ARTICLE pubs.acs.org/JPCA
Shapes of Sulfur, Oxygen, and Nitrogen Mustards Janos Nadas, Xiaohua Zhang, and Benjamin P. Hay* Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-6119, United States
bS Supporting Information ABSTRACT: Thorough conformational analyses have been performed on representative sulfur, oxygen, and nitrogen mustards. A total of 23, 18, and 38 unique conformers have been located for SM, OM, and NM, respectively, at the MP2/ aug-cc-pVDZ level of theory. Despite the fact that these molecules differ only in the identity of the central heteroatom, comparison of their low energy conformations reveals that the shapes they adopt are distinctive to each molecule. Potential energy surfaces for CH2X (X = S, O, and NCH3) and CH2CH2 bond rotations are presented and, where possible, compared with dihedral angle distributions observed in crystal structure data. These results were used to benchmark and improve the performance of the MM3 and MMFF94 force fields.
’ INTRODUCTION Mustards are a class of organic molecules consisting of a heteroatom center (S, O, or N-R) substituted with two 2-chloroethyl groups (Figure 1). Sulfur mustard (bis(2-chloroethyl)sulfide, also known as mustard gas) is a potent chemical warfare agent (CWA) first used on the battlefield during World War I (WWI) and since used sporadically in subsequent wars and terrorist attacks.1 Research concerning sulfur mustard, SM, has focused on its mechanism of action,2 diffusion and sorption properties,3 ease of its incineration,4 and on creating tools for its detection.5,6 Oxygen mustard, OM, has been used as a surrogate for SM in diffusion and sorption studies.3,7 Nitrogen mustard, NM, was developed initially as a CWA, and although it has been stockpiled, it has never been used as a weapon.8 Instead, NM and analogs obtained through variation of the N-R substituent have been extensively studied as anticancer agents.9 Our interest in these molecules is motivated by the challenge of designing synthetic host molecules capable of recognizing their shapes. The application of structure-based computer-aided molecular design methods in the development of host architectures10 requires prior knowledge of the guest molecule conformation and the availability of efficient methods to evaluate the structures of the hosts and hostguest complexes. In the absence of experimental data, the results from electronic structure calculations provide (i) a means to identify stable guest comformations, (ii) rank these conformations by energy, and (iii) a basis for benchmarking and tuning existing force field models to facilitate subsequent design work by providing a tool for the rapid scoring of candidate host architectures. For the mustards shown in Figure 1, various conformations arise from rotation about four bonds, two interior CH2X bonds (X = S, O, NCH3) and two exterior CH2CH2 bonds. Given that each bond has three possible rotamers, trans, t, gaucheþ, gþ, and gauche, g, there are up to 81 possible conformations for SM, OM, and NM. Because some rotamer combinations result in r 2011 American Chemical Society
Figure 1. Molecular structure of sulfur mustard, SM, oxygen mustard, OM, and the methyl-substituted nitrogen mustard, NM.
Figure 2. Conformers t t t t and t gþ gþ t of SM.
severe steric hindrance and because many conformers have degenerate forms, the actual number of conformers is less than these projections. However, it can be anticipated that multiple conformations are possible in each case. Of the three compounds considered in this study, SM is the only one that has been subjected to prior conformational evaluation. Following early computational studies that focused exclusively on the t t t t conformation,2a,11 an exhaustive conformational analysis of SM identified 22 unique conformations and found the all-trans form not to be the lowest energy structure of the molecule.12 The MP2/6-31G* level of theory predicted that the t gþ gþ t conformer was lower in energy than Received: April 4, 2011 Revised: May 13, 2011 Published: May 17, 2011 6709
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Table 1. Relative MP2/aug-cc-pVDZ Energies (ΔE), Relative MP2/6-31G* Energies (ΔEold), Point Group, Degeneracy, and Dihedral Angles for All SM Conformersa ΔE
a
ΔEoldb
point group
degeneracy
Φ1
conformer
Φ2
Φ3
Φ4
SM1
0.00
0.00
C2
2
t
gþ
gþ
t
178
82
82
SM2
0.52
0.74
C1
4
t
gþ
g
t
177
67
101
178 179
SM3
0.99
C1
4
t
gþ
gþ
g
177
61
68
83
SM4
1.06
C1
4
t
g
gþ
gþ
177
97
57
61
SM5
1.10
1.39
C1
4
t
gþ
gþ
g
179
80
97
69
SM6 SM7
1.36 1.66
0.93 2.37
C1 C2
4 2
t gþ
t g
gþ g
t gþ
177 69
155 96
70 96
180 69
C1
4
t
gþ
gþ
gþ
178
82
80
68
1.95
C1
4
t
gþ
t
gþ
180
71
151
63
C1
4
t
g
gþ
gþ
179
70
103
66
C1
4
gþ
gþ
g
gþ
66
116
86
72
C1
4
t
gþ
t
g
177
82
154
62
C1
4
gþ
gþ
gþ
g
67
75
95
71
C2v C1
1 4
t gþ
t t
t gþ
t g
180 63
180 143
180 84
180 71
SM8
1.69
SM9
2.18
SM10
2.18
SM11
2.33
SM12
2.50
SM13
2.62
SM14 SM15
2.86 2.86
1.97 2.65
2.23
C1
4
t
t
gþ
gþ
178
161
60
62
C1
4
gþ
gþ
g
g
68
96
57
59
C2
2
gþ
gþ
gþ
gþ
68
78
78
68
C1
4
t
t
t
gþ
179
176
165
64
4.19
C1
4
gþ
gþ
t
gþ
63
64
154
63
SM21
4.23
C1
4
g
t
gþ
gþ
69
173
51
56
SM22 SM23
4.84 5.16
C2 Cs
2 2
gþ gþ
t t
t t
gþ g
64 65
166 169
166 169
64 65
SM16
2.95
SM17
3.20
SM18
3.71
SM19
3.79
SM20
3.43
4.19
All energies reported in kcal/mol. b Ref 12.
Table 2. Relative MP2/aug-cc-pVDZ Energies, Point Group, Degeneracy, and Dihedral Angles for the 10 Lowest Energy OM Conformersa ΔE
a
point group
degeneracy
conformer
Φ1
Φ2
Φ3
Φ4
OM1
0.00
C2v
1
t
t
t
t
180
180
180
180
OM2
0.39
C1
4
t
t
t
gþ
180
179
177
68
OM3
0.79
C1
4
t
gþ
t
gþ
179
84
144
70
OM4
0.79
C2
2
gþ
t
t
gþ
69
176
176
69 67
OM5
0.85
C2
2
gþ
g
g
gþ
67
105
105
OM6
0.86
C1
4
t
t
gþ
gþ
179
170
58
55
OM7
0.87
C1
4
t
t
gþ
t
179
170
77
178
OM8 OM9
1.23 1.26
C1 C2
4 2
g t
t gþ
gþ gþ
gþ t
69 180
165 88
58 88
55 180
OM10
1.30
Cs
2
gþ
t
t
g
69
177
177
69
All energies reported in kcal/mol.
the t t t t conformer (Figure 2) by 1.97 kcal/mol. Comparison of the relative energies obtained from these ab initio calculations with those obtained using a variety of force field models revealed a poor correspondence and all of the models tested (MM2, MM3, AMBER, and OPLSA) incorrectly predicted the t t t t form to be the global minimum.12 Herein, we report the results of exhaustive conformational analyses performed on SM, OM, and NM. After locating all possible low energy conformations with force field models, geometry optimizations at the MP2/aug-cc-pVDZ level of theory were performed to obtain accurate relative energies. All three molecules were found to exhibit multiple low energy forms and
population analyses were performed to determine the extent to which each form is present in the gas phase. Potential energy surfaces for CH2X (X = S, O, and NCH3) and CH2CH2 bond rotations are presented and, where possible, compared with dihedral angle distributions observed in crystal structure data. These results were used to benchmark and improve the performance of the MM3 and MMFF94 force fields.
’ COMPUTATIONAL DETAILS Electronic Structure Calculations. Initial geometries for subsequent electronic structure calculations were generated by 6710
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Table 3. Relative MP2/aug-cc-pVDZ Energies (kcal/mol), Point Group, Degeneracy, and Dihedral Angles for the 10 Lowest Energy NM Conformersa ΔE
a
point group
degeneracy
Φ1
conformer
Φ2
Φ3
Φ4
NM1
0.00
C1
4
t
gþ
t
gþ
176
81
148
69
NM2
0.01
C1
4
t
t
gþ
t
179
154
81
178
NM3
0.32
C1
4
t
g
gþ
gþ
178
104
62
63
NM4
0.34
Cs
2
t
t
t
t
179
162
162
179
NM5
0.43
C1
4
t
t
gþ
gþ
178
150
75
63
NM6 NM7
0.46 0.71
C1 C1
4 4
t t
t gþ
t gþ
gþ g
179 176
156 141
178 81
56 62
NM8
0.73
C1
4
gþ
gþ
gþ
g
55
48
75
70
NM9
0.74
C1
4
t
gþ
g
t
178
108
67
177
NM10
0.75
C1
4
t
t
g
t
179
152
62
179
All energies reported in kcal/mol.
Table 4. Ten Most Populated Conformers of SM, OM, and NM SM
OM
NM
2
t
gþ
g
t
28%
2
t
t
t
gþ
24%
1
t
gþ
t
gþ
13%
1
t
gþ
gþ
t
17%
3
t
gþ
g
gþ
12%
2
t
t
gþ
t
13%
3
t
gþ
gþ
g
13%
6
t
t
gþ
gþ
11%
3
t
g
gþ
gþ
8%
4
t
g
gþ
gþ
11%
7
t
t
gþ
t
11%
5
t
t
gþ
gþ
6%
5 6
t t
gþ t
gþ gþ
g t
11% 7%
8 1
gþ t
t t
gþ t
gþ t
6% 6%
6 7
t t
t gþ
t gþ
gþ g
6% 4%
8
t
gþ
gþ
gþ
7%
11
t
t
gþ
t
5%
8
gþ
gþ
gþ
g
4%
9
t
gþ
t
gþ
2%
12
g
t
gþ
gþ
4%
9
t
gþ
g
t
4%
10
t
g
gþ
gþ
2%
13
t
gþ
gþ
t
4%
10
t
t
g
t
4%
7
gþ
g
g
gþ
1%
4
gþ
t
t
g
3%
4
t
t
t
t
Total
96%
86%
4% 66%
Figure 3. MP2/aug-cc-pVDZ optimized geometries for the 10 lowest energy conformers of SM, OM, and NM.
molecular mechanics conformational searches using the MM313 and MMFF9414 molecular mechanics force fields as implemented in PCModel.15 Although the MMFF94 force field contained parameters for all three molecules, the default MM3 force field was missing parameters for SM and NM, and only able to treat OM. For initial searches on SM and NM, the missing XCCCl (X = S and N) torsion parameters in MM3 were set to zero. The conformers
less than 5 kcal/mol relative to the lowest energy conformer were chosen for optimization using second-order MøllerPlesset (MP2) perturbation theory16 with the NWChem program.17 Calculations were done using the correlation consistent aug-cc-pVDZ basis set.18 Frozen-core approximations were not used to allow for the full treatment of the electrons. When the t t t t conformer was used, rotational potential energy surfaces were calculated at the 6711
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Figure 5. Simultaneous rendering of the HOMO and HOMO-1 in representative molecules dimethyl sulfide and dimethyl ether (isovalue = 0.032 e/Å3) illustrates the difference in the size of S and O lone pairs.
Figure 6. Newman projections of the CH2X (X = S, O, NCH3) bond in SM, OM, and NM.
(X = S, O, NCH3), from 0 to 360° in 30° increments and fully optimizing the remaining internal coordinates. Population Analysis. The relative free energies, ΔGi = Gi Glow, for a series of conformers can be used to estimate the extent to which they are populated. The ΔGi values are approximated by ΔEi values if it can be assumed that differences from most other enthalpic and entropic contributions are small. For a set of conformations of the same molecule, vibrational, and rotational contributions to the free energy are relatively invariant with the exception of that arising from rotational symmetry.19 Assuming that all other enthalpy and entropic factors are constant for a set of mustard conformers, the relative free energy for the ith conformer is given by ΔGi ¼ ΔEi þ RT ln σi
ð1Þ
where ΔEi = Ei Elow, σi is the symmetry number,20 and R is the gas constant (1.9859 cal K1 mol1).20 The ΔGi values can then be used in the eq 2 to estimate the population of each conformer at 298.15 K: Ni ¼ Ntotal
Di eΔGi =RT Nconf
∑ Dk
ð2Þ
eΔGk =RT
k¼1
Figure 4. Distributions of CH2XCH2CH2 (X = S, O, NCH2R) dihedral angles observed in crystal structures are compared with MP2/ aug-cc-pVDZ potential energy surfaces obtained by rotation about one CH2X bond in the t t t t conformer of SM, OM, and NM.
MP2/aug-cc-pVDZ level of theory by constraining the dihedral angle for one bond, either CH2X CH2CH2 or XCH2CH2Cl
where Ni is the number of molecules in the ith conformation, Ntotal is the total number of molecules, Nconf is the number of conformations, Di and Dk are the degeneracies of the ith and kth conformers, R is the gas constant, and T is the absolute temperature (298.15 K). Cambridge Structural Database. Dihedral angle distributions in crystal structures were obtained through analysis of the Cambridge Structural Database (CSD).21 The CSD program ConQuest22 was used to locate structures containing the fragment ZCH2CH2XCH2CH2Z (X = S, O, or NCH2Z and Z = any atom) to obtain data on CH2XCH2CH2 dihedral angle distributions. All bonds in the fragment were required to be acyclic. To avoid distortions caused by possible substitution at 6712
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Figure 8. Newman projections of the CH2CH2 bond in SM, OM, and NM.
Figure 7. MP2/aug-cc-pVDZ potential energy surfaces obtained by rotation about one CH2CH2 bond in the t t t t conformer of SM, OM, and NM.
the heteroatom (protonation, alkylation or metalation), the total coordination number was constrained to 2 for S and O, and 3 for N. Additional constraints included an R factor of less than 10%, no disorder and no errors.
’ RESULTS AND DISCUSSION MP2/aug-cc-pVDZ geometry optimizations of initial coordinates obtained from molecular mechanics calculations yielded 23 unique local energy minima summarized in Table 1. In agreement with the prior study,12 the lowest energy geometry for sulfur mustard, SM1, is the C2 symmetric t gþ gþ t conformer possessing dihedral angles of 178 and 82°. These dihedral angles are nearly identical to those observed in the crystal structure of the analog 2-chloroethyl ethyl sulfide: 177.4° (ClCH2CH2S), 83.17° (CH2CH2SCH2), and 73.8° (CH2SCH2CH2).23 The t t t t conformer SM14 was ranked 14th energetically. In addition to the 22 conformers reported previously,12 two new conformers, SM3 and SM10,
were located. Comparison of the ΔE values from MP2/aug-ccpVDZ calculations to 11 of the 12 low-energy conformers reported at the MP2/6-31G* level of theory show a fairly good correspondence, with an average difference of (0.43 kcal/mol. One of the prior low energy forms at the MP2/6-31G* level of theory, t t gþ g, was not a minimum on the MP2/aug-cc-pVDZ potential surface and optimized instead to give t gþ gþ g (SM5). The ΔE values calculated in this work using aug-ccpVDZ should be more accurate since the basis set is almost twice the size of 6-31G* and it has been variationally optimized for MP2 calculations.18a Following the same computational approach used for SM, 18 unique local energy minima were identified for OM and 38 unique local energy minima were identified for NM. Data for the 10 lowest energy conformers of OM and NM are summarized in Tables 2 and 3, respectively (see Supporting Information for complete lists). Figure 3 shows these OM and NM conformers with the 10 lowest energy conformers of SM. The lowest energy conformers for OM and NM are t t t t and t gþ t gþ, respectively. Neither of these corresponds to the lowest energy SM conformer, t gþ gþ t. Each molecule exhibits a variety of low energy shapes, with the t t gþ t conformation being the only one that is present for all three mustards (SM6, OM7, and NM2). The population distributions for the 10 most populated conformers of each mustard are presented in Table 4 (see Supporting Information for complete distributions). In each case, the analysis predicts that multiple conformers are populated in the gas phase. The 10 most populated conformers for SM, OM, and NM account for 96, 86, and 66% of each mustard, respectively, reflecting the increasing number of low energy forms on changing the central heteroatom from S to O to N. After accounting for symmetry and degeneracy, the population analysis reveals that the lowest energy conformation is not necessarily the most populated conformation. The most populated structures are as follows: SM2, 28%, t gþ g t; OM2, 24%, t t t gþ; NM1, t gþ t gþ; and NM2 t t gþ t, each present at 13%. The conformational behavior of each molecule is quite distinct, demonstrating that neither OM nor NM is a geometric analog of SM. To better understand why these seemingly similar molecules exhibit different conformational behavior, potential energy surfaces (PESs) for rotation about the CH2X and CH2CH2 bonds (X = S, O, or NCH3) were generated at the MP2/aug-cc-pVDZ level of theory. The PESs for rotating one CH2X bond in the t t t t conformer of each mustard are shown in Figure 4. The SM PES exhibits two degenerate gauche minima at (73° and a trans minimum at 180°. The gauche rotamers are 1.49 kcal/mol lower in energy than the trans rotamer. The OM PES also exhibits two degenerate gauche minima at (75° and a trans minimum at 180°. However, here the gauche rotamers are 6713
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Table 5. Adjusted MM3 and MMFF94 Torsion Parametersa torsion angle
atom types
MM3* V2
V1 CSCC SCCCl
1 15
15 1
1 1
1 12
MMFF94* V3
1
6
1
1
6
1
1
0.900
1.760
1.365
0.150
2.094
(0.260)
(0.600)
(1.047)
1.250
0.700
0.400
1.700 (0.000)
0.800
0.095 (0.450)
OCCCl
V2
(0.440) not available COCC
V1
(0.050)
0.355
(0.757)
(0.681)
(0.755)
(0.755)
0.558
0.400
0.180
(0.200) 0.950
(0.180) 0.472
(0.000) 0.000
(0.958)
(0.155)
(0.766)
(0.439)
0.000
0.600
0.000
2.100
1
1
NCCCl
8
1
1
12
not available
(0.300)
0.705
0.000
8
0.600
2.500
(0.000) 1.839
1
1.000 (0.000)
0.100 (0.398)
0.757
12
CNCC
(0.170)
V3
(0.000)
0.697
0.300
(0.000) 0.686
(0.300) 0.072
(0.786) 1.250 (0.000)
(0.272) 0.500 (0.300)
a
Barrier heights, V1, V2, and V3, are given in kcal/mol. Default parameters given in parentheses. The barrier heights are used in the equation E = V1/2 [1 þ cos(Φ)] þ V2/2 [1 cos(2Φ)] þ V3/2 [1 þ cos(3Φ)], which gives torsional energy, E, as a function of the dihedral angle, Φ.
higher in energy than the trans rotamer by 0.80 kcal/mol. The NM PES differs from the prior two by exhibiting three distinct minima, a gauche form at 81°, a trans form at 166°, and a gauche form at 298° (62°). The relative energy of these three forms is 0, 0.33, and 0.74 kcal/mol, respectively. The differences in the rotational PESs for the CH2X bonds can be rationalized by consideration of the size and number of lone pairs on the heteroatom, X. As Figure 5 illustrates, the lone pairs on sulfur are significantly larger than the lone pairs on oxygen. If it is assumed that steric bulk increases in the order O lone pair < alkyl group < S lone pair, then Newman projections for rotation about the CH2X bond illustrate that repulsion between substituents would be minimized by the gauche form when X = S and by the trans form when X = O. Unlike the S and O case, the PES for rotation about the CH2N bond differs due to asymmetry imposed by the NCH3 substituent. Assuming that the steric bulk of the N lone pair < an alkyl group, then the Newman projection for this bond, Figure 6, shows that steric repulsion is minimized when the R2 group is located gauche to the N lone pair. This gives rise to the two lower energy rotamers in the PES, one trans to CH3 (81°) and one trans to R1 (166°). The highest energy rotamer occurs when R2 is gauche to both alkyl substituents (298°). Experimental validation of the PESs for CH2X bond rotation in SM, OM, and NM is obtained from dihedral angle distributions observed in crystal structures for molecules containing the fragment ZCH2CH2XCH2CH2Z (X = S, O, or NCH2Z and Z = any atom). Searches yielded 70 examples for sulfides, 1900 examples for ether compounds, and 890 examples for amine compounds. A histogram showing the observed frequency of CH2XCH2CH2 dihedral angles in the solid-state structures is shown above the corresponding PES in Figure 4. The experimental data are consistent with the calculated PESs. The bulk of the data is located in the predicted potential wells. Sulfides show a clear preference for the gauche form, ethers show a clear preference for the trans form, and amines show a clear preference for forms that are gauche to the N lone pair. The PESs for rotating one CH2CH2 bond in the t t t t conformer of each mustard are shown in Figure 7. The SM PES exhibits a low energy trans minimum at 180° and two degenerate
gauche minima at (64° that are 0.93 kcal/mol higher in energy. The OM exhibits an analogous PES with a low energy trans minimum and two degenerate gauche minima at (68° that are higher in energy by 0.39 kcal/mol. The NM PES again shows three distinct minima: a trans minimum at 179°, a gauche minimum at 56°, and a gauche minimum at 92°. The relative energies of these three forms are 0, 0.12, and 0.88 kcal/mol, respectively. In contrast to the CH2XCH2CH2 dihedral angles, there are insufficient crystal structure data (3 sulfide, 5 ether, and 2 amine examples) to warrant plotting histograms of the XCH2CH2Cl dihedral angles. As with the CH2X bonds above, the differences in the CH2CH2 rotational PESs are readily understood from the Newman projections shown in Figure 8. In all cases, the Cl substituent prefers to be gauche to both H atoms and trans to the larger heteroatom. The fact that OM exhibits a more stable gauche form than SM is consistent with the smaller size of the O atom. The asymmetry in the NM gauche forms arises from the fact that the more stable gauche form (56°) occurs when the Cl atom is closer to the N lone pair and the less stable gauche form (92°) occurs when the Cl atom is closer to the NCH3 group. In addition to providing insight into the origin of the differing shapes of these molecules, the rotational PESs also provide a basis for improving the parametrization of the force field models. Although these models contain torsion parameters for the HCCCl interaction, the default MM3 model was missing XCCCl (X = S or N) torsion parameters and the MMFF94 model applies a generic ZCCZ (Z = any atom) torsion parameters for the XCH2CH2Cl (X = S, O, or N) dihedral angles. The torsion parameters, V1, V2, and V3, for each type of XCCCl interaction were adjusted to achieve the best agreement between rotational PESs generated by the models versus those shown in Figure 7. The default and adjusted torsion parameters are presented in Table 5. The PESs for rotation about the CH2X (X = S, O, or N) bond, Figure 4, were compared with those from force field models to verify the performance of the default parameters applied to CH2XCH2CH2 dihedral angles. Discrepancies were observed in all cases and better fits were achieved by adjusting torsion parameters for the CXCC interactions 6714
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The Journal of Physical Chemistry A without disturbing those used for CXCH interactions. In the case of SM, both default force fields incorrectly predict the trans form being more stable than the gauche form. In the case of OM, both default force fields incorrectly predict that the gauche form to be ∼2 kcal/mol higher in energy than the trans form whereas MP2 gives a difference of 0.8 kcal/mol. Finally, in the case of NM, both default force fields predict incorrect dihedral angles for the rotamers that place the ethyl group gauche to the N lone pair. These discrepancies were eliminated using the adjusted torsion parameters presented in Table 5. Because of the above issues with the default force field models, it was possible that initial conformer searches performed with them might have failed to locate unique low lying conformers. To eliminate this possibility, conformational searches were repeated using the adjusted force fields, MM3* and MMFF94*. No new conformations were found. However, comparison of the relative energies from MP2 with those obtained from the force field models reveals that the latter models fail to reproduce exactly the stability ordering. This is illustrated by showing the MM3* rank order for the five most stable conformers by MP2 (molecule, order): SM 1, 3, 5, 7, 4; OM 1, 2, 3, 4, 6; NM 1, 3, 12, 6, 2. Similarly, the MMFF94* rank order was: SM 1, 12, 8, 9, 5; OM 1, 2, 4, 5, 17; NM 1, 2, 27, 5, 4 (see Supporting Information for a complete rankings for both force fields). This represents a marked improvement over the default force fields, which were either missing parameters (SM and NM with MM3) or gave an incorrect global minimum (SM and NM with MMFF94). Although the level of agreement is not perfect, both force field models now predict the correct global minimum for each molecule and identify many of the most stable forms as being among the five lowest energy forms.
’ CONCLUSION Thorough conformational analyses have been performed on representative sulfur, oxygen, and nitrogen mustards. A total of 23, 18, and 38 unique conformers have been located for SM, OM, and NM, respectively, at the MP2/aug-cc-pVDZ level of theory. Although there has been a prior conformational analysis of SM,12 these are the first reported analyses for OM and NM. Despite the fact that these molecules differ only in the identity of the central heteroatom, comparison of their low energy conformations reveals that the shapes they adopt are distinctive to each molecule. Each one has a different global minimum, and population analyses show that three most populated forms for SM, OM, and NM are all different; in other words, conformers most populated for one molecule are not among those most populated for either of the other two molecules. Therefore, in future studies concerning these molecules, SM, OM, and NM should not be viewed as structural analogs of one another when conformational properties are important. This has potential implications in the design and testing of novel receptors that are based on the molecular shape recognition. Finally, the results of this study provided a basis for extending and improving parameters for popular force field models that can be used to predict the shape of mustards with improved accuracy. ’ ASSOCIATED CONTENT
bS
Supporting Information. Cartesian coordinates and absolute energies for all MP2/aug-cc-pVDZ optimized structures and tables giving relative energies and the population calculations
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for all SM, OM, and NM conformers. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Phone: (865) 574-6717. Fax: (865) 574-4939. E-mail: haybp@ ornl.gov.
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