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Quantum chemical conformational analysis and X-ray structure of 4-methyl-3-thiosemicarbazide
ELSEVIER
THEO CHEM Journal of Molecular Structure (Theochem) 388 (1996) 161-167
Quantum chemical conformational analysis and X-ray structure of 4 -methyl -3 -thiosemicarbazide Candee C. Chambers a'*, Edet F. Archibong b, Sam M. Mazhari b, Ali Jabalameli h, Jeffrey D. Zubkowski b, Richard H. Sullivan b, Edward J. Valente c, Christopher J. Cramer d, Donald G. Truhlar d aArmy High Performance Computing Research Center and Department of Chemistry, Universityof Minnesota, Minneapolis, MN 55415, USA bDepartment of Chemistry, Jackson State University,Jackson, MS 39217, USA CDepartment of Chemistry, Mississippi College, Clinton, MS 39058, USA dDepartment of Chemistry, Supercomputer Institute and Army High Performance Computing Research Center, University of Minnesota, Minneapolis, MN 55455-0431, USA
Received 27 February 1996; accepted 15 April 1996
Abstract We present X-ray crystallographic results and gas-phase electronic structure calculations of the geometry of 4-methyl-3thiosemicarbazide. Using the Hartree-Fock theory with a 6-31G' basis set, we calculated relative energies for eight different conformations. For the lowest-energy conformations of each of the four possible combinations of rotamers about the two C-N bonds, we also included electron correlation by M¢ller-Plesset second-order (MP2) perturbation theory with the same basis set. From these calculations, we selected the lowest-energy structure and calculated structural parameters at the MP2 level of theory with the larger correlation-consistent cc-pVDZ basis set. The geometry of the minimum-energy gas-phase structure is in good agreement with the structure observed experimentally in the crystal. Keywords: Crystal; Potential energy surface; Rotamers; Thiourea
1. Introduction Internal rotational barriers of ureas [1-5], thioamides [6,7] and thioureas [1,8-10] have been widely studied. There are many reasons for the interest in such molecules. For example, urea and some of its derivatives denature proteins. In addition, the conformational issues in these molecules are analogous to those arising in folded proteins and polypeptides.
* Corresponding author. Current address: Departments of Physics and Chemistry, Mercyhurst College, Erie, PA 16546, USA.
Furthermore, it has been shown [11] that there is a relationship between the structure of certain thiosemicarbazides and their biological activity. In particular, various thiosemicarbazides have been shown to induce osteolathyrism (the failure of connective tissue to polymerize properly [12]). A first step towards understanding the conformational isomerism of molecules in solution is to understand their intrinsic conformational preferences in the gas-phase. Here, we present results for the gas-phase conformational energetics of a derivative of thiourea, 4-methyl-3-thiosemicarbazide. In particular, we present relative energies for eight chemically relevant
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C.C. Chambers et aL /Journal of Molecular Structure (Theochem ) 388 (1996) 161-167
conformers. X-ray crystallographic results presented and compared to the calculations.
are
2. Experimental A crystalline sample of the compound was mounted atop a glass fiber with epoxy glue. Data was collected on a Siemens R3m/V automated diffractometer fitted with a molybdenum source and a graphite monochromator. Diffractometer data collection was controlled by P3-PC version (Siemens, Madison, WI, USA). Automatic peak search and indexing procedures yielded a monoclinic reduced primitive cell. Inspection of the Niggli values revealed no conventional cell of higher symmetry. Data was collected using omega scans ( + 1°) from 3.5 < 20 < 70 ° giving 4477 independent reflections of which 2577 reflections were observed (F > 4.0 a(F)). The structure was determined using direct methods (SHELXS-86 [13]) and refined by full-matrix leastsquares methods (SHELXL-93 [14]). In a difference Fourier map calculated following the refinement of all non-hydrogen atoms with anisotropic vibrational parameters, features were found corresponding to the positions of the hydrogen atoms. Their positions and isotropic vibrational amplitudes were refined. The hydrogens on the methyl groups, C5 and C10, were disordered over alternate 3-fold positions. The final R l was 0.0382 for 124 variables (wR 2 = 0.1013: goodness-of-fit = 0.900), and the final difference features did not exceed +0.340 and -0.211 e- .~-3. The crystallographic data, atomic coordinates and equivalent isotropic displacement parameters, bond lengths, bond angles, and dihedral angles are given in Tables 1-3, respectively. Fig. 1 shows the structure of the two molecules in the unit cell.
3. Computational methods Gas-phase energies of 4-methyl-3-thiosemicarbazide were calculated by ab initio electronic structure methods using the Gaussian92/DFT [15] computer program. Difficulties were encountered in optimizing two of the structures at the lower level of theory used in this study. We were able to optimize these problematic structures by using Cartesian coordinates and
Table 1 Crystallographic data for 4-methyl-3-thiosemicarbazide Empirical formula: C2H7N3S Formula weight: 105.17 Space group P21/c, (#14) a = 6.0090(10)/k b = 8.937(2) A c = 19.012(4) .~ fl = 92.82(2) ° T = 292(2) K
)~ = 0.71073 .~ V = 1019.8(4) ~3 Z=8 Density (calculated) = 1.370 Mg/m 3 RI[I > 2o(/)1 a ~ 0.0382 wR 2 = 0.1013 Goodness-of-fit b on F 2 = 0.900 Extinction coefficient = 0.016(2)
~Rl=~l[Fol_lFcll/~lFol~wR2=
[ (wFo-Fc) / Y(wFo)] 2
b Goodness_of_Fit = [ ~(wlFol 2 -IFcl 2) 2
2 2
4
1/2
/(no-nv)]
71/2 whereno
= number of observations, nv = number of parameters and w = weights. Weight = 1/[tr2(F2) + 0.0589P) 2], where P = (max(F~,O) + 2F2)/3.
the Gamess [16] computer program. The final energies of these structures were confirmed with Gaussian92/DFT. Relative energies were calculated at the Hartree-Fock (HF) level of theory [17] using the polarized basis set, 6-31G* [18] for eight different conformers, derived from internal rotations about the N - N bond and the two thioamide C - N bonds. All of these structures are shown in Fig. 2. The lowest energy conformers for the four possible combinations of rotations about the C - N bonds were then calculated using second-order M¢ller-Plesset perturbation theory (MP2) [17], again utilizing the 6-31G" basis set. Finally, the lowest in energy of these conformations was calculated at the MP2 level of theory using the Table 2 Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (,~2 x 103) for 4-methyl-3-thiosemicarbazide
S(1) S(2) N(1) N(2) C(3) N(4) C(5) N(6) N(7) C(8) N(9) C(10)
x
y
z
U(eq)
4994(1) 329(1) 10382(2) 8700(2) 7002(2) 7041(2) 5375(2) -5168(2) -3375(2) -1796(2) -1999(2) -472(2)
-3095(1) 1864(1) -620(1) -1679(1) -1794(1) -878(1) -803(2) 4299(1) 3373(1) 2986(1) 3527(1) 3209(2)
-2289(1) -827(1) -2390(1) -2532(1) -2099(1) -1556(1) -1034(1) -914(1) -1089(1) -600(1) 43(1) 635(1)
46(1) 47(1) 56(1) 49(1) 36(1) 39(1) 55(1) 44(1) 45(1) 36(1) 42(1) 55(1)
U(eq) is defined as one third of the trace of the orthogonalized U tensor.
163
C.C. Chambers et al./Journal of Molecular Structure (Theochem) 388 (1996) 161-167 Table 3 Bond lengths (,~) and angles (degrees) for 4-methyl-3-thiosemicarbazide from the X-ray crystallographic experiment"
Molecule 1
Molecule 2
S(1)-C(3) N(1)-N(2) N(2)-C(3) C(3)-N(4) N(4)-C(5) C(3)-N(2)-N(1) N(4)-C(3)-N(2) N(4)-C(3)-S(1) N(2)-C(3)-S(1) C(3)-N(4)-C(5) N(1)-N(2)-C(3)-N(4) N(1)-N(2)-C(3)-S(1) N(2)- C(3)-N(4)-C(5 ) S(1)-C(3)-N(4)-C(5)
1.7018(11) 1.4008(14) 1.345(2) 1.3172(14) 1.445(2) 119.76(10) 116.57(10) 125.16(9) 118.27(8) 125.53(10) -0.20(16) -179.98(9) 179.21(11) -1.02(16)
S(2)-C(8) N(6)-N(7) N(7)-C(8) C(8)-N(9) N(9)-C(10) C(8)-N(7)-N(6) N(9)-C(8)-N(7) N(9)-C(8)-S(2) N(7)-C(8)-S(2) C(8)-N(9)-C(10) N(6)-N(7)-C(8)-N(9) N(6)-N(7)-C(8)-S(2) N(7)- C(8)-N(9)-C(10) S(2)-C(8)-N(9)-C(10)
1.6962(11) 1.4116(14) 1.3412(14) 1.3246(14) 1.4448(14) 120.65(9) 116.85(10) 123.72(8) 119.43(8) 124.24(10) -0.79(15) 179.90(8) 179.08(11) -1.43(16)
a The two molecules are the two non-identical molecules in the unit cell.
correlation-consistent polarized valence-double-zeta basis set, abbreviated cc-pVDZ [19]. They are labelled based on the conformations of three bonds from left to right (see Fig. 2), i.e. based on the conformations of the N - N , N - C and C - N bonds, respectively. Syn and anti refer to the orientation of the lone pair on the -NH2 group with respect to the C N bond. The first E or Z refers to the NNCS dihedral N(6)
(~
N(7 C(8}
~ C1101 ~S(2)
E or Z refers to the
CNCS
4. Results and discussion Initially we examined eight possible conformations, shown in Fig. 2. Each row of the figure has structures corresponding to a distinct pair of internal rotations about the thioamide C - N bonds. The two structures in each row are obtained by rotating the terminal amino group about the N - N bond. The syn,E,Z motif corresponds to the structure found in the X-ray crystallographic study. In Table 4, we present the absolute and relative energies for the Table 4 Energies of various conformers of 4-methyl-3-thiosemicarbazide (including -NH2 rotations) at the HF/6-31G* level
o•_51
_~ 5Ill
N(41
N(ll ~ Fig. 1. Structures observed in the X-ray crystallographic study, showing the two independent molecules in the unit cell (ORTEP plot, 50% thermal ellipsoids, hydrogens are spheres of arbitrary
size).
angle, and the second dihedral angle.
Energy Conformer
Absolute"
Relative b
syn,E,E anti,E,E syn,E,Z anti,E,Z syn,Z,E anti, Z,E syn,Z,Z anti,Z,Z
-640.63020 -640.62620 -640.64075 -640.63354 -640.62229 -640.63686 -640.62166 -640.63580
6.62 9.13 0.00 4.53 11.59 2.45 11.98 3.11
a Hartrees. b kcal/mol.
164
CC. Chambers et al./Journal of Molecular Structure (Theochem) 388 (1996) 161-167
H~N~
CH'~
H"I
I
H
H
/ N T N "
~ N x~''"H
"
]'~H H
H
/N_
"
N~
T
S
S
syn,E,E
anti, E,E
H ' ° N~
H
/N
N,,,,,,,. CH 3
N
N S
syn, E,Z
anti, E,Z
H
CH3
H
I
I
l
-- jN
CH 3
I
N
H
syn,ZE
H
H
~ N~,,..H
S
S
is in the E conformation (structures syn,E,E, anti,E,E, syn,E,Z and anti,E,Z), the lower-energy conformation
~H~
anti, Z, E
H
CH3
s
s
syn,Z Z
anti, Z, Z
Fig. 2. Eight different conformers of 4-methyl-3-thiosemicarbazide as calculated at the HF/6-31G* level. The conformational notations are labelled as they appear in the molecule from left to right. Syn and anti refer to the position of the lone pair on the NH2 nitrogen relative to the N-C bond. The first E or Z refers to the conformation about the N-C bond (relationship of the H2N and S substituents). The second E or Z refers to the conformation about the C-N bond (relationship of the S and CH3 substituents).
stationary points corresponding to all eight structures at the HF/6-31G* level of theory; all of the structures are predicted to have Cs symmetry, i.e. planar backbones, at this level of theory. When the NNCS linkage
is always that which has the lone pair on the nitrogen situated syn to the C - N bond. Thus, structure syn,E,E is lower in energy than structure anti,E,E, and structure syn,E,Z is lower in energy than structure anti,E,Z. This preference is dictated by unfavorable steric interactions between the amino group hydrogen atoms and the methyl group for the anti orientation. In particular, the shortest intramolecular (N)H-H(C) distance is 1.65 A, in the anti,E,E structure, and the shortest (N)H-H(N) distance is 1.36 A in the anti,E,Z structure. Furthermore, when the SCNC linkage is in the Z conformation, there is a favorable electrostatic interaction between the amino group lone pair and the thioamide proton. This contributes to the syn,E,Z conformer being predicted to be the global minimum on the potential-energy surface (vide infra). On the other hand, when the NNCS linkage is in the Z conformation (structures syn,Z,E, anti,Z,E, syn,Z,Z and anti,Z,Z), the conformations that are lower in energy are those that have the nitrogen lone pair anti to the C - N bond. These differences are attributable to electrostatics. The thioamide group is strongly dipolar with negative charge localized on sulfur. The syn amino orientation reinforces this charge separation, while the anti orientation opposes it and is thus lower in energy. This analysis is supported by the molecular dipole moments calculated at the HF/631G* level: 7.7, 5.3, 7.2 and 4.9 D for syn,Z,E, anti,Z,E, syn,Z,Z and anti,Z,Z, respectively. Based on these results, we selected structures syn,E,E, syn,E,Z, anti,Z,E and anti,Z,Z as the most chemically relevant structures (lowest-energy N - N rotamers for the four combinations of rotamers about the thioamide C - N bonds), and we carried out higher-level electronic structure calculations on them. MP2/6-31G* calculations on structures syn,E,E, syn,E,Z, anti,Z,E and anti,Z,Z show that all four structures correspond to local minima on the potentialenergy surface, but now they are predicted to have C1 symmetry. Thus, including electron correlation causes the structures to pyramidalize at the N atoms. Table 5 gives calculated values of the energy (electronic energy plus nuclear repulsion), relative values of the energy, vibrational-rotational-translational (vrt) standard-state enthalpy H, entropy S, and free energy G, and absolute and relative standard-state
165
C.C. Chambers et al./Journal of Molecular Structure (Theochem) 388 (1996) 161-167 Table 5 Energies and thermodynamic functions (298 K) of various conformers of 4-methyl-3-thiosemicarbazide at the MP2/6-31G ° level Conformer
syn,E,E syn,E,Z anti, Z,E anti, Z,Z
Hv~.roc
Energy a Absolute b
Relative c
-641.4935 -641.5034 -641.4999 -641.5002
6.17 0.00 2.15 2.01
S
73.51 73.26 73,27 73.20
vrt.rod
0.0827 0.0838 0.0843 0.0838
G~.r oc,e
o Gtotal,T
48.87 48.29 48.13 48.22
Absolute c
Relative c
-402494.42 -402501.17 -402499.18 -402499.22
6.75 0.00 1.99 1.94
a Electronic plus nuclear repulsion energy. b Hartrees. c kcal mol-1. d kcal mol-1 K-J. Temperature is 298 K.
total free e n e r g i e s for e a c h c o n f o r m e r . T h e v a l u e s are r e l a t e d as
G°vrt, T = H°vrt, T - TS°vrt, T
(1)
and G°total, T = E + G°vrt, T
(2)
w h e r e T i s the temperature. T h e syn, E , Z c o n f o r m a t i o n is
f o u n d to h a v e b o t h the lowest e n e r g y a n d the l o w e s t total free e n e r g y at this level o f theory, w i t h the anti,Z,E, a n d anti, Z , Z c o n f o r m e r s calculated to b e 1.99 a n d 1.94 kcal/ m o l h i g h e r in total free energy, respectively. T h e syn, E , E c o n f o r m e r h a s the h i g h e s t total free e n e r g y o f those c o n f o r m e r s in T a b l e 5; this h i g h e r free e n e r g y m a y derive f r o m u n f a v o r a b l e steric interactions b e t w e e n the t e r m i n a l m e t h y l and a m i n o groups,
Table 6 Comparison of structural data from X-ray crystallographic experiments and MP2/cc-pVDZ calculations Experiment a Molecule 1 Bond Lengths (,~) N-NH2 1.401 H2NHN-C 1.345 S-C 1.702 C-NHCH3 1.317 HN-CH3 1.445 Bond angles (degrees) NNC 119.76 NCN 116.57 NCS (NH2) 118.27 SCN (methyl) 125.16 CNC 125.53 Dihedral angles b (degrees) NNCN -0.2 NNCS 180.0 NCNC 179.2 SCNC -1.0
Calculation Molecule 2
MP2/6-31G'
1.412 1.341 1.696 1.325 1.445
1.413 1.388 1.665 1.342 1.449
120.65 116.85 119.43 123.72 124.24 -0.8 -179.9 179.1 -1.4
118.03 114.26 120.30 125.40 123.01 18.8 -163.4 175.8 -1.9
MP2/cc-pVDZ 1.411 1.392 1.671 1.347 1.449 117.74 114.18 120.51 125.28 122.76 18.9 -163.1 175.9 -2.0
a The two sets of values correspond to the two distinct molecules found in the unit cell. The estimated standard deviations for the experiment are given in Table 3. b The sign convention for a dihedreal angle WXYZrefers to a viewer on the WX side looking clown the XY bond toward YZ. If Z is rotated clockwise from X, the dihedral angle is considered positive.
166
C. C. Chambers et al./J ournal of Molecular Structure (Theochem ) 388 (1996) 161-167
Repeating the MP2 calculation for the syn,E,Z structure with the cc-pVDZ basis set lowers the energy to - 641.5924 Hartrees. Table 6 lists the geometrical parameters obtained at the MP2/cc-pVDZ level for the syn,E,Z structure. Included in Table 6 for comparison with these calculations are selected bond lengths, bond angles and dihedral angles obtained from MP2/6-31G* calculations and from the X-ray data. It is not clear whether the deviations of theory from experiment are due to lack of convergence of the electronic structure calculations with respect to oneelectron basis and/or level of electron correlation, or due to the crystalline environment or both. The geometries of the two molecules in the unit cell agree much better with each other than either agrees with theory. An especially interesting difference of theory and experiment is the degree of nonplanarity, which is much larger in the theory. Some other structural parameters show good agreement of theory and experiment, in particular most bond lengths and bond angles. The most notable differences between the calculated and crystal structures are found for the C=S, H2NHN-C and C-NHCH3 bond lengths. The two molecules found in the unit cell have longer C=S bonds and shorter C - N bonds (where C is the thiocarbonyl C) than are indicated by the calculations. One possible explanation of these differences is based on the following resonance structures: S
I
L
We have presented gas-phase relative energies for eight different conformers of 4-methyl-3-thiosemicarbazide at the HF/6-31G* level of theory and for four of these at the MP2/6-31G* level. The lowest-energy gas-phase stereostructure, syn,E,Z, corresponds to that found experimentally in the crystal. The optimized structure at the MP2/cc-pVDZ level is in generally good agreement (3 degrees for bond angles and 0.008 A for bond lengths) with the experimental structural parameters, but three bond leng!hs show larger deviations in the range 0.02-0.05 A, giving possible evidence for condensed-phase effects on molecular structure.
Acknowledgements The authors are grateful to Kiet Nguyen for assistance with some of the calculations and to Doyle Britton and Thomas Hoye for helpful discussions. This work was sponsored in part by the Army High Performance Computing Research Center under the auspices of the Department of the Army, Army Research Laboratory cooperative agreement number DAAH04-95-2-0003/contract number DAAH04-95C-0008. The content does not necessarily reflect the S-
S-
--.-
5. Summary
---.-
I
+
In the condensed-phase environment, with its higher dielectric constant, the contribution of the charged mesomers is expected to be larger than in the gas-phase, thereby lengthening the C=S bond and shortening the two C - N bonds as is observed. This analysis implies an increased negative charge on S, which is consistent with the presence of three short intermolecular hydrogen-sulfur distances ( - 2 . 5 A) for each molecule in the crystal. Quantitatively similar discrepancies between theory and neutron diffraction crystal data were noted by Jeffrey et al. [20] for thioacetamide and analogously ascribed to intermolecular hydrogen bonding effects on the C=S and C - N bond lengths.
position or the policy of the government, and no official endorsement should be inferred. This work was also supported in part by the National Science Foundation. Authors EJV and JDZ acknowledge the support of the Office of Naval Research.
References [1] K. T6th, P. Bopp, M. Perikyl/i, T.A. Pakkanen and G. Jancs6, J. Mol. Struct. (Theochem), 312 (1994) 93. [2] Y. Zhao, M.K. Raymond, H. Tsai and J.D. Roberts, J. Phys. Chem., 97 (1993) 2910. [3] J.C. Williams and A.E. McDermott, J. Phys. Chem., 97 (1993) 12393.
C.C. Chambers et aL/Journal of Molecular Structure (Theochem) 388 (1996) 161-167
[4] P. Stilbs and M.E. Moseley, J. Magn. Resonance, 31 (1978) 55. [5] G. Barone, G. Castronuovo, C.D. Volpe and V. Elia, J. Solut. Chem., 6 (1977) 117. [6] W.E. Stewart and T.H. Siddall III, Chem. Rev., 70 (1970) 517. [7] J. Sandstr6m, J. Phys. Chem., 71 (1967) 2318. [8] G. Gonz~ilez, N. Yutronic and M. Jara, Spectrochim. Acta, Part A, 46 (1990) 1729. [9] R.H. Sullivan, P. Nix, E.L. Summers and S.L. Parker, Org. Magn. Reson., 21 (1983) 293. [10] G. Vassilev, V. Koleva, M. Ilieva and B. Galabov, J. Mol. Struct., 82 (1982) 35. [11] D.A. Dawson, T.W. Schultz, L.L. Baker and A. Mannar, J. Appl. Toxicol., 10 (1990) 59. [12] H. Selye, Rev. Can. Biol., 16 (1957) 1. [13] G.M. Sheldrick, Acta Crystallogr., 46A (1990) 467. [14] G.M. Sheldrick, Methods Enzymol., in press. [15] Gaussian 92/DFT, Revision G.1, M.J. Frisch, G.W. Trucks, H.B. Schlegel, P.M.W. Gill, B.G. Johnson, M.W. Wong,
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J.B. Foresman, M.A. Robb, M. Head-Gordon, E.S. Replogle, R. Gomperts, J.L. Andres, K. Raghavachari, J.S. Binkley, C. Gonzalez, R.L. Martin, D.J. Fox, D.J. Defrees, J. Baker, J.J.P. Stewart and J.A. Pople, Gaussian, Pittsburg, PA, USA, 1993. Gamess Version ~ 10 Mar. 1995. M.W. Schmidt, K.K. Baldridge, J.A. Boatz, S.T. Elbert, M.S. Gordon, J.H. Jensen, S. Koseki, N. Matsunaga, K.A. Nguyen, S.J. Su, T.L. Windus, M. Dupuis and J.A. Montgomery, J. Comput. Chem., 14 (1993) 1347. W.J. Hehre, L. Radom, P.v.R. Schleyer and J.A. Pople, Ab lnitio Molecular Orbital Theory, Wiley, New York, 1986. P.C. Hariharan and J.A. Pople, Theor. Chim. Acta, 28 (1973) 213; M.M. Francl, W.J. Pietro, W.J. Hehre, J.S. Binkley, M.S. Gordon, D.J. DeFrees and J.A. Pople, J. Chem. Phys., 77 (1982) 3654. T.H. Dunning Jr, J. Chem. Phys., 90 (1989) 1007; D.E. Woon and T.H. Dunning Jr, J. Chem. Phys., 98 (1993) 1358. G.A. Jeffery, J.R. Ruble and J.H. Yates, J. Am. Chem. Soc., 106 (1984) 1571.
THEO CHEM Journal of Molecular Structure (Theochem) 388 (1996) 161-167
Quantum chemical conformational analysis and X-ray structure of 4 -methyl -3 -thiosemicarbazide Candee C. Chambers a'*, Edet F. Archibong b, Sam M. Mazhari b, Ali Jabalameli h, Jeffrey D. Zubkowski b, Richard H. Sullivan b, Edward J. Valente c, Christopher J. Cramer d, Donald G. Truhlar d aArmy High Performance Computing Research Center and Department of Chemistry, Universityof Minnesota, Minneapolis, MN 55415, USA bDepartment of Chemistry, Jackson State University,Jackson, MS 39217, USA CDepartment of Chemistry, Mississippi College, Clinton, MS 39058, USA dDepartment of Chemistry, Supercomputer Institute and Army High Performance Computing Research Center, University of Minnesota, Minneapolis, MN 55455-0431, USA
Received 27 February 1996; accepted 15 April 1996
Abstract We present X-ray crystallographic results and gas-phase electronic structure calculations of the geometry of 4-methyl-3thiosemicarbazide. Using the Hartree-Fock theory with a 6-31G' basis set, we calculated relative energies for eight different conformations. For the lowest-energy conformations of each of the four possible combinations of rotamers about the two C-N bonds, we also included electron correlation by M¢ller-Plesset second-order (MP2) perturbation theory with the same basis set. From these calculations, we selected the lowest-energy structure and calculated structural parameters at the MP2 level of theory with the larger correlation-consistent cc-pVDZ basis set. The geometry of the minimum-energy gas-phase structure is in good agreement with the structure observed experimentally in the crystal. Keywords: Crystal; Potential energy surface; Rotamers; Thiourea
1. Introduction Internal rotational barriers of ureas [1-5], thioamides [6,7] and thioureas [1,8-10] have been widely studied. There are many reasons for the interest in such molecules. For example, urea and some of its derivatives denature proteins. In addition, the conformational issues in these molecules are analogous to those arising in folded proteins and polypeptides.
* Corresponding author. Current address: Departments of Physics and Chemistry, Mercyhurst College, Erie, PA 16546, USA.
Furthermore, it has been shown [11] that there is a relationship between the structure of certain thiosemicarbazides and their biological activity. In particular, various thiosemicarbazides have been shown to induce osteolathyrism (the failure of connective tissue to polymerize properly [12]). A first step towards understanding the conformational isomerism of molecules in solution is to understand their intrinsic conformational preferences in the gas-phase. Here, we present results for the gas-phase conformational energetics of a derivative of thiourea, 4-methyl-3-thiosemicarbazide. In particular, we present relative energies for eight chemically relevant
0166-1280/96/$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved PII S0166-1280(96)04681-7
162
C.C. Chambers et aL /Journal of Molecular Structure (Theochem ) 388 (1996) 161-167
conformers. X-ray crystallographic results presented and compared to the calculations.
are
2. Experimental A crystalline sample of the compound was mounted atop a glass fiber with epoxy glue. Data was collected on a Siemens R3m/V automated diffractometer fitted with a molybdenum source and a graphite monochromator. Diffractometer data collection was controlled by P3-PC version (Siemens, Madison, WI, USA). Automatic peak search and indexing procedures yielded a monoclinic reduced primitive cell. Inspection of the Niggli values revealed no conventional cell of higher symmetry. Data was collected using omega scans ( + 1°) from 3.5 < 20 < 70 ° giving 4477 independent reflections of which 2577 reflections were observed (F > 4.0 a(F)). The structure was determined using direct methods (SHELXS-86 [13]) and refined by full-matrix leastsquares methods (SHELXL-93 [14]). In a difference Fourier map calculated following the refinement of all non-hydrogen atoms with anisotropic vibrational parameters, features were found corresponding to the positions of the hydrogen atoms. Their positions and isotropic vibrational amplitudes were refined. The hydrogens on the methyl groups, C5 and C10, were disordered over alternate 3-fold positions. The final R l was 0.0382 for 124 variables (wR 2 = 0.1013: goodness-of-fit = 0.900), and the final difference features did not exceed +0.340 and -0.211 e- .~-3. The crystallographic data, atomic coordinates and equivalent isotropic displacement parameters, bond lengths, bond angles, and dihedral angles are given in Tables 1-3, respectively. Fig. 1 shows the structure of the two molecules in the unit cell.
3. Computational methods Gas-phase energies of 4-methyl-3-thiosemicarbazide were calculated by ab initio electronic structure methods using the Gaussian92/DFT [15] computer program. Difficulties were encountered in optimizing two of the structures at the lower level of theory used in this study. We were able to optimize these problematic structures by using Cartesian coordinates and
Table 1 Crystallographic data for 4-methyl-3-thiosemicarbazide Empirical formula: C2H7N3S Formula weight: 105.17 Space group P21/c, (#14) a = 6.0090(10)/k b = 8.937(2) A c = 19.012(4) .~ fl = 92.82(2) ° T = 292(2) K
)~ = 0.71073 .~ V = 1019.8(4) ~3 Z=8 Density (calculated) = 1.370 Mg/m 3 RI[I > 2o(/)1 a ~ 0.0382 wR 2 = 0.1013 Goodness-of-fit b on F 2 = 0.900 Extinction coefficient = 0.016(2)
~Rl=~l[Fol_lFcll/~lFol~wR2=
[ (wFo-Fc) / Y(wFo)] 2
b Goodness_of_Fit = [ ~(wlFol 2 -IFcl 2) 2
2 2
4
1/2
/(no-nv)]
71/2 whereno
= number of observations, nv = number of parameters and w = weights. Weight = 1/[tr2(F2) + 0.0589P) 2], where P = (max(F~,O) + 2F2)/3.
the Gamess [16] computer program. The final energies of these structures were confirmed with Gaussian92/DFT. Relative energies were calculated at the Hartree-Fock (HF) level of theory [17] using the polarized basis set, 6-31G* [18] for eight different conformers, derived from internal rotations about the N - N bond and the two thioamide C - N bonds. All of these structures are shown in Fig. 2. The lowest energy conformers for the four possible combinations of rotations about the C - N bonds were then calculated using second-order M¢ller-Plesset perturbation theory (MP2) [17], again utilizing the 6-31G" basis set. Finally, the lowest in energy of these conformations was calculated at the MP2 level of theory using the Table 2 Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (,~2 x 103) for 4-methyl-3-thiosemicarbazide
S(1) S(2) N(1) N(2) C(3) N(4) C(5) N(6) N(7) C(8) N(9) C(10)
x
y
z
U(eq)
4994(1) 329(1) 10382(2) 8700(2) 7002(2) 7041(2) 5375(2) -5168(2) -3375(2) -1796(2) -1999(2) -472(2)
-3095(1) 1864(1) -620(1) -1679(1) -1794(1) -878(1) -803(2) 4299(1) 3373(1) 2986(1) 3527(1) 3209(2)
-2289(1) -827(1) -2390(1) -2532(1) -2099(1) -1556(1) -1034(1) -914(1) -1089(1) -600(1) 43(1) 635(1)
46(1) 47(1) 56(1) 49(1) 36(1) 39(1) 55(1) 44(1) 45(1) 36(1) 42(1) 55(1)
U(eq) is defined as one third of the trace of the orthogonalized U tensor.
163
C.C. Chambers et al./Journal of Molecular Structure (Theochem) 388 (1996) 161-167 Table 3 Bond lengths (,~) and angles (degrees) for 4-methyl-3-thiosemicarbazide from the X-ray crystallographic experiment"
Molecule 1
Molecule 2
S(1)-C(3) N(1)-N(2) N(2)-C(3) C(3)-N(4) N(4)-C(5) C(3)-N(2)-N(1) N(4)-C(3)-N(2) N(4)-C(3)-S(1) N(2)-C(3)-S(1) C(3)-N(4)-C(5) N(1)-N(2)-C(3)-N(4) N(1)-N(2)-C(3)-S(1) N(2)- C(3)-N(4)-C(5 ) S(1)-C(3)-N(4)-C(5)
1.7018(11) 1.4008(14) 1.345(2) 1.3172(14) 1.445(2) 119.76(10) 116.57(10) 125.16(9) 118.27(8) 125.53(10) -0.20(16) -179.98(9) 179.21(11) -1.02(16)
S(2)-C(8) N(6)-N(7) N(7)-C(8) C(8)-N(9) N(9)-C(10) C(8)-N(7)-N(6) N(9)-C(8)-N(7) N(9)-C(8)-S(2) N(7)-C(8)-S(2) C(8)-N(9)-C(10) N(6)-N(7)-C(8)-N(9) N(6)-N(7)-C(8)-S(2) N(7)- C(8)-N(9)-C(10) S(2)-C(8)-N(9)-C(10)
1.6962(11) 1.4116(14) 1.3412(14) 1.3246(14) 1.4448(14) 120.65(9) 116.85(10) 123.72(8) 119.43(8) 124.24(10) -0.79(15) 179.90(8) 179.08(11) -1.43(16)
a The two molecules are the two non-identical molecules in the unit cell.
correlation-consistent polarized valence-double-zeta basis set, abbreviated cc-pVDZ [19]. They are labelled based on the conformations of three bonds from left to right (see Fig. 2), i.e. based on the conformations of the N - N , N - C and C - N bonds, respectively. Syn and anti refer to the orientation of the lone pair on the -NH2 group with respect to the C N bond. The first E or Z refers to the NNCS dihedral N(6)
(~
N(7 C(8}
~ C1101 ~S(2)
E or Z refers to the
CNCS
4. Results and discussion Initially we examined eight possible conformations, shown in Fig. 2. Each row of the figure has structures corresponding to a distinct pair of internal rotations about the thioamide C - N bonds. The two structures in each row are obtained by rotating the terminal amino group about the N - N bond. The syn,E,Z motif corresponds to the structure found in the X-ray crystallographic study. In Table 4, we present the absolute and relative energies for the Table 4 Energies of various conformers of 4-methyl-3-thiosemicarbazide (including -NH2 rotations) at the HF/6-31G* level
o•_51
_~ 5Ill
N(41
N(ll ~ Fig. 1. Structures observed in the X-ray crystallographic study, showing the two independent molecules in the unit cell (ORTEP plot, 50% thermal ellipsoids, hydrogens are spheres of arbitrary
size).
angle, and the second dihedral angle.
Energy Conformer
Absolute"
Relative b
syn,E,E anti,E,E syn,E,Z anti,E,Z syn,Z,E anti, Z,E syn,Z,Z anti,Z,Z
-640.63020 -640.62620 -640.64075 -640.63354 -640.62229 -640.63686 -640.62166 -640.63580
6.62 9.13 0.00 4.53 11.59 2.45 11.98 3.11
a Hartrees. b kcal/mol.
164
CC. Chambers et al./Journal of Molecular Structure (Theochem) 388 (1996) 161-167
H~N~
CH'~
H"I
I
H
H
/ N T N "
~ N x~''"H
"
]'~H H
H
/N_
"
N~
T
S
S
syn,E,E
anti, E,E
H ' ° N~
H
/N
N,,,,,,,. CH 3
N
N S
syn, E,Z
anti, E,Z
H
CH3
H
I
I
l
-- jN
CH 3
I
N
H
syn,ZE
H
H
~ N~,,..H
S
S
is in the E conformation (structures syn,E,E, anti,E,E, syn,E,Z and anti,E,Z), the lower-energy conformation
~H~
anti, Z, E
H
CH3
s
s
syn,Z Z
anti, Z, Z
Fig. 2. Eight different conformers of 4-methyl-3-thiosemicarbazide as calculated at the HF/6-31G* level. The conformational notations are labelled as they appear in the molecule from left to right. Syn and anti refer to the position of the lone pair on the NH2 nitrogen relative to the N-C bond. The first E or Z refers to the conformation about the N-C bond (relationship of the H2N and S substituents). The second E or Z refers to the conformation about the C-N bond (relationship of the S and CH3 substituents).
stationary points corresponding to all eight structures at the HF/6-31G* level of theory; all of the structures are predicted to have Cs symmetry, i.e. planar backbones, at this level of theory. When the NNCS linkage
is always that which has the lone pair on the nitrogen situated syn to the C - N bond. Thus, structure syn,E,E is lower in energy than structure anti,E,E, and structure syn,E,Z is lower in energy than structure anti,E,Z. This preference is dictated by unfavorable steric interactions between the amino group hydrogen atoms and the methyl group for the anti orientation. In particular, the shortest intramolecular (N)H-H(C) distance is 1.65 A, in the anti,E,E structure, and the shortest (N)H-H(N) distance is 1.36 A in the anti,E,Z structure. Furthermore, when the SCNC linkage is in the Z conformation, there is a favorable electrostatic interaction between the amino group lone pair and the thioamide proton. This contributes to the syn,E,Z conformer being predicted to be the global minimum on the potential-energy surface (vide infra). On the other hand, when the NNCS linkage is in the Z conformation (structures syn,Z,E, anti,Z,E, syn,Z,Z and anti,Z,Z), the conformations that are lower in energy are those that have the nitrogen lone pair anti to the C - N bond. These differences are attributable to electrostatics. The thioamide group is strongly dipolar with negative charge localized on sulfur. The syn amino orientation reinforces this charge separation, while the anti orientation opposes it and is thus lower in energy. This analysis is supported by the molecular dipole moments calculated at the HF/631G* level: 7.7, 5.3, 7.2 and 4.9 D for syn,Z,E, anti,Z,E, syn,Z,Z and anti,Z,Z, respectively. Based on these results, we selected structures syn,E,E, syn,E,Z, anti,Z,E and anti,Z,Z as the most chemically relevant structures (lowest-energy N - N rotamers for the four combinations of rotamers about the thioamide C - N bonds), and we carried out higher-level electronic structure calculations on them. MP2/6-31G* calculations on structures syn,E,E, syn,E,Z, anti,Z,E and anti,Z,Z show that all four structures correspond to local minima on the potentialenergy surface, but now they are predicted to have C1 symmetry. Thus, including electron correlation causes the structures to pyramidalize at the N atoms. Table 5 gives calculated values of the energy (electronic energy plus nuclear repulsion), relative values of the energy, vibrational-rotational-translational (vrt) standard-state enthalpy H, entropy S, and free energy G, and absolute and relative standard-state
165
C.C. Chambers et al./Journal of Molecular Structure (Theochem) 388 (1996) 161-167 Table 5 Energies and thermodynamic functions (298 K) of various conformers of 4-methyl-3-thiosemicarbazide at the MP2/6-31G ° level Conformer
syn,E,E syn,E,Z anti, Z,E anti, Z,Z
Hv~.roc
Energy a Absolute b
Relative c
-641.4935 -641.5034 -641.4999 -641.5002
6.17 0.00 2.15 2.01
S
73.51 73.26 73,27 73.20
vrt.rod
0.0827 0.0838 0.0843 0.0838
G~.r oc,e
o Gtotal,T
48.87 48.29 48.13 48.22
Absolute c
Relative c
-402494.42 -402501.17 -402499.18 -402499.22
6.75 0.00 1.99 1.94
a Electronic plus nuclear repulsion energy. b Hartrees. c kcal mol-1. d kcal mol-1 K-J. Temperature is 298 K.
total free e n e r g i e s for e a c h c o n f o r m e r . T h e v a l u e s are r e l a t e d as
G°vrt, T = H°vrt, T - TS°vrt, T
(1)
and G°total, T = E + G°vrt, T
(2)
w h e r e T i s the temperature. T h e syn, E , Z c o n f o r m a t i o n is
f o u n d to h a v e b o t h the lowest e n e r g y a n d the l o w e s t total free e n e r g y at this level o f theory, w i t h the anti,Z,E, a n d anti, Z , Z c o n f o r m e r s calculated to b e 1.99 a n d 1.94 kcal/ m o l h i g h e r in total free energy, respectively. T h e syn, E , E c o n f o r m e r h a s the h i g h e s t total free e n e r g y o f those c o n f o r m e r s in T a b l e 5; this h i g h e r free e n e r g y m a y derive f r o m u n f a v o r a b l e steric interactions b e t w e e n the t e r m i n a l m e t h y l and a m i n o groups,
Table 6 Comparison of structural data from X-ray crystallographic experiments and MP2/cc-pVDZ calculations Experiment a Molecule 1 Bond Lengths (,~) N-NH2 1.401 H2NHN-C 1.345 S-C 1.702 C-NHCH3 1.317 HN-CH3 1.445 Bond angles (degrees) NNC 119.76 NCN 116.57 NCS (NH2) 118.27 SCN (methyl) 125.16 CNC 125.53 Dihedral angles b (degrees) NNCN -0.2 NNCS 180.0 NCNC 179.2 SCNC -1.0
Calculation Molecule 2
MP2/6-31G'
1.412 1.341 1.696 1.325 1.445
1.413 1.388 1.665 1.342 1.449
120.65 116.85 119.43 123.72 124.24 -0.8 -179.9 179.1 -1.4
118.03 114.26 120.30 125.40 123.01 18.8 -163.4 175.8 -1.9
MP2/cc-pVDZ 1.411 1.392 1.671 1.347 1.449 117.74 114.18 120.51 125.28 122.76 18.9 -163.1 175.9 -2.0
a The two sets of values correspond to the two distinct molecules found in the unit cell. The estimated standard deviations for the experiment are given in Table 3. b The sign convention for a dihedreal angle WXYZrefers to a viewer on the WX side looking clown the XY bond toward YZ. If Z is rotated clockwise from X, the dihedral angle is considered positive.
166
C. C. Chambers et al./J ournal of Molecular Structure (Theochem ) 388 (1996) 161-167
Repeating the MP2 calculation for the syn,E,Z structure with the cc-pVDZ basis set lowers the energy to - 641.5924 Hartrees. Table 6 lists the geometrical parameters obtained at the MP2/cc-pVDZ level for the syn,E,Z structure. Included in Table 6 for comparison with these calculations are selected bond lengths, bond angles and dihedral angles obtained from MP2/6-31G* calculations and from the X-ray data. It is not clear whether the deviations of theory from experiment are due to lack of convergence of the electronic structure calculations with respect to oneelectron basis and/or level of electron correlation, or due to the crystalline environment or both. The geometries of the two molecules in the unit cell agree much better with each other than either agrees with theory. An especially interesting difference of theory and experiment is the degree of nonplanarity, which is much larger in the theory. Some other structural parameters show good agreement of theory and experiment, in particular most bond lengths and bond angles. The most notable differences between the calculated and crystal structures are found for the C=S, H2NHN-C and C-NHCH3 bond lengths. The two molecules found in the unit cell have longer C=S bonds and shorter C - N bonds (where C is the thiocarbonyl C) than are indicated by the calculations. One possible explanation of these differences is based on the following resonance structures: S
I
L
We have presented gas-phase relative energies for eight different conformers of 4-methyl-3-thiosemicarbazide at the HF/6-31G* level of theory and for four of these at the MP2/6-31G* level. The lowest-energy gas-phase stereostructure, syn,E,Z, corresponds to that found experimentally in the crystal. The optimized structure at the MP2/cc-pVDZ level is in generally good agreement (3 degrees for bond angles and 0.008 A for bond lengths) with the experimental structural parameters, but three bond leng!hs show larger deviations in the range 0.02-0.05 A, giving possible evidence for condensed-phase effects on molecular structure.
Acknowledgements The authors are grateful to Kiet Nguyen for assistance with some of the calculations and to Doyle Britton and Thomas Hoye for helpful discussions. This work was sponsored in part by the Army High Performance Computing Research Center under the auspices of the Department of the Army, Army Research Laboratory cooperative agreement number DAAH04-95-2-0003/contract number DAAH04-95C-0008. The content does not necessarily reflect the S-
S-
--.-
5. Summary
---.-
I
+
In the condensed-phase environment, with its higher dielectric constant, the contribution of the charged mesomers is expected to be larger than in the gas-phase, thereby lengthening the C=S bond and shortening the two C - N bonds as is observed. This analysis implies an increased negative charge on S, which is consistent with the presence of three short intermolecular hydrogen-sulfur distances ( - 2 . 5 A) for each molecule in the crystal. Quantitatively similar discrepancies between theory and neutron diffraction crystal data were noted by Jeffrey et al. [20] for thioacetamide and analogously ascribed to intermolecular hydrogen bonding effects on the C=S and C - N bond lengths.
position or the policy of the government, and no official endorsement should be inferred. This work was also supported in part by the National Science Foundation. Authors EJV and JDZ acknowledge the support of the Office of Naval Research.
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