Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0105 157

3. Chiroptical properties of amino compounds

145

E conformation [ E - S -146] whereas 3-substituted nitrosopyrrolidines [ S -147] exist roughly as an equimolar mixture of the E and Z conformers [ E - and Z - S -147]. Thus the CD spectrum of S -3-methyl-N-nitrosopyrrolidine shows pronounced fine structure and crosses the zero line within the n ! Ł transition spectral region (Figure 12). The bisignate CD curves for the n ! Ł transition of the nitrosamine chromophore is ascribed to the E Z equilibrium of the chromophore or to vibrational electronic coupling, and on either of these bases, the general validity of the symmetry sector rule (148) proposed134 some years ago for the planar nitrosamine chromophore was questioned. More recently the chiroptical properties of the enantiomers of a substantial number of N-nitrosopyrrolidines, including S -145 and S -146, were studied in some detail135, and it was shown that the CD of monocyclic compounds such as S - 145 and S -146 depends on substituent, solvent and temperature effects and, as a result, some of the N-nitrosamines exhibit bisignate CD curves in the region of the n ! Ł transition. Conformationally rigid biand tricyclic N-nitrosamines, such as (1S,5R)-N-nitroso-1-methyl-3-azabicyclo[3.1.0]hexane [(1S,5R)-149], show monosignate CEs, the rotational strengths of which are almost solvent-independent. Thus bisignate curves result from the presence of two half-chair conformers of the pyrrolidine ring in equilibrium and contributing opposite CD signs. On the basis of the molecular geometries as calculated by the molecular mechanic (MM2) method for a particular ringsubstituted N-nitrosopyrrolidine and taking into consideration the amounts of and the rotational contributions of the E Z and half-chair conformations, the CE signs were predicted using the sector rule for the planar nitrosamine chromophore shown in 148.

[θ]

+ 400

+ 300

+ 200

+ 100

λ nm

0

300

325

350

375

400

425

− 100

− 200

methanol

− 300

acetonitrile

FIGURE 12. Electronic circular dichroism spectra of S-3-methyl-N-nitrosopyrrolidine [S-147]. Reproduced from Reference 133 by permission of Acta Chemica Scandinavica

146			Howard E. Smith
H		CH3		CH3
						CH3
	N		N		N
				NO
		NO				NO
	[(1S,5R)-149]		[(R)-150]		[(R)-151]

The stereochemistry and chiroptical properties of the nonplanar nitrosamine group in chiral ring-substituted N-nitrosaziridines136 and N-nitrosazetidines137, such as R- 2-methyl-1-nitrosaziridine [R-150] and R-2-methyl-1-nitrosazetidine [R-151], were investigated by means of nonempirical quantum chemical calculations and by measurement of their CD spectra. For R-150, four conformational diastereomers can contribute to the observed CEs, and on the basis of the calculated equilibrium of these diastereomers and the rotational contribution of each as given by a spiral sector rule, the same as that for chiral N-acylaziridine, the known absolute configuration of R-150 is correlated with the sign of its n ! Ł CE in the 350 500 nm region. Similar considerations allow the correlation of the sign of this same CE with the absolute configuration of 2S-trans- 2,3-dimethyl-1-nitrosaziridine [(2S,3S)-152]. A second transition at shorter wavelength near 240 nm which has an oppositely signed and stronger CE is assigned as a ! Ł transition of the inherently chiral nitroso chromophore136. The presence of the ester functionality, however, in an N-nitrosaziridine results in a reversal of the CE sign of both the n ! Ł and ! Ł transitions.

H3C CH3

N

NO

[(2S,3S)-152]

For alkyl-substituted N-nitrosazetidines, it was shown that the CD spectra can be interpreted on the basis of conformational diastereoisomerism, taking into account the nonplanarity of the nitrosazetidine chromophore137. For a particular configuration, the CE sign of the n ! Ł transition in the 350 400 nm region is determined by the intrinsic chirality of the chromophore and obeys a spiral rule, the same as that for nonplanar nitrosaziridines where the absence of the local plane of symmetry in the nitrosamine chromophore does not permit the use of the planar sector rule 148.

V.VIBRATIONAL OPTICAL ACTIVITY (VOA)

A.Vibrational Circular Dichroism (VCD)

Although Lowry in his classical treatise in 1935 discussed the possibility of detection of circular dichroism arising from molecular vibration transitions138, only in the past two decades has it been possible to measure optical activity associated with infrared absorption transitions, CD maxima first being detected in the VCD spectrum for the C H stretching modes of the enantiomers of 2,2,2-trifluoro-1-phenylethanol as the neat liquid139. This work was initiated with the view that such measurements would eventually yield information concerning absolute configurations and molecular conformations of

3. Chiroptical properties of amino compounds		147
CH3	CH3
C NH2	C N(CH3)2
H	H
[(R)-(+)-22]	[(R)-(+)-153]

FIGURE 13. Vibrational circular dichroism and transmission spectra of R- C - and S- -N,N- dimethyl-˛-phenylethylamine [R- C - and S- -153] in carbon tetrachloride. Reprinted with permission from Reference 140. Copyright (1976) American Chemical Society

such molecules139. A more extensive study of the VCD in the C H, O H and N H stretching bands of a number of chiral compounds as the neat liquid and in carbon tetrachloride, including the enantiomers of ˛-phenylethylamine [R- C - and S- - 22] and their N,N-dimethyl derivatives [R- C - and S- -153] (Figure 13), was reported140. This work was also undertaken for the development of the formal theory of VCD to explore the accuracy of calculations on simple well-defined systems for which unambiguous calculations and experiments can both be performed. To assess the possible role of the methyl group as a probe for the assignment of absolute configuration, the VCD spectra of several chiral ˛-substituted phenylethanes, including R-˛-phenylethylamine [R-22] and its p-bromo derivative, were examined in the 1400 1480 cm 1 region both as the neat liquid and in carbon tetrachloride141. In these compounds, all with the same

148	Howard E. Smith

generic configuration, the negative VCD maximum at about 1450 cm 1 was interpreted as being due to interaction of the methyl group deformation with a near-degenerate phenyl mode141.

The VCD spectra of R- and S)-22 were also examined in the mid-infrared region (900 1625 cm 1)142. These spectra, with unusual VCD features, showed that the VCD associated with the C-˛ hydrogen atom and the phenyl ring vibrational modes appears to be significant in understanding the relationship of VCD features to stereochemistry and that the mid-infrared VCD of R- and S-22 as the neat liquid differ from those of a dilute solution in carbon tetrachloride140. In connection with this work, the infrared and Raman spectra of several ˛-substituted phenylethanes were measured so as to identify the stretching vibrations of the methine and methyl groups143. These identifications were facilitated by the deuteriation of the methine group in all of the molecules examined, including ˛-phenylethylamine (22), and of the methyl group and phenyl group in ˛- phenylethyl alcohol, and it was found that the methine stretching vibrational frequency and its intensity are significantly affected by substitution at the carbon atom to which the methine hydrogen atom and methyl group are directly attached143.

The VCD of R- and S-1-aminoindan [R- and S-154], R- and S-1- methylindan [R- and S-155], and R-1-methylindan-1-d[R-156] were measured in the 800 1600 cm 1 region, and in each spectrum, the sign of the VCD maximum at about 1350 cm 1, positive for the R configuration and negative for the S configuration,

was found to correlate with the absolute configuration144. This correlation is in agreement with one found for S-methyloxirane145 [S-157] and R-methylthiirane144,146 [R-158] and reflects the importance of VCD measurements in stereochemical analysis of chiral ring systems. General correlation rules, however, have not been established to relate the absolute configuration at a particular chiral center in a chiral molecule of substantial size with CD maxima in its VCD spectrum.

R

CH3 D

[(R)-154] R = NH2
[(R)-155] R = CH3			[(R)-156]
CH3	H3 C		CH3	CH3
X	N			N
				H
	H
[(S)-157] X = O
[(S)-158] X = S	[(2S,3S)-159]			[(1R,2R)-160]

Small, rigid chiral molecules, such as methyl-substituted oxiranes147, thiiranes148 and aziridines149,150, have attracted much attention for VOA studies since they have a potential for serving as a bench mark for rigorous theoretical investigations. Thus the

3. Chiroptical properties of amino compounds

149

ν −

FIGURE 14. Theoretically simulated and experimental vibrational circular dichroism (VCD) and infrared (IR) spectra of (2S,3S)-2,3-dimethylaziridine [(2S,3S)-159] carbon tetrachloride in the region 700 1600 cm 1. Reproduced from Reference 149 by permission of the National Research Council of Canada

experimental VCD spectra of (2S,3S)-2,3-dimethylaziridine149 [(2S,3S)-159] and 2R -2- methylaziridine150 [ 2R -160] were measured in the 800 1500 cm 1 region. The VCD spectrum of (2S,3S)-159 (Figure 14) was interpreted with the help of ab initio vibronic coupling theory (VCT) both in the common origin (CO) and distributed origin (DO) gauge. Both VCT-CO and VCT-DO methods predict VCD and IR spectra that are in good agreement with the experimental spectra (Figure 14). The VCT method together with the 6-31GŁ 0.3 basis set can be employed with confidence in determining the absolute configuration for rigid chiral molecules such as (2S,3S)-159. Using the VCT method with the 6-31GŁ 0.3 basis set, the VCD spectrum was computed for each of the cis and trans conformational diastereomers of 2R -2-methylaziridine [ 2R -160], the rotatory strengths of many absorptions being oppositely signed and of similar magnitude in the two conformational enantiomers which differ in configuration at the nitrogen atom150. The experimental VCD spectrum of 2R -160 was found to be dominated by the contribution of the trans conformational diastereomer [(1R,2R)-160] present in greater abundance.

A similar ab initio computational and VCD study in the 800 1500 cm 1 range using5S -1-azabicyclo[3.1.0]hexane [ 5S -115] gave VCD spectra calculated at three different computational levels which are well reproduced in the experimental VCD spectrum151.

150	Howard E. Smith

The success of these ab initio calculations in predicting the signs of many of the VCD features of molecules of particular absolute configurations suggests that it should eventually be possible to interpret VCD spectra at a fundamental level, rather than simply relying on empirical correlations.

In connection with this suggestion, VCD measurements and calculations were also investigated with S-1-amino-2-propanol [S-161] and S-2-amino-1-propanol [S- 162]152, two similar molecules which can assume a number of intramolecularly hydrogenbonded conformations. The goal of this work was the assessment of the relative influence on VCD intensity of hydroxyl and amino groups at a chiral center and the applicability of a priori VCD calculations to the interpretation of the spectra for molecules with several conformers of similar energy. The vibrational frequencies, infrared intensities and VCD intensities, the latter using the vibronic coupling theory (VCT), were calculated for all hydrogen-bonded conformers with ab initio wave functions at a 6-31G 0.3 basis set. Comparison of the experimental and calculated spectra allowed correlation of the major VCD features with only a few predominant conformers152.

CH2NH2	CH2OH
HO C H	H2N C H
CH3	CH3
[(S)-161]	[(S)-162]

The VOA of ˛-amino acids has also been examined in some detail as an aid to the use of VCD measurements in the understanding of peptide conformation153,154. The VCD spectra of L-alanine (L-163)153,154, several other L-˛-amino acids and dipeptides were measured in water and deuterium oxide between 900 and 1700 cm 1. In both solvents, a characteristic ( ,C) VCD pattern near 1325 cm 1 (negative at higher frequency) was observed for the two orthogonal methine bending modes in L-˛-amino acids and in L- dipeptides only for a methine bond adjacent to a carboxylate group. For the L-˛-amino acids at the low pH or for the N-terminus of a dipeptide, no VCD intensity, which was interpreted in terms of a ring current mechanism, was observed for these methine bending modes155. The CH-stretching VCD spectra of several amino acids were examined as a function of pH156. At neutral and high pH, the VCD spectra exhibited a large positive VCD intensity bias which is associated with the C˛ H methine stretching mode. At low pH, the bias is absent and only weak VCD spectra are observed, and the VCD spectra were interpreted within the framework of the ring current mechanism155. It was proposed, however, that closed pathways due to a variety of intramolecular interactions in the amino acids can support vibrationally generated ring currents which give rise to VCD intensity enhancement156.

CO2−

+

H3NCH

CH3

(L-163)

B. Raman Optical Activity (ROA)

In the last two decades, interest has also turned to the possible use of Raman optical activity (ROA) as an additional probe into the stereochemistry of chiral molecules157. The

3. Chiroptical properties of amino compounds

151

term Raman circular dichroism is not used since the word dichroism refers to differential absorption. The process responsible for Raman scattering is different from that producing infrared absorption, and the effect cannot be regarded as a manifestation of infrared circular dichroism although both are forms of vibrational optical activity158. For the phenomena, the term Raman circular intensity differential (CID) is used with the symbolexpressed as in equation 3,

D IR IL/ IR C IL

3

where IR and IL are intensities of the scattered light in right and left circularly polarized incident light. The CID can be defined for light scattered at 90° which is linearly polarized perpendicular x and parallel z to the scattering plane158.

The first report for observation of the differential Raman scattering, using the enantiomers of ˛-phenylethylamine (22)159, could not be verified and in fact was based on artifacts158,160. Using improved instrumentation, the sum and difference spectra for R-˛-phenylethylamine [R-22] were successfully measured with parallel scattering (Figure 15), the signal intensities measured in photon counts160 from which its CIDs were calculated. With these data and those using the spectra of -˛-pinene (164),

FIGURE 15. Raman circular intensity spectra for R-˛-phenylethylamine [R-22] in photon counts:

(A) difference spectrum, IRz ILz ; (B) sum spectrum, IRz C ILz ; (C) difference spectrum, IRx ILx . Reprinted with permission from Reference 160. Copyright (1975) American Chemical Society

152		Howard E. Smith
		CH3	H3C	CH3
Br		C	NH2	S
		H
(164)		[(R)-165]	[(2R,3R)-166]

it was suggested that the degenerate antisymmetric CH3 deformation mode centered at 1450 cm 1 has important potential for probing the local environment of methyl groups160. In R-22 the local degeneracy of the methyl group is removed by the asymmetric environment and a sizable CID couplet (negative at higher wave number) was found, and no change in sign of this couplet at 1450 cm 1 was expected by replacing the phenyl group with a substituted phenyl group160. Other work also suggested that for Raman CIDs in methyl asymmetric deformations and methyl torsions, the methyl group could function as a powerful new probe of chirality161, and the R absolute configuration of C - 1-methylindan [ C -155] was confirmed on a comparison of its ROA spectrum, especially using the antisymmetric deformation mode of the methyl group at 1450 cm 1, with that of R-˛-phenylethylamine [R-22]162. When the Raman CID spectrum between 80 and 2000 cm 1 of R-˛-(p-bromophenyl)ethylamine [R-165] was examined163, however, no corresponding CID couplet at 1450 cm 1 was found, but instead a new Raman band associated with a large positive CID appeared at 1410 cm 1 and is almost certainly a stretching mode of the substituted aromatic ring163. On this basis then the methyl asymmetric deformation at 1450 cm 1 should be used with caution163. In line with this conclusion and as discussed above in connection with the interpretation of vibration circular dichroism, the infrared and Raman spectra of several ˛-substituted phenylethanes were measured to identify the stretching vibrations of the methine and methyl groups143, and it was found that the methine stretching vibrational frequency and its intensity are significantly affected by substitution at the carbon atom to which the methine hydrogen atom and methyl group are directly attached143.

As discussed above, the VCD studies of small, rigid chiral molecules, such as methylsubstituted oxiranes147, thiiranes148 and aziridines149,150, have attracted much attention since they have a potential for serving as benchmarks for theoretical investigations. The same is true for ROA studies, and the experimental ROA spectrum in the 200 1500 cm 1 region of C -trans-2,3-dimethythiirane, known to have the 2R,3R absolute configuration, was compared with that calculated by ab initio quantum calculations for (2R,3R)-2,3- dimethylthiirane [(2R,3R)-166]164. The excellent level of agreement obtained for the observed and calculated ROA signs suggests that the absolute configuration of such chiral molecules can be determined confidently using a comparison of ROA observations and ab initio quantum mechanical calculations of the ROA of a particular enantiomer164.

Recently there has also developed an interest in the ROA of biologically significant molecules such as ˛-amino acids in aqueous solution due to a substantial increase in instrument sensitivity based on backscattering of the scattered light instead of the usual

perpendicular (90°) scattering arrangement165. Using this new instrumentation, the experimentally observed ROA of L-alanine165,166 (L-163) in water, 1 N sodium hydroxide and

1 N hydrochloric acid between 720 and 1700 cm 1 and the ab initio calculated Raman and ROA intensities for the zwitterionic form of L-alanine (L-163) using the 6-31G and 6-31GŁ basis sets were found to agree remarkably well with experimental parameters in the lower frequency region165. With a small revision for the experimental observation for L-163 in aqueous sodium hydroxide and hydrochloric acid, refinement of Raman and ROA

3. Chiroptical properties of amino compounds

153

band assignments were made166. Also, comparison of the backscattered ROA spectra of L-alanine (L-163), L-alanine-2-d1, and L-alanine-3,3,3-d3 in water and deuterium oxide in the 800 1700 cm 1 frequency region and the ab initio calculations of Raman and ROA intensities with a 6-31GŁ basis set for the zwitterionic forms (L-163) gave excellent agreement between experiment and calculation for both Raman and ROA spectra167. The success of these ab initio calculations in correctly predicting the signs of many of the observed ROA features of a molecule as large as L-alanine suggests that it should eventually be possible to interpret ROA spectra at a fundamental level, rather than relying on empirical correlations to extract stereochemical information. Unfortunately, ˛-amino acids larger than L-alanine are too large at this time for similar ab initio calculations, but the L-alanine results reported earlier165 were used to interpret the backscattered ROA spectra between 600 and 1600 cm 1 of a number of simple ˛-amino acids larger than L-alanine, L-serine, L-cysteine, L-valine, L-threonine and L-isoleucine, in water168. It was shown that similarities between the ˛-amino acid ROA spectra will enable ROA to make important contributions to solution conformation studies. It appears that the C(2) H deformations and symmetric CO2 stretch offer the most reliable ROA signature for stereochemical correlations, including the determination of absolute configurations.

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