13C NMR shifts in ppm in solid state and in DMSO

13C NMR shifts in DMSO

13C CPMAS NMR spectrumcy5

212.5179.3

83.341.8 25.3

210.0178.0

85.545.5;42.0

27.8;25.4

209.6

178.929.325.4

84.1

42.3

in CDCl3

NH

HN S

S

280 260 240 220 200 180 160 140 120 100 80 60 40 20 ppm

** * * * *

C4 C2 C5

13C NMR shifts in ppm in solid state and in DMSO

13C NMR shifts in DMSO

13C CPMAS NMR spectrum

203.8 182.3

130.0 - 121.8

85.7

206.8 182.8

144.2 – 123.9

84.8

NO X-ray structure

13C CPMAS NMR spectrumcy4

13C NMR shifts in ppm in solid state and in DMSO

13C NMR shifts in DMSO

182.5 157.762.8

33.8 15.1

178.5 155.960.9

32.1 13.2

Powder diffraction data

Gas-phase modelsof crystal packing

Solid-statecalculations

Structure &13C NMR shiftsin gas phase

Structure & 13C NMR shiftsin solution (DMSO)

Solid-state 13C NMRSolution 13C NMR (DMSO)

Single crystal X-ray diffraction

EXPERIMENTAL DATA

CALCULATIONS

??? How do intermolecular interactions affect the structural and spectroscopic data ???

Compare structural parameters in the hydantoin ring13C NMR shifts of C2-, C4- and C5-carbon atoms

X-ray data vs gas-phase optimizations (B3LYP/6-31G**) ofisolated molecules and

trimers connected via intermolecular H bonding

13C NMR in DMSO-d6 vs calculated (GIAO-B3LYP/6-31G**) and in solid state shielding constants in gas phase(CPMAS) in DMSO media (IEF-PCM)

or of the optimised trimers

13C NMR shiftsC5 – 79.5 ppmCPMAS: C4 – 209.2 ppm C2 – 178.8 ppm

GIAO-DFT: C5 – 78.1 ppm C4 – 207.0 ppm C2 – 175.0 ppm

EXP in DMSOC5 – 77.1 ppmC4 – 211.8 ppmC2 – 180.0 ppm

CALC in DMSOC5 – 80.8 ppmC4 – 212.0 ppmC2 – 176.6 ppm

1.628 Å

1.665 Å

1.353 Å

1.382 Å

1.320 Å

X-ray data 1.646 Å

1.360 Å

1.398 Å

1.348 Å1.657 Å

Isol.mol.calc.

cy6

1.628 Å

1.665 Å

1.353 Å

1.382 Å

1.320 Å

X-ray data 1.645 Å

1.365 Å

1.333 Å1.689 Å

CALC Trimer

13C NMR shiftsC5 – 79.5 ppmCPMAS: C4 – 209.2 ppm C2 – 178.8 ppm

GIAO-DFT: C5 – 80.1 ppm C4 – 209.0 ppm C2 – 177.2 ppm

1.384 Å

cy6

13C NMR shiftsC5 – 81.1 ppmCPMAS: C4 – 211.8 ppm C2 – 177.6 ppm

GIAO-DFT: C5 – 79.8 ppm C4 – 209.2 ppm C2 – 174.2 ppm

EXP in DMSOC5 – 79.1 ppmC4 – 213.5 ppmC2 – 179.6 ppm

CALC in DMSOC5 – 82.6 ppmC4 – 214.0 ppmC2 – 175.8 ppm

1.626 Å

1.668 Å

1.349 Å

1.380 Å

1.317 Å

X-ray data 1.647 Å

1.360 Å

1.398 Å

1.347 Å

1.657 Å

Isol.mol.calc.

Cy7

1.626 Å

1.668 Å

1.349 Å

1.317 Å

X-ray data 1.645 Å

1.365 Å

1.331 Å1.689 Å

13C NMR shiftsC5 – 81.1 ppmCPMAS: C4 – 211.8 ppm C2 – 177.6 ppm

GIAO-DFT: C5 – 81.2 ppm C4 – 211.1 ppm C2 – 176.0 ppm

Cy7

CALC Trimer

1.384 Å1.380 Å

3D Calculations ☺

Calculation of periodic structures with DFT

Use of plane waves and ultrasoft pseudopotentials(GGA PBE functional)

The relaxed structures were used for the calculations of the nuclear magnetic resonance (NMR) chemical shifts of 13C nuclei via the GIPAW method (gauge-

including projector augmented wave )

Calculations were performed in the three main groups:•for isolated molecules•for layers•for bulk materials

The energies of the interaction between the molecules in the bulk Emb per one molecule were calculated using the following equation:

Emb=(Ebulk-Nb.Emol)/Nb

0 50 100 150 2000

50

100

150

200

250

R=0,9997

CPMAS 13C NMR shiftsQ

E c

alcu

late

d fo

r bul

k

cy6

0 50 100 150 200 2500

50

100

150

200

250

R=0,9998

QE

cal

cula

ted

for b

ulk

CPMAS 13C NMR shifts

cy7

0 20 40 60 80 100 120 140 160 180 2000

50

100

150

200

QE

cal

cula

ted

for b

ulk

CPMAS 13C NMR shifts

R=0,9995

cy4

NO single-crystal X-ray structure available

Solid-state (QE) calculations were usedto REFINE

the initial powder diffraction data

Acknowledgements

Prof. I. WawerDr. K. Paradowska Dr. R. Petrova

Dr. B. ShivachevDr. G.Pavlovic

Prof.Ana Proykova for calculation timeon PHYSON computer cluster

NATIONAL SCIENCE FUNDMinistry of Education and Science

NH

HN S

S

Get the solid-statestructure