E,Z Isomers of a-Chloro-@-aminocrotonamideby NMR
The Journal of Physical Chemistry, Vol. 83, No. 5, 1979 637
(unsubstituted) protons have couplings nearly equal to the corresponding values in benzyl (Table 11). However, the methyl splittings in these xylyls are smaller than the splittings of the protons they replace. This is particularly striking in o -xylyl. McLachlan calculations, which admittedly did not predict good values for the apparent spin density in benzyl, predicted only very small variations in the n-spin density upon methyl substitution. It is not clear whether spin density redistribution is responsible for these methyl substitution effects. In the case of rn-xylyl a small hyperconjugative coupling from the large, positive spin densities at the neighboring ortho and para positions would reduce the absolute value of the methyl coupling. This is because there is a relatively small and negative spin density at the meta position.20 However, this mechanism is not a resonable explanation of the results for 0-xylyl because the ring neighbors of the ortho position have little spin density. Observation of 13C splittings in these systems would be informative. References ,and Notes
H. Itzei and H. Fischer, Helv. Chim. Acta, 59, 880 (1976). R. S.Davidson and R. Wilson, J. Chem. SOC. B, 71 (1970). J. G. Calvert and J. N. Pitts, Jr., ”Photochemistty”, Wiley, New York, 1966, pp 263-268, 377-379. H. Yoshda and T. Warashina, Bull. Chem. Soc. Jpn., 44, 2950 (1971). R. Livingston and H. Zeldes, J. Chem. Phys., 44, 1245 (1966). R. W. Fessenden, J . Chem. Phys., 37, 747 (1962). P. Neta and R. H. Schuler, J. Phys. Chem., 77, 1368 (1973). R. W. Fessenden and R. H. Schuler, J. Chem. phys., 39, 2147 (1963). P. D. Sullivan and J. R. Boiton in “Advances in Magnetic Resonance”, Vol. 4, J. S. Waugh, Ed., Academic Press, New Yolk, 1970, pp 39-85. J. A. Pople, W. G. Schneider, and H. J. Bernstein, “High-Resolution Nuclear Magnetic Resonance”, McGraw-Hill, New York, 1959, pp 218-225. 0. K. Fraenkel, J . Chem. Phys., 42, 4275 (1965). F. W. King, Chem. Rev., 78, 157 (1976). H. Wahlquist, J. Cbem. Phys., 35, 1708 (1961). The factor of HI/: that appears in eq 14 and Figure 1 of this work should be H,/*instead. We have verified the dependences in Figure 1. G. V. H. Wilson, J. Appl. Phys., 34, 3276 (1963). C. Heller and H. M. McConnell, J . Cbem. Phys., 32, 1535 (1960). E. W. Stone and A. H. Maki, J . Chem. Phys., 37, 1326 (1962). P. 6. Ayscough, “Eleotron Spin Resonance in Chemistry”, Methuen, London, 1967, pp 74-78. A. M. Ihrig, P. R. Jones, I. N. Jung, R. V. Lloyd, J. L. Marshall, and D. E. Wood, J. Am. Chem. Soc., 97, 4477 (1975).
(1) ORNL Eugene P. Wigner Fellow. (2) S. Ogawa and R. W. Fessenden, J. Chem. Phys., 41, 994 (1964).
E , Z Isomers of a-Chloro-P-aminocrotonamide. Determination of Absolute Configurations by Nuclear Magnetic Resonance Spectroscopy Pranab K. Bhattacharyya” and Yakub G. Bankawala Hoffmann-La Roche Incorporated, Quality Control Department, Nutley, New Jersey 07 110 (Received September 18, 1978) Pubiication costs assisted by Hoffmann-La Roche Incorporated
The geometrical isomers of a-chloro-P-aminocrotonamide provide an interesting example of the application of the long-range shielding effect of the magnetically anisotropic carbonyl bond in the determination of absolute configurations in terms of the Cahn-Ingold-Prelog nomenclature by NMR spectroscopy. For the purpose of stereochemical identification, the observed differential shifts are interpreted to be mainly due to magnetic susceptibility anisotropy of the carbonyl bond. The contribution due to the direct electrostatic effects of bond dipoles is found to be relatively negligible. The absolute configurations of the major and minor isomers observed in the NMR spectrum are determined to be E and 2, respectively.
Introduction The identification of stereoisomers in a mixture is frequently a problem in analytical studies. An important aspect of NMR spectroscopy for specific stereochemical applications is the long-range shielding effect of magnetically anisotropic groups such as C=O, CrC, and N=O. This is because of the fact that the shielding influence of these strongly anisotropic bonds is dependent on the spatial irelationship of the shielded proton and the function in question, which is the carbonyl group in this case. Since the susceptibility tensor is isotropic due to inner-shell electrons, the anisotropy is essentially due to bonding electrons and lone pairs. The susceptibility anisotropy of bonds can be separated into two parts: diamagnetic and paramagnetic. Since the electronic distribution of the anisotropic bonds is not spherical, it is expected that the anisotropy is mainly due to the paramagnetic part which arises from the mixing of the ground state with the excited electronic states. 0022-3654/79/2083-0637$01 .OO/O
Shielding Effect of Anisotropic Groups The gist of the theory necessary to interpret the long-range shielding effects due to anisotropic groups is described below. If the proton is at a vector distance 2 from a magnetic dipole, the contribution to the chemical shift tensor of the proton is given by1!2
x fJ=---
r3
3i.x.i r5
(1)
where x is the magnetic suseptibility tensor of the group. Hence, if the induced magnetic moments are considered to act as point dipoles, the contribution to the chemical shielding due to an anisotropic bond is given by 1 AU = - C xii(1 - 3 COS’ 6i) (2) 3r3i=x,y,r where r is the distance between the proton under con0 1979 American Chemical Society
638 The Journal of Physical Chemistry, Vol. 83, No. 5, 1979
L
10
I
I
1
I
9
8
7
6
P. K. Bhattacharyya and Y. G. Bankawala
I
1
I
5
4
3
,I
2
I 0
I
I
PPMW
Figure 1. The proton magnetic resonance spectrum of a-chloro-P-aminocrotonamidein Me,SO-d, asterisks.
sideration and the electrical center-of-gravity of the bond and 0, is the angle between the axis i and ?. xiL is a principal element of the bond susceptibility tensor. In most cases, for the purpose of stereochemical assignments, the principal axes for bond susceptibilities will be along or perpendicular to the bond. That is, the general nature of shielding is such that there is a nodal cone of elliptical cross section whose axis is in the direction of one of the principal susceptibilities. Equation 2 then reduces to AIS = (1/3r3)[(xll - X11)(3
COS'
- 1)
+ (xi1
(3 cos2
-
Xltr) X
solvent. The solvent peaks are marked with
TABLE I: Experimental Proton Chemical Shift Data of oi -Chloro-P-aminocrotonamide
proton
isomer
s /(ppm)"
CH,
major minor major minor major minor
1.97 2.24 6.60 6.04 1.64
*"
COOH
a Me,SO-d, was used as the solvent. &(minor).
A 6 /(ppm)b
-0.21 0.56
A 6 = 6(major) -
e l f /- l)] (3)
where xII is the principal component along the bond direction, and xLt and xIJ are the principal components perpendicular to the bond. el!and OL,(are the angles between 5 and the appropriate perpendicular to bond. In the cases involving double bonds, the I' direction is taken to be in the nodal plane of the 7~ electrons. Typical values for carbonyl bond susceptibilities are3 xII - xL( = 25 and - xt,I = 33 in units of A3/molecule. The following approximate form of eq 3 will be used in this paper: (4)
where xl = (xLt + xln)/2, = el,,, and 0 is the angle between the bond axis and ?. Assuming free rotations about single bonds, the shielding contribution due to the magnetic anisotropy of the carbonyl bond is given by 1 (5) ( A n ) sz -[(XI/ - X L ) ( ~- 3 ( C O S 2 @))I 3r03
where ro is the distance between the center-of-gravity of the magnetically equivalent protons and the electrical center-of-gravity of the carbonyl bond which is assumed to lie at the midpoint of this bond. The notation ( ) denotes the rotational average value. The above equations are very useful in determining the contribution to chemical shielding due to the presence of the magnetically anisotropic bonds in molecules. While the magnitude and nature of shielding (or deshielding) depend on the absolute values and signs of the bond susceptibility anisotropies, this effect which causes thru-space shielding at a distance is extremely valuable
k 6 E-Isomer
'H
'H 2-Isomer
Figure 2. Geometrical isomers of a-chloro-P-aminocrotonamidein the nomenclature of Cahn, Ingold, and Prelog. The double bonds are indicated by the darker lines.
in making stereochemical assignments. Experimental Results The NMR spectrum of a-chloro-0-aminocrotonamide is presented in Figure 1. A Varian XL-100 NMR spectrometer was used in obtaining the necessary NMR spectrum for this study. The NMR spectrum clearly shows from an intuitive understanding that the sample is a mixture of two geometrical isomers in the mole ratio of major to minor equal to 9O:lO. The chemical shift values are given in Table I. Assignment of Absolute Configurations The next problem is to assign the absolute configurations of the geometrical isomers (Figure 2) of the compound in terms of Cahn-Ingold-Prelog n ~ m e n c l a t u r e . ~ The observed chemical shift differences (major - minor = -0.27 ppm for methyl protons and 0.56 ppm for amine protons) are not expected from electronegativity considerations since the inductive effect, which propagates by successive polarization of the intervening chemical bonds,
The Journal of Physical Chemistry, Vol. 83, No. 5, 7979 639
E,Z Isomers of a-Chioro-6-aminocrotonamide by NMR
TABLE 11: Calculated Shielding C o n t r i b u t i o n s Due to t h e C a r b o n y l Bond proton
isomer
CH,
E
NH,
E Z
2:
0
(cosz
AU/
valuesa
0)
PPmb
32-78" 3-54' 0-52" 32-55'
0.3468 0.7377 0.7672 0.5255
0.00 0.25 0.39 0.02
A(AU)/ (PPmY
-0.25 0.37
The a O b t a i n e d from diagrams of m o l e c u l a r models. signs of t h e calculated values have been reversed so t h a t positive and negative signs r e f e r t o relative deshielding a n d shielding, respectively. A ( A u ) = A u ( m a j o r ) - Au(minor).
is expected i o be practically independent of the spatial relationship between the proton and the carbonyl group. However, the diamagnetic part of the shielding constant can be influenced by a term which is a function of the electric field caused by the existence of charges or dipoles in a molecule. The differential contribution from the direct electrostatic effect which arises from the presence of the bond dipoles in the molecule can be estimated from the following e q ~ a t i o n : ~
where qi is the charge on the ith atom in units of le1 where le1 is the absolute value of the electronic charge, rojis the between the ith atom and the center-ofdistance (in gravity of the equivalent protons in question, and 4i is the angle of the field vector with respect to the C-H bond axis for the particular proton. The contribution due to eq 6 has been calculated by assigning partial charges equivalent to the following bond dipole moments on the atoms of the bonds under consideration: C-N, 1.5 D; C-C1,2.0 D; and C=O, 2.5 D. 'These values have been estimated from those of the electric dipole moments of relevant molecules given in ref 6. The inet differential contribution to the shielding of the E and Z isomers is found to be relatively negligible (-0.05 ppm) as a result of cancellations. It has been ascertained that the differential chemical shift between the isomers may be approximately fitted to the eq 5 based on the long-range effect of carbonyl deshielding. If the effective center of the carbonyl bond magnetic dipole is assumed to lie at the middle of the bond axis, calculations based on the Dreiding models7 of the geometrical isomers (Figure 2) and free rotation about single bonds yield the contributions which are listed in Table 11. This table shows that the methyl protons in the 2 configuration (where CH, is cis to C=O bond) are deshielded by 0.25 ppm relative to those in the E configuration (where CH, is trans to C=O bond). Also the amine protonzi in the E configuration are deshielded by 0.37 ppm with respect to those in the 2 configuration. The differential chemical shift between the amide protons of the E and Z isomers is practically zero since the spatial orientation of the carbonyl group with respect to these
rs)
protons remains the same in the two isomers. A comparison of the observed and calculated chemical shift data for the methyl and amine protons, listed in Tables I and 11, respectively, leads to the unambiguous assignment that the absolute configuration of the major isomer is E , and that of the minor isomer 2 (see Figure 2). It is important to note that the results of this investigation are in agreement with the determination by X-ray diffraction' of the absolute configuration of the major isomer.
Discussion The stereochemical assignments described above demonstrate the utility of the long-range effect of the carbonyl bond which is magnetically anisotropic. An investigation of this effect has resulted in the positive identification of the absolute configurations of the geometrical isomers of the compound under study. Consequently, the distinctive chemical shifts can be used for conclusive identification of the E and Z isomers present singly or as a mixture in a sample. The agreement between the observed and calculated differential chemical shifts is good quantitatively for the methyl protons and qualitatively for the amine protons which are also influenced by effects due to intermolecular hydrogen bonding. Because of the long-range influence of the carbonyl bond in this case, the point dipole and point charge approximations seem to be adequate, a t least, for a qualitative interpretation of the observed differential chemical shifts. In general, any strongly magnetically anisotropic group is useful in stereochemical studies. However, since the magnitude and sign of the long-range shielding depend on the geometric relationship of the proton to the anisotropic bond, stereochemical models are helpful for a qualitative understanding of this effect. Finally, it is interesting to mention that the stereochemical assignments made in this investigation would not have been possible without the sample being obtained in isomerically impure form. Acknowledgment. The authors are grateful to Dr. S. A. Moros for his comments and support, Dr. A. Mlodozeniec and Dr. J. Sheridan for their support, and Dr. D. L. Coffen for use of the sample recently synthesized and patented by him.
References and Notes (1) H. M. McConnell, J . Chem. Phys., 27, 226 (1957). (2) J. A. Pople, Pfoc. R. SOC. London, Ser. A , 239, 550 (1957). (3) R. M. Lynden-Bell and R. K. Harris, "Nuclear Magnetic Resonance Spectroscopy", Thomas Nelson and Sons Ltd., London 1969, p 88. (4) R. Cahn, C. Ingold, and V. Prelog, Angew. Chem., Int. Ed. Engl., 5 , 385 (1966). (5) M. P. Shcweizer, S. I. Chan, G. K. Helmkamp, and P. 0. P. Ts'O, J. Am. Chem. SOC., 86, 696 (1964). (6) "Handbook of Chemistry and physics", 57th ed,CRC Press, Cleveland, Ohio, 1976-1977, p F-218. (7) The following values' of bond lengths and angles are used: C-H, 1.1 A; C-C, 1.5 A; C=C, 1.3 k C-N (amine group), 1.5 A; C-N (amide group), 1.3 A; C=O, 1.3 A; C-CI, 1.7 A; LH-C-H, 109'; LN-C=O, 122'; LH-N-H, 106'. (8) Private communicatiins from J. Blount (X-ray investiitor) to D. Coffen, and from D. Coffen to authors.
