The geometry and internal rotational barrier of carbamic acid and several derivatives

Journal of Molecular Structure (Theochem), 180 (1988) 175-188 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands

175

THE GEOMETRY AND INTERNAL ROTATIONAL BARRIER OF CARBAMIC ACID AND SEVERAL DERIVATIVES

MILAN REMKO* and STEVE SCHEINER** Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale, IL 62901 (U.S.A.) (Received 1 October 1987)

ABSTRACT The geometries of the following carbamate-containing molecules have been optimized at the ab initio SCF level using the MINI-l, 3-21G, and 6-31G* basis sets: carbamic acid, methylcarbamate, ethylcarbamate, N-methyl methylcarbamate, N,N-dimethyl methylcarbamate, N-vinyl methylcarbamate and N-phenyl methylcarbamate. The latter two basis sets yield geometries in best agreement with experimental data. Calculated energy barriers for rotation about the C-N bond become progressively higher as the basis set is enlarged; electron correlation leads to a modest reduction. At the MP2/6-31G*//6-31G* level, the barriers lie in the range of SO-90 kJ mol-‘. Alkyl substitution on either end of the carbamate group increases the +C = O- charge separation. N-substitution reduces the electron density on the nitrogen whereas the negative charge of this atom is increased by esterification of carbamic acid.

INTRODUCTION

Due in part to its great importance as a structural link in proteins, the -NHCO- amide group has been the subject of a great deal of experimental and theoretical scrutiny that has led to a solid understanding of its properties. In contrast, the closely related -NH-COO- carbamate group has been relatively ignored despite its occurrence in biologically active compounds [l-3] such as anticonvulsants, local anaesthetics, sedatives, hypnotics, and muscle relaxants as well as polyurethane polymers which are of great industrial importance [ 41. With regard to structure, X-ray structures have been solved for a number of carbamates including the methyl and ethyl esters [ 5,6]. Since the first study of hindered rotation about the N-C bond in N,N-disubstituted carbamates by *Fulbright Scholar. Permanent address: Department of Pharmaceutical Chemistry, Comenius University, 832 32 Bratislava, Czechoslovakia **Recipient of NIH Research Career Development Award

0166-1280/88/$03.50

0 1988 Elsevier Science Publishers B.V.

176

Lustig, Benson, and Day in 1967 [ 71, NMR techniques have been used to evaluate the rotational barrier heights in numerous such molecules [8-121. Theoretical techniques have also been brought to bear on this problem. Most of these calculations were limited by certain assumptions made concerning the geometries of the molecules [ 13-171. Exceptions include the work of Kydd and Rank [ 181 who optimized the geometries of various conformers of methylcarbamate using the semiempirical MNDO procedure. Schafer et al. applied the 4-21G basis set within the ab initio formalism to study carbamic acid [ 191 and its methyl and ethyl esters [ 201. Very recently, SCF calculations were combined with microwave spectroscopy to analyze the conformation of methyl hydrazinocarboxylate [ 211. The H-bonding characteristics of some aromatic carbamates have been investigated by theoretical methods as well [ 22,231. The present paper reports the results of a systematic theoretical treatment of the carbamate group. Beginning with the fundamental carbamic acid species, the effects of progressive methyl substitution are considered. The 0 atom is first substituted, followed by mono and di-substitution of N. Enlarging the alkyl group to ethyl is also studied, as are the vinyl and phenyl groups. The latter two are chosen to model the effects of longer conjugated chains and aromatic groups, respectively. In order to clearly separate genuine chemical effects from spurious trends that might be introduced by a particular theoretical method, a number of different basis sets ranging from a minimal type to a splitvalence set including polarization functions are applied. Of particular interest are the details of the molecular geometries and the rotational barriers and how these properties are affected by various degrees of substitution. COMPUTATIONAL DETAILS

Ab initio calculations were carried out with the aid of the GAUSSIAN-80 package of computer codes [ 241. Basis sets included the minimal MINI-l set of Huzinaga et al. [25] and the larger 3-21G [26] and 6-31G* [27] sets. The effects of electron correlation on selected structures were examined using second and third-order Msller-Plesset perturbation theory (MP2) [ 28 1, in conjunction with the 6-31G* basis set. Geometries of all species were fully optimized using the gradient procedures contained within the program. In conformity with X-ray crystal studies of a number of carbamates [ 5,6,29,30], the geometries were assumed to belong to the C, point group. Due to computational limitations, the geometry of N-phenyl methylcarbamate was optimized using MINI-l only. The rotational barrier about the C-N bond in each molecule wBs evaluated as the difference in energy between the planar equilibrium geometry and the structure optimized with the dihedral angle 9 held fixed at 90”. The atom numbering scheme used for each of the molecules studied is presented in Fig. 1.

177

$,H3

9,

/NTy2 ,c H3 6H3 ‘6’

Fig. 1. Numbering scheme used for atoms. Carbamic acid is depicted in its tram configuration as are ail the esters. GEOMETRIES

Carbamic acid The carboxyl hydrogen may adopt positions either trans or ck to the nitrogen atom. The optimized geometries of both trans and cis carbamic acid are presented in Table 1 for each of the three basis sets. Note first that bonds not involving hydrogen atoms are approximately 0.1 A longer with the MINI-l basis set than with either of the larger sets which are by and large in good agreement with one another. On the other hand, MINI-l N-H and O-H bond lengths are intermediate between the longer 3-21G bonds and the shorter 631G* values. Most of the bond angles appear rather insensitive to the basis set, lying within lo or 2’ of one another. The major exception is the C-O-H angle where each basis enlargement leads to a progressve increase in the angle. There are a number of clear differences between trans and cis carbamic acid that are evident with all basis sets. Upon rotation of the hydrogen from a trans to a cis position, the C-N bond elongates by some 0.02 A, accompanied by a contraction of the C=O bond by about half that amount; the O-H bond length undergoes a smaller reduction. Most prominent of the angular changes are increases of 3”-5” in 8(COH), B(CNH,) and 8(NC06), all of which may be attributed to steric repulsion between H4 and the carboxylic hydrogen in the ck geometry. In order to illustrate the effects upon the geometry of bond rotation, the geometries optimized for carbamic acid with the dihedral angle

178 TABLE 1 Optimized bond lengths (A) and angles (degrees) of truns and cis carbamic acid tran.9'

rGOl 1 r(C,N,) rGW r0U-L) rUW%) r(0J-b) W&01) W’J&W f%C,N,Hd WzN&) ~(WciH,) - ESCF,a.u.

CiP

MINI-l

3-21G

6-31G*

6-31G* (@=90”)

MINI-l

1.305 1.442 1.458 0.999 0.999 0.966 127.3 110.1 118.1 118.6 107.5 242.0989

1.209 1.343 1.362 1.003 1.003 0.975 127.1 110.1 120.5 119.3 110.3 242.4529

1.220 1.340 1.355 0.990 0.990 0.952 126.3 111.2 120.7 119.1 112.9 243.7084

1.210 1.384 1.356 0.990 0.990 0.954 126.3 112.9 120.4 120.3 113.2 243.6737

1.298 1.200 1.210 1.462 1.363 1.359 1.458 1.364 1.359 0.996 1.002 0.990 1.004 0.991 0.999 0.972 0.950 0.963 123.7 124.5 124.0 114.7 115.4 115.4 124.2 122.8 124.4 116.0 117.5 117.6 110.9 115.7 118.1 242.0838 242.4358 243.6903

3-21G

6-31G*

6-31G* (qk90”) 1.200 1.403 1.358 0.991 0.991 0.950 125.6 114.6 120.6 120.5 114.4 243.6668

“Relative to N atom. TABLE 2 Difference in energy between cis and trans conformations of carbamic acid Method

EC,-E,,,

MINI-l//MINI-l 3-21G//3-21G 4-21G//4-21G” 6-31G*//6-31G* MP2/6-31G*//6-31G*

69.6 44.7 44.7 47.5 44.7

(kJ mol-‘)

“From ref. 19.

#(H,NCO,) =90” have also been listed in Table 1. This structure represents the transition state for rotation about the N-C bond. Comparison with the planar equilibrium geometries in the preceding column reveals an elongation of the C-N bond by some 0.04 A and a concomitant 0.01 A contraction of C = 0. This pattern is entirely consistent with a disruption of the conjugation of the C-N and C=O bonds. The bond angles are not substantially affected by the rotation except for the release of the interhydrogen steric strain which was noted above for the cis structure. All three basis sets predict the truns conformation of carbamic acid to be more stable than ci.s, consistent with observations of carboxylic acids [31]. Table 2 reports the difference in energy between these two structures computed with each basis set. The MINI-l basis predicts a very high difference,

179

about 70 kJ mol-‘. This quantity is lowered to 45 kJ mol-’ with 3-21G (or 421G [ 191) and is only slightly higher (47.5) with 6-31G*. Including electron correlation has only a small influence on the cis-trans energy difference, lowering it by less than 2.8 kJ mol-‘, as seen in the last row of the table. Methyl and ethylcarbamte

The geometries of the methyl and ethyl esters of carbamic acid are reported in Table 3. In keeping with results for the acid and consistent with the X-ray structures [ 5,6], the tram orientation about the C-O bond is used for these esters as well as all the following molecules, i.e., $(N3C20&) = 180”. The supposition of lowest energy for the tram geometry has been confirmed by prior ab initio calculations by Manning et al. [20] who found a 46 kJ mol-’ higher energy for the cis structure of methylcarbamate. Firstly, note that the geometrical parameters for these two esters are nearly identical to one another. Comparison with (trans) carbamic acid in Table 1 indicates that the only significant changes in the bond lengths accompanying esterification are a $004 A elongation of the C-N bond, coupled to a shortening of C&-O6by 0.007 A. The bond angles are also essentially unaffected by subTABLE 3 Optimized geometries (A and degrees) of methyl and ethylcarbamate methylcarbamate MINI-l

r(C*O,) r(GW rG,W r(NJ-U @JJ-M r(a3G) r(C,H) r(C&.d r(W) ~NLW,) W,C,W ~(GJW-L) NC&&) wxw) ~(O,GH) fmwb) ~(Gw-u - ESCF,a.u.

1.303 1.446 1.449 0.998 0.998 1.519 1.089

126.6 109.7 118.4 118.5 111.0 107.3

280.8582

“Ref. 6. bRef. 5.

3-21G 1.211 1.346 1.355 1.003 1.003 1.452 1.084

126.6 110.1 120.3 119.4 117.0 108.6

281.2645

ethylcarbamate 6-31G* 1.222 1.344 1.348 0.989 0.989 1.445 1.077

125.5 111.2 120.5 119.1 118.9 108.4

282.7136

expt” 1.227 1.334 1.338 0.82 0.85 1.440 0.95

124.2 112.8 125.0 117.0 115.2 110.0

MINI-l

3-21G

6-31G*

1.303 1.446 1.449 0.998 0.998 1.519 1.089 1.616 1.079 126.4 110.0 118.4 118.5 111.2 108.1 105.8 108.7 319.6245

1.211 1.346 1.355 1.003 1.003 1.457 1.085 1.527 1.089 126.5 110.3 120.3 119.4 117.6 109.1 105.5 110.1 320.0866

1.223 1.344 1.348 0.990 0.990 1.454 1.079 1.514 1.083 125.4 111.3 120.5 119.1 119.5 108.7 106.1 110.5 321.7387

exptb 1.223 1.349 1.333

1.473 1.509 122.4 114.7

116.8 105.7

180

stitution of the carboxylic hydrogen by methyl or ethyl groups, changing by less than 1”. As in the case of carbamic acid, the C-N b,ond undergoes significant lengthening in the two esters upon 90’ rotation about this bond. There is available experimental information about the structures of these two esters from X-ray diffraction data [5,6]. Although the crystal environment is appreciably different from the gas phase which the calculations are designed to mimic, it is nevertheless useful to compare the geometrical parameters. Bond lengths appear to be best reproduced by 6-31G*, generally to within 0.01 A of experiment. (The X-ray O-H and C-H bond lengths seem unreasonably short, reflecting the difficulty of locating H atoms to high precision.) 321G lengths are also quite good whereas MINI-1 tends to overestimate the nonhydrogen bonds by perhaps 0.1 A. The bond angles are predicted to within about 2’ or 3’ of the experimental values with 6-31G* or 3-21G, both of which are only slightly closer than MINI-l. N-Methylated derivatives

The effects of replacing either one or both N-H hydrogens by methyl groups are contained in Table 4. Comparing first the N-methyl carbamate in this table with the methylcarbamate in Table 3 indicates subtle changes in geometry caused by single methyl substitution. The two C-O bonds are predicted by 631G* to be slightly elongated (by around 0.003 A) with a similarly small contraction of CzN3. The only appreciable change in angles is a reduction in f3(CzN3H,) by some 3”. This motion takes the N-H hydrogen away from the N-methyl group, presumably to relieve steric crowding. Although the above changes are pretty much consistent with 3-21G, they are not reproduced by MINI-l at all. The failure of the minimal basis set to indicate steric crowding between the H and CHB groups attached to N is probably due to its overly compact atomic orbital description of each center. Adding a second N-methyl group leads to no major changes in the geometry. The &C&N&) angle is reduced by some 3 o so as to allow the two methyl groups to move away from one another. In addition to the trans conformer of N-methyl methylcarbamate illustrated in Fig. 1, it is also reasonable to presume a structure in which the O-methyl group is cis-oriented with respect to the nitrogen atom. Optimization of the latter structure, however, yielded a conformer higher in energy than the tram geometry by 5.1,6.7, and 7.2 kJ mol-’ with the MINI-l, 3-21G, and 6-31G* basis sets, respectively. The more stable tram conformation agrees with experimental observations [29,30] of similar molecules as well as quantum chemical calculations of N-substituted amides [ 32-341 where the energy differences are typically quite small, in the range of 2-14 kJ mol-‘.

181 TABLE 4 Optimized geometries (A and degrees) of N-methyl methylcarbamate and iV,ZV-dimethyl methylcarbamate N-methyl methylcarbamate MINI-l

r(G20,) r(C,N,) r(W,) T(NJ-L) WJA) r(W%) r(O&) r(C&) r(C&) r(W-I) B(N,C,O,) WW,O,) 0(&N&) @C&C,) B(C,N,C,) e(czo6c7) ~(O,C,H) WN,C,H)

3-21G

N,iV-dimethyl methylcarbamate 6-31G*

MINI-l 1.305 1.431 1.448

1.216 1.344 1.356

1.228 1.344 1.350

1.526 1.525 1.518 1.088 1.085 1.084 125.8 111.2

1.466 1.464 1.452 1.084 1.088 1.087 126.5 111.2

1.460 1.459 1.444 1.077 1.081 1.080 125.9 112.1

119.8 117.5 110.7 107.4 108.1 108.4 358.3770

121.3 119.2 117.1 108.6 109.7 110.1 358.8887

121.6 119.6 118.7 108.5 110.0 110.3 360.7290

1.303 1.437 1.450 0.998

1.214 1.343 1.355 1.004

1.225 1.342 1.351 0.991

1.527 1.518 1.089 1.086

1.462 1.452 1.084 1.088

1.451 1.445 1.077 1.081

126.2 110.2 118.6

126.5 110.4 117.7

126.1 111.0 117.1

118.2 110.8 107.4 108.2

122.0 117.0 108.6 109.8

123.2 118.9 108.5 110.1

319.6174

320.0776

321.7231

NN,C,H) -ESCF, a.u.

3-21G

6-31G*

N-Vinyl and N-phenyl derivatives The above types of substitution (see Table 5) appear to have a stronger influence upon the geometry of the carbamate group than replacement by methyl groups. Comparison with methylcarbamate in Table 3 indicates the vinyl group induces a substantial lengthening of the CzN3 and N3H, bonds, coupled with a slight shortening of r( Cz06). Similar patterns are noted for phenyl methylcarbamate. As in the case of methyl substitution, the vinyl group pushes the N-H hydrogen away from itself, reducing 0( C,N,H,) . The angles in the phenyl case are all within 2 ’ of their values in unsubstituted methylcarbamate. The phenyl group leads to a 0.005 A shorter N3-C5 bond and a larger 0( C,N,C,) angle than the vinyl group. The tram geometries of N-vinyl methylcarbamate pictured in Fig. 1 were found more stable than cis structures by 4.1,4.2, and 5.7 kJ mol-’ by MINI-l, 3-21G, and 6-31G*, respectively. These values are slightly smaller than the energy differences in N-methyl methylcarbamate but fit well into the experimental range of 4-6 kJ mol-’ reported for substituted amides [ 351.

182 TABLE 5 Optimizedgeometries (A and degrees) of N-vinyl methylcarbamate and N-phenyl methylcarbamate N-vinyl methylcarbamate

N-phenyl methylcarbamate

MINI-l

3-21G

6-31G*

1.299 1.449 1.444 1.002 1.472 1.520 1.089 1.090 1.386 1.078 1.078 125.5 109.9 119.2 117.8 110.9 107.2 112.5 122.9 122.0 118.8 357.1781

1.211 1.356 1.347 1.006 1.401 1.455 1.084 1.075 1.317 1.079 1.076 125.7 110.3 117.6 121.9 117.3 108.5 112.4 124.8 122.6 120.4 357.7185

1.221 1.352 1.345 0.993 1.399 1.447 1.077 1.070 1.323 1.074 1.070 125.7 110.8 116.9 123.1 119.0 108.4 113.4 124.1 122.7 120.4 359.5611

MINI-l 1.298 1.448 1.446 1.001 1.467 1.519 1.089

128.8 107.9 116.7 123.2 110.8 107.2 118.5

508.7038

Overall comparison with experiment Any critical evaluation of the performance of a theoretical method for a class of compounds should include a number of different molecules of this type. In order to arrive at a statistical basis for comparison with the experimental geometry of the carbamate group, the data for the entire set of molecules has been compiled in a composite fashion. Table 6 reports the value of each geometrical parameter, averaged over all the molecules studied. For example, the average r(01C2) bond length predicted by MINI-l in the seven molecules is 1.302 A, as shown by the first entry in the table. The last column summarizes the results of a survey of a large number of crystalline polymers which contain the carbamate group [ 301. Of course, the geometry of the carbamate group is sensitive to the nature of its substituents and probably to the environment as well. Hence the geometry of any given molecule in the gas phase cannot be expected to match precisely the average crystal values. Nevertheless, the experimental average should serve as a useful

183 TABLE 6

Summary of average cakuiated and experimental geometrical parameters (in A and degrees) of carbamate group” Parameter

MINI-l

3-21G

6-31G*

Exptb

r(W2)

1.302(7) 1.442(7) 1.456(7) 1.497 (4) 1.518(6) 126.7(7) 119.2(4) 109.8(7) 110.9(6)

1.212 (6) 1.346(6) 1.355(6) 1.442(3) 1.453(5) 126.5 (6) 121.0(3) 110.4(6) 117.2(5)

1.223(6) 1.344(6) 1.349(6) 1.436(3) 1.447(5) 125.8(6) 122.0(3) 111.2(6) 119.0(5)

1.210 1.325 1.352 1.425 1.446 126.7 125.8 109.7 115.6

r(G,N,) r(G2W r(N,W r(G&) 6(G&NJ 6(&N&) B(N,C,G,) 6(G*G&7)

“Number of compounds calculated in parentheses. bRef. 30.

yardstick with which to compare the theoretical values in order to estimate their accuracy. The MINI-l r(OICz) bond length of 1.310 A represents an overestimation of 0.09 A in comparison to the experimental value in the final column of Table 6. Due presumably to cancellation between certain errors, 3-21G predicts the 01C2 bond length to near perfect precision while 6-31G* is too high by 0.01 A. (Since it was beyond our computational resources to optimize the geometry of N-phenyl methylcarbamate with the larger 3-21G and 6-31G* basis sets, our test group is reduced to six molecules for these sets.) Scanning down the succeeding rows, it is apparent that MINI-l overestimates all bond lengths by amounts varying from 0.05 A for the peripheral 06C, bond to a maximum of 0.11 A for r(C,N3). 3-21G is much better, within 0.01 A for all three C-O bonds but too high by approximately 0.02 for the two bonds involving the nitrogen atom. The results with 6-31G* are of about the same caliber as 3-21G, predicting the O& and C206 bond lengths with excellent precision but overestimating the remaining distances by less than 0.02 A. Turning now to the bond angles, 8(O,C,N,) and 0(N3C206) are reproduced the best by the theoretical calculations, within about 1” or so, while larger errors are encountered in the two remaining angles. In particular, all the basis sets substantially underestimate f3(C&N&). In summary, the 3-21G and 6-31G* basis sets appear about equally successful in predicting the geometry of the carbamate group. The MINI-l bond lengths are somewhat too long but the calculated angles are comparable in accuracy to the two larger sets. ROTATIONAL BARRIERS

The energy difference between the equilibrium geometry of each molecule, and that optimized with the dihedral angle $ about the N3-C2 bond set equal

184

to 90’) is reported as the rotational barrier in Table 7. The barriers in parentheses were obtained using the rigid rotor approximation wherein a separate geometry optimization is not carried out for the @=90° structure; instead, all geometrical parameters are set equal to their values in the optimized $=O” geometry. While the numerical values of the barriers depend upon the theoretical method, all procedures agree on the following trends. Scanning down any given column, it is first clear that the height of the rotational barrier is only slightly sensitive to the nature of the substituents present. Replacing the carboxyl hydrogen of carbamic acid by a methyl or ethyl group lowers the barrier by only 1 or 2 kJ mol-l, a reduction of 4% at most. On the other hand, a significant increase of up to 12 kJ mol-’ is associated with methyl substitution on the Natom. Adding a second N-methyl group has little further effect. If instead of a methyl group, a vinyl group is bonded to the nitrogen, the increase in the barrier height is considerably smaller in magnitude. In contrast, the phenyl group has no apparent effect upon the barrier. Comparing the various basis sets, each extension of the basis set generally leads to an enlargement in the computed barrier. Including the effects of electron correlation at the MP2 level within the 6-31G* framework lowers the barrier by some 5-11 kJ mol-I. Extension of the correlation treatment to thirdorder MP was carried out in the case of carbamic acid, yielding only a negligible correction (less than 0.7 kJ mol-‘) to the MP2 barrier. Direct measurement of the barrier height is particularly difficult, with the results highly sensitive to experimental conditions, methods used, and procedures for data interpretation [ 8-121. Published values of the activation enthalpy for rotation of carbamates fall in the range of 45-95 kJ mol-‘, consistent with our calculated barriers. Of the molecules which have been studied here, the internal rotation of only N,N-dimethyl carbamate has been investigated experimentally [g-12]. In probably the most accurate measurement of the barrier, Martin et al. [ 121 obtained values of 65-95 kJ mol-’ by various kinetic techniques. Our best calculated barrier is 91 kJ mol-l at the MP2/6-31G*// 6-31G* level, within the experimental range. However, direct comparison between theory and experiment is risky since the former applies to the isolated molecule and the latter to condensed phase. Of particular relevance would be a measurement of the rotational barrier in the gas phase. Despite the favorable interaction one would expect between the x-electronic systems of the benzene ring and the carbamate moiety, both empirical calculations and CND0/2 have predicted an equilibrium structure in which these two groups are perpendicular to one another, i.e., # = 90’ [ 141. This finding is not surprising in the light of the well known inability of CNDO/B to treat conjugated systems correctly [ 361. Another semiempirical technique, PCILO, predicts a dihedral angle of approximately 30”-35” [ 13,151. The rotational profile obtained with the ab initio MINI-l method contains a minimum cor-

66.5 64.0 64.1 76.1 79.7 69.3 64.6 (72.7) (69.6) (69.6) (82.7) (86.1) (75.0) (72.4) 88.6 88.2 88.4 98.1 96.5 93.4

_

_

(96.3) (96.0) (96.2) (105.8) (102.9) ( loo.3 )

3-21G//3-21G

‘Parentheses contain barriers computed using rigid rotor approximation.

(H& = CH)NHCOOCH3 CGH6NHCOOCH,

NH$OOH NH,COOCH, NHzCOOCzHS CH,NHCOOCHB (CH&NCOOCH3

MINI-l//MINI-l

Calculated rotational barriers” (kJ mol-‘)

TABLE 7

91.3 90.1 99.3 99.5 96.0 93.0

(98.5) (97.2) (98.8) (106.9) (102.8) ( 99.7)

6-31G*//6-31G*

90.5 91.2

82.4 78.9

MP2/6-31G*//6-31G*

186

responding to a fully planar structure. This result is consistent with an earlier ab initio study using a different minimal basis set [ 16,371. There is unfortunately no gas-phase structure available for N-phenyl carbamates, leaving Xray data as the only source of structural information. The dihedral angle is fairly small, between 10” and 35 ‘, in the X-ray structures of relevant molecules [ 29,301. However, since it is unclear whether the small deviation from planarity is intrinsic to the molecule or is due to crystal packing forces, the question remains incompletely resolved. ELECTRON DISTRIBUTIONS

It is important to investigate the manner in which each type of substitution alters the distribution of electron density within the carbamate group. As a means of quantifying differences in density from one molecule to another, it is particularly convenient to evaluate the partial charge on each atomic center. Of course, there is no unique way of partitioning the density among the various atoms without introducing some measure of arbitrariness. Of those procedures used over the years, the Mulliken technique [ 381 has a long history of bringing to the surface helpful insights regarding a wide range of chemical systems. The atomic charges calculated in the Mulliken framework using the 6-31G* basis set are exhibited in Table 8 for each of the carbamate-containing molecules. While the magnitudes of these charges are fairly arbitrary, depending upon the method of partitioning and the specific basis set, the changes induced in these charges by different substituents are of greatest interest. These changes tend to be much less arbitrary and to realistically reflect electron density rearrangements occurring in the systems. The O1 carbonyl oxygen atom of carbamic acid becomes more negatively charged as each successive hydrogen atom is replaced by an alkyl group. At the same time, the C atom to which it is attached becomes more positive. Alkyl substitution may hence be connected with a greater degree of +C = O- charge TABLE 8 Atomic Mulliken charges computed with 6-31G* basis set

NH,COOH” NH,COOCH, NH2COOCPH, CH3NHCOOCH3 (CH,),NCOOCH3 (H,C = CH)NHCOOCH, NH,COOH (cis)

0,

C,

N3

06

H,(G)

H,(G)

H,(G)

-0.59 -0.61 -0.61 -0.62 -0.63 -0.60 -0.55

0.97 1.02 1.03 1.05 1.08 1.06 1.00

-0.90 -0.92 -0.92 -0.87 -0.85 -0.93 -0.94

-0.73 -0.73 -0.75 -0.74 -0.75 -0.75 -0.72

0.40 0.40 0.40 0.39 -0.17 0.41 0.38

0.40 0.39 0.39 -0.22 -0.22 0.20 0.41

0.45 -0.11 0.04 -0.11 -0.11 -0.12 0.43

“All molecules are in the truns conformation with the exception of the last.

187

separation. The N3 atom picks up additional negative charge when the alkyl group is added to the other end of the carbamate (on 0,) while the opposite is true when the substitution occurs on itself (except for the vinyl group which makes N3 more negative). The charge on the ester 0, oxygen atom is fairly insensitive to the substituents, as are the remaining atoms. The charge on H, is consistently close to +0.40 except when it is replaced by a methyl group in (CH3)2NCOOCH, in which case the charge on C, is -0.17. The same is true of the other N-H hydrogen Hg. Note that the charge on C5 is -0.22 when it is part of a methyl group and +0.20 when incorporated into the vinyl group. The carbon atom attached to O6 has a charge of -0.11 if a methyl group and +0.04 if an ethyl group. Comparison of the first and last rows of Table 8 illustrates the electronic redistributions accompanying the trans to cis transition in carbamic acid. The 0, and Cz atoms become more positive while N3 increases its negative charge. Coupled with the trends on the other atoms, this pattern may be summarized as an overall transfer of charge from the -COOH to the -NH2 group. ACKNOWLEDGEMENT

M.R. is grateful to the Fulbright Foundation for an award. Grants to S.S. from the National Institutes of Health (GM29391, GM36912, and AM01059) and from the National Science Foundation (DMB-8612768) provided partial financial support of this work.

REFERENCES 1 2 3 4

5 6 7 8 9 10 11 12

M.E. Wolff (Ed.), Burger’s Medicinal Chemistry, 4th Ed., Parts II and III, The Basis of Medicinal Chemistry, Wiley, New York, 1979,198l. D.R. O’Brien, The Design of Organophosphate and Carbamate Inhibition of Choline&erases, in E.J. Arii+ns (Ed.), Drug Design, Vol. II, Academic Press, London, 1971, pp. 162-212. G.S. Hartley in E.J. AriiSns(Ed.), Drug Design, Vol. VI, Academic Press, London, 1975, pp. 298-351. D.J. David and H.B. Staley, Analytical Chemistry of the Polyurethanes, in H. Mark, P.J. Flory, C.S. Marvel and H.W. Melville (Eds.), High Polymers, Vol. XVI, Part 3, Wiley-Interscience, New York, 1969. B.H. Bracher and R.W.H. Small, Acta Crystallogr., 23 (1967) 410. B. Sepehrnia, J.R. Ruble and G.A. Jeffrey, Acta Crystallogr., C43 (1987) 249. E. Lustig, W.R. Benson and N. Day, J. Org. Chem., 32 (1967) 851. C.H. Bushweller, P.E. Stevenson, J. Golini and J.W. O’Neil, J. Phys. Chem., 74 (1970) 1155. P.T. Inglefield and S. Kaplan, Can. J. Chem., 50 (1972) 1594. A.E. Lemire and J.C. Thompson, Can. J. Chem., 53 (1975) 3732. S. Hoogasian, C.H. Bushweller, W.G. Anderson and G. Kingsley, J. Phys. Chem., 80 (1976) 643. M.L. Martin, F. Mabon and M. Trierweiler, J. Phys. Chem., 85 (1981) 76.

188 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

M. Remko and J. Cizmarik, Eur. J. Med. Chem., 15 (1980) 556. J. Blackwell and M.R. Nagarajan, Polymer, 22 (1981) 202. M. Remko, V. Frecer and J. Cizmarik, Arch. Pharm. (Weinheim, Ger.), 316 (1983) 9. M. Remko and P. Th. Van Duijnen, J. Mol. Struct. (Theochem), 105 (1983) 1. M. Remko, I. Sekerka and P.Th. Van Duijnen, Arch. Pharm. (Weinheim, Ger.), 317 (1984) 45. R.A. Kydd and A. Rank, J. Mol. Struct., 77 (1981) 227. C. Van Alsenoy, J.O. Williams and L. Schiifer, J. Mol. Struct. (Theochem), 76 (1981) 179. J. Manning, V.J. Klimkowski, K. Siam, J.D. Ewbank and L. Schiifer, J. Mol. Struct. (Theothem), 139 (1986) 305. W. Caminati, A.C. Fantoni, L. Schiifer, K. Siam and C. Van Alsenoy, J. Am. Chem. Sot., 108 (1986) 4364. M. Remko, V. Frecer and J. Cizmarik, Coil. Czech. Chem. Commun., 48 (1983) 533. M. Remko, P.Th. Van Duijnen, I. Sekerka and J. Cizmarik, Drugs Exp. Clin. Res., 12 (1986) 739. J.S. Binkley, R.A. Whiteside, R. Krishnan, R. Seeger, D.J. DeFrees, H.B. Schlegel, S. Topiol, L.R. Kahn and J.A. Pople, QCPE, 13, Prog. No. 406 (1981). H. Tatewaki and S. Huzinaga, J. Comput. Chem., 1 (1980) 205; S. Huzinaga (Ed.), Gaussian Basis Sets for Molecular Calculations, Elsevier, Amsterdam, 1984. J.S. Binkley, J.A. Pople and W.J. Hehre, J. Am. Chem. Sot., 102 (1980) 939. P.C. Hariharan and J.A. Pople, Theor. Chim. Acta, 28 (1973) 213. J.A. Pople, R. Seeger and R. Krishnan, Int. J. Quantum Chem., 11s (1977) 149; R. Krishnan and J.A. Pople, Int. J. Quantum Chem., 14 (1978) 91. F. Pavelcik, M. Remko, J. Cizmarik and J. Majer, Coll. Czech. Chem. Commun., 51’( 1986) 264. J. Blackwell, J.R. Quay, M.R. Nagarajan, L. Born and H. Hespe, J. Polym. Sci., Polym. Phys. Ed., 22 (1984) 1247. R.D. Gandour, Bioorg. Chem., 10 (1981) 169. I. Tvaroska, S. Bystricky, P. Maion and K. Blaha, Coll. Czech. Chem. Commun., 47 (1982) 17; M. Remko, I. Sekerka and V. Frecer, Coll. Czech. Chem. Commun., 48 (1983) 3214. A. Savaryn and J.S. Jadav, Int. J. Quantum Chem., 22 (1982) 547. L. Radom and N.V. Riggs, Aust. J. Chem., 35 (1982) 1071. R.A. Russel and H.W. Thompson, Spectrochim. Acta, 8 (1956) 138; F.A.L. Anet and M. Squiiiacote, J. Am. Chem. Sot., 89 (1967) 4300. 0. Gropen and N.M. Seip, Chem. Phys. Lett., 11 (1971) 445. M. Remko and J. Cizmarik, Acta Fat. Pharm. Univ. Comenianae, 40 (1986) 43. R.S. Mulliken, J. Chem. Phys., 23 (1955) 1833.