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				135
	(+)			(−)
	(+)
	C*
	(−)			(+)
	(−)
near quadrants	all quadrants

FIGURE 8. Quadrant projections for application of the benzene sector rule to chiral monosubstituted benzene compounds

phenylcarbinamines, phenylcarbinols and related compounds105 suggest the quadrant projection shown in Figure 8 to predict the sign of the 1Lb CEs of a monosubstituted benzene compound. The signs shown on the projection in Figure 8 give the CD contribution to the 1Lb CEs for groups lying in the four quadrants. For groups lying on sector boundaries, there is no contribution to the CEs. The sum of these contributions gives the sign to the CEs of the 1Lb band, the signs for the particular quadrants following from the observed negative CEs for R -1-phenylethanol (118, R1 D CH3, R3 D OH). Again using ECD

data, sequences for the summation of rotatory contributions to the 1Lb CEs are SH, CO2 , C(CH3)3 > CH3 > NH2, C NH3, C N(CH3)3, OH, OCH3, Cl; and CH3 > CO2H > CNH3, OH, OCH3. These sequences may be used in connection with the sector signs in Figure 8

and will have a general usefulness for the establishment of the absolute configuration of related benzene compounds in which one substituent at the chiral center is a hydrogen atom. Since a methyl group makes a larger contribution to the 1Lb CEs than does an amino group or ammonium group, any phenylalkylcarbinamine, phenylalkylcarbinamine salt or their N-alkyl derivatives with the same generic absolute configuration as S -22 is predicted to show positive 1Lb CEs (Figure 7). With the opposite generic configuration, R -1-methyl-2-phenylpyrrolidine [ R -119] and R -1-methyl-2-phenylpiperidine [ R -120] show negative 1Lb CEs105 as is predicted by the benzene sector rule.

2. Benzene chirality rule

The sign of the 1Lb CEs from about 250 to 270 nm in the CD spectra of chiral phenylcarbinamines such as S -22 is determined by vibronic borrowing from allowed transitions at shorter wavelength. On ring substitution, transition moments are induced in the ring bonds adjacent to the attachment bond of the chiral group, resulting in enhanced coupling of the 1Lb transition with the chiral group. As given by the benzene chirality rule104 and as summarized in Table 1 for the rotatory contributions to the 1Lb CEs for a chiral benzene compound such as R -˛-phenylethylamine [ R -22] with a chiral substituent giving a negative vibronic contribution to the 1Lb CEs, a sign reversal for the 1Lb CEs on para substitution with an atom or group with a positive spectroscopic moment106 CH3 can be viewed as the overshadowing of the vibronic rotational strength by a positive induced contribution of opposite sign. Thus R -˛-phenylethylamine [ R -22] gives negative 1Lb CE38 while that for CEs of R -˛-(p-methylphenyl)ethylamine [ R -123] is positive38. On para substitution with a group with a negative spectroscopic moment106 CF3 , the sign of the 1Lb CEs is unchanged since the vibronic and induced contributions have the same sign, and R -˛-(p-trifluoromethylphenyl)ethylamine [ R -124] shows negative 1Lb CEs,

136	Howard E. Smith

TABLE 1. Rotational contributions to the 1Lb Cotton effects for a chiral benzene compound with a single chiral substituent giving a negative vibronic contribution to the 1Lb Cotton effects

			Substituent
Contributiona		para	metab	ortho
		No additional ring substituent
vibronic		negative	negative	negative
induced		š0	š0	š0
	Substitution by a group with a positive spectroscopic momentc
vibronic		negative	negative	negative
induced		positive	negative	positive
	Substitution by a group with a negative spectroscopic momentc
vibronic		negative	negative	negative
induced		negative	positive	negative

a For the enantiomers the respective signs for the contributions are reversed. b The signs are the same for the 3,5-disubstituted compounds.

c See Reference 106 for spectroscopic moments.

an unchanged sign from that of the unsubstituted parent38. Meta substitution by an atom or group will result in bond moments in an opposite sense from that caused by the same atom or group in the para position. Thus on meta substitution by a group with a positive spectroscopic moment, both the vibronic and induced contribution have the same sign, and the sign of the 1Lb CEs is the same as the unsubstituted parent. For meta substitution by a group with a negative spectroscopic moment, the sign of the induced contribution is opposite to that of the vibronic contribution. Ortho substitution again reverses the sense of the induced bond transition moments from those induced by the same meta substituents.

	CH3
R	C NH2
	H

[(R)-123] CH3 [(R)-124] CF3

If the vibronic and induced contributions to the 1Lb CEs have the same sign (Table 1), the sign of the CEs for an enantiomer for a particular ring-substituted phenylalkylcarbinamine or carbinol can be predicted with certainty. When the vibronic and induced contributions are of opposite sign (Table 1), a prediction as to the sign of the 1Lb CEs shown by a particular enantiomer is ambiguous. However, all of the phenylcarbinamines and carbinols so far reported that are para- or ortho-substituted with an atom or group with a positive spectroscopic moment106 (CH3, F, Cl, Br, OH and OCH3) show 1Lb CEs of opposite sign to that of the unsubstituted parent. Thus while R- 1-methyl-2-phenylpyrrolidine [R-119] and R-1-methyl-2-phenylpiperidine [R-120] show negative 1Lb CEs105, their ortho methyl-substituted derivatives, R-1-methyl- 2-(o-methylphenyl)pyrrolidine [R-121] and R-1-methyl-2-(o-methylphenyl)piperidine [R-122], each with a preferred conformation such that the hydrogen atom at the chiral center eclipses the benzene ring plane, show positive 1Lb CEs104. For the few phenylcarbinamines and carbinols with a group having a negative spectroscopic moment (CN, CF3) in the meta position, the sign of the 1Lb CEs did not change from that of the

3. Chiroptical properties of amino compounds

137

unsubstituted parent38. The benzene chirality rule has been successfully used to correlate the signs of the 1Lb CEs for enantiomers of a substantial number of ring-substituted benzene compounds38,104,107, including chiral perhydrobenzocycloalkanes, some with amino groups at chiral centers108.

C. Chromophoric Derivatives

1. N-Salicylidene derivatives and the salicylidenamino chirality rule

Of the number of chromophoric derivatives of chiral amines for potential use in the establishment of their absolute configuration by ECD measurement1, only a few have proven to be generally useful. Of these, intensive investigation of the N-salicylidene (Schiff base) derivatives of chiral primary amines, including unsubstituted and ringsubstituted ˛- and ˇ-arylalkylamines, ˛-amino acids, unsaturated and saturated aliphatic and alicyclic amines, and amino sugars, has resulted in the formulation of the salicylidenamino chirality rule109,110. The application of this rule has recently been reviewed110 and has been successfully used for the establishment of absolute configuration of chiral primary amines in connection with other stereochemical studies38. In related studies, the conformations of a series of pyridoxyl-L-˛-amino acid Schiff bases were deduced from their CD spectra111.

N-Salicylidene Schiff bases derivatives, such as S -N-salicylidene-˛-phenylethyl- amine112 [ S -124], can be formed in situ by reaction of sodium salicylaldehyde (125) with S -˛-phenylethylamine hydrochloride112 [ S -126] in methanol, and show a number of CEs from about 210 to 400 nm (Figure 9), the sign of the CEs associated with the electronic transitions near 315 nm and 255 nm being correlated with the absolute configuration of the chiral center to which the nitrogen atom is attached110. The derivatives can also be formed by reaction of salicyaldehyde with the corresponding amine, and when the Schiff base is formed on a macro scale it can be isolated in the usual way. The formation in situ, however, is a substantial asset associated with salicylidenamino (SA) chromophoric derivatives. Since 125 and an amine salt are usually solids at room temperature, semimicro amounts (1 or 2 mg) of 125 and the amine salt can easily be weighed before mixing.

	H	Ph
	+			CH3 OH
		ClH3 N C H
	O
		CH3
	ONa
	(125)	[(S)-126]

H

Ph

NCH + NaCl

O H CH3 [(S)-124]

138	Howard E. Smith

[q ] × 10−3

+40

+20

0

−20

−40

CD

EA

250

350

450

wavelength, nm

40

20

		3
	0	10
		ε ×

FIGURE 9. Electronic absorption (EA) and circular dichroism (CD) spectra of S-N-salicylidene-˛- phenylethylamine [S-124] in methanol. Reprinted with permission from Reference 109. Copyright (1974) American Chemical Society

In the ECD spectrum of the N-salicylidene derivatives, such as S-N-salicylidene- ˛-phenylethylamine [S-124], the CEs associated with the electronic transition near 315 (band I) and 255 nm (band II) are the result of exciton coupling of the respective electronic transition moments of the salicylidenamino (SA) chromophore with electronic transition moments in the amine moiety and lead to the statement of the salicylidenamino chirality rule: when the coupled electronic transition moments are arbitrarily viewed as being directed away from each other (Figure 10), positive chirality (right-handed screw) results in a positive contribution of bands I and II and negative chirality (left-handed) screw results in a negative contribution to the CEs. The sign of the observed CEs is then the algebraic sum of the positive and negative contributions to the CEs of bands I and II, the sum being related to the distribution of groups in the amine moiety with respect to

	1L
	a
O	1B	(+)
H	a,b

H3 C

N

C C

H H

FIGURE 10. Chirality of the coupled electronic transition moments in the preferred conformation of the S-N-salicylidene-˛-phenylethylamine [S-124]. Reproduced with permission from Reference 110. Copyright (1983) American Chemical Society

3. Chiroptical properties of amino compounds

139

the salicylidenamino chromophore. Simple conformational analysis can be used to predict the sign of the observed CEs for a particular enantiomer110. A recent X-ray study and force field calculation on the R -N-benzylidene-2-amino-1-butanol113 [ R -127] support the preferred conformation for S -124 and, as shown in Figure 10, the benzene ring and the conjugated CDN bond in both S -124 and R -127 form an almost planar system with the hydrogen atom at the chiral center eclipsing the azomethine hydrogen atom.

H		H
C	N	C	CH2 CH3
			CH2 OH

[(R)-127]

In the cases of the N-salicylidene derivatives of amines with one or more unsaturated groups, ˛- and ˇ-arylalkylamines, ˛-amino acid salts and esters, and unsaturated aliphatic amines, coupling of the transition moments of the N-salicylidene moiety with theelectron transition moments of the unsaturated group is extremely strong, and the chirality of this coupling gives the sign to the observed CEs at 315 nm (band I) and 255 nm (band II). For the N-salicylidene derivatives of amines without unsaturated groups, including aliphatic and cyclic amines and amino sugars, the CEs are less intense, but application of the salicylidenamino chirality rule is also based on the coupled oscillator mechanism. The CEs associated with bands I and II originate from coupling of the SA chromophore with transition moments in the rest of the molecule. The effect due to the polarizability of the C H bond is assumed to be negligible, and C C and C O bond transition moments vicinal and homovicinal to the SA chromophore are the dominant contributors to the CEs. Since the polarizability of a C O bond is smaller than that of a C C bond, the contribution of a vicinal or homovicinal C O bond is less than that of a corresponding C C bond. Conformational analysis then gives the algebraic sum of this coupling and relates the sign of the CEs of bands I and II in the CD spectrum with a particular absolute configuration of the N-salicylidene derivative110.

2.Exciton coupled circular dichroism (ECCD) spectra

a. N-Benzylidene derivatives. A series of Schiff base derivatives was prepared by reaction of an enantiomer of (1S)- C -threo-1-(4-aminophenyl)-2-dimethylamino-1,3-

propanediol114 and of (1S)- C -threo-1-(4-nitrophenyl)-2-amino-1,3-propanediol115 with benzaldehyde and a number of ring-substituted benzaldehydes, including salicylaldehyde, [(1S,2S)-128] and [(1S,2S)-129] as chromophoric derivatives for the establishment of the preferred conformations and absolute configurations of amines by CD measurements. The CD spectra of the Schiff bases of both of these chiral amines, even those of (1S,2S)-128 in which the chromophore is not attached to a chiral center but to the benzene ring of the amine moiety, show strong CD maxima associated with the N-benzylidene chromophore similar to those shown by the N-salicylidene derivatives. The correlation of the CEs shown by ring-substituted derivatives such as (1S,2S)-128 with their absolute configurations has not been studied extensively, and in the case of the 1S, 2S -129 derivatives, none appears to be superior to the N-salicylidene derivative for the establishment of absolute configurations115.

Three other substituted benzaldehydes, p-dimethylaminobenzaldehyde (130), julolidinecarboxaldehyde (131) and p-dimethylaminocinnamaldehyde (132), have been reported for use in the preparation of chromophoric derivatives of chiral amines116,117.

140				Howard E. Smith
	CH2 OH				CH2 OH
H	C		N(CH3 )2	H				CHC6 H4 X
					C		N
HO			H	HO			H
	C				C

N CHC6 H4 X		NO2
[(1S,2S)-128]	[(1S,2S)-129]
O				O
(CH3 )2 N	N
H				H
(130)			(131)
(CH3 )2 N				O
				H
	(132)
NH2	H		N Ar
				C
NH2		N	H	H
	H C
	Ar
[(R,R)-133]	[(R,R)-134]

The three aldehydes react readily under very mild conditions with R -trans-1,2- cyclohexanediamine [(R,R)-133] to afford the respective bis(Schiff) bases (R,R)-134 which show exciton coupled circular dichroism (ECCD) spectra118 (Figure 11). Figure 11 shows the CD spectrum of the derivative formed by condensation of 131 with (R,R)-133. The chromophore using 131 has a long-wavelength absorption maximum at 331 nm, and thus the bis(Schiff) base shows a negative bisignate CD curve centered near this same wavelength, the negative sign of the long-wavelength CD maximum at 351 nm correlating with the negative torsion angle of the nitrogen atom attachment bonds in the diamine moiety. Upon protonation of the tertiary amino groups in the aldehyde moiety of the Schiff bases, the absorption spectra undergo drastic bathochromic shifts, and the intensities of the

			3. Chiroptical properties of amino compounds								141
				404 (+204)
			CD
150
50			311 (+34)
0
	−50
			351 (−83)
∆e −150											e × 10−4
				404 (93 400)		452 (−220)		UV
	−250
				448 (54 800)
	−350		327 (37 500)								5.0
											0.0
200			300	400		500		600
				l [nm]
FIGURE 11. Electronic			absorption (UV)	and circular		dichroism (CD)		spectra			in acetonitrile: neu-

tral (solid line) and protonated (dashed line) bis(Schiff) base (R,R)-134 prepared by condensation of julolidinecarboxaldehyde (131) with R -trans-1,2-diaminocyclohexane [(R,R)-133]. Reproduced from Reference 116 by permission of VCH Publishers

respective CEs are inhanced 2 3-fold (Figure 11). This increase in the sensitivity of the method and the bathochromic shift may be important when samples themselves contain chromophoric groups or impurities whose absorption bands may overlap with those of the chromophores and interfere with analysis.

The ECD spectra of the bis(Schiff) base derivatives prepared from 130 132 were successfully correlated with the absolute configurations of chiral 1,2- and 1,3- diamines116,117 and chiral 1-amino-2-hydroxyl compounds in which the amino group was converted to the imine group and the hydroxyl group was converted to 5-(p- methoxyphenyl)pentadienoate group, the latter with an absorption minimum at about 330 nm and thus also strongly coupling with the imine chromophore116,117.

In work related to the bisimine derivatives discussed above, the ultraviolet-visible and circular dichroism behaviour due to exciton coupling in a biscyanine dye, prepared by condensation of two equivalents of 7-piperidinohepta-2,4,6-trienal (merocyanine, 135) with S -trans-1,2-diaminocyclohexane [(S,S)-133], was reported119. The CD spectrum of the resulting protonated bisimino compound is unusual in that it shows two CD maxima at 547 and 476 nm, negative and positive, respectively, of similar intensity119, termed a negative bisignate CD curve or a negative exciton coupled Cotton effect (ECCE). These maxima were shown to be the result of exciton coupling of the protonated chromophores, but the negative sign is opposite to that predicted on the basis of CD observations with the dibenzamide derivative of (S,S)-133, also the result of exciton coupling118 120. In the chiral biscyanine dyes, such a large CE separation arising from exciton coupling has

142	Howard E. Smith

not been encountered before, but calculations by molecular mechanics and the -electron SCF-CI-DV MO method yield typical exciton split CD curves. The calculations also indicate that the sign reversal in the bisignate CD of the bicyanine dye in comparison with that of the corresponding dibenzoate derivative is due to the unique conformation of the two cyanine dye side chains121.

CHO

N

(135)

b. N-Benzoyl derivatives. The dibenzoate chirality rule122, which correlates the sign of exciton coupled CD spectra of the dibenzoate derivatives of vicinal diols [(R,R)- 136)] with their absolute configurations, has been extended to the benzoyl derivatives of vicinal amino alcohols [(R,R)-137] and vicinal diamines (R,R)-138123. The dibenzoyl chirality rule is based on the fact that the transition dipole responsible for the 230 nm band of each benzoate group in R -trans-O,O0 -dibenzoyl-1,2-cyclohexanediol [(R,R)-136] is nearly parallel to the C O bond in the alcohol moiety. The coupling of these moments results in two strong CEs of the same amplitude but of opposite signs around 233 (first CE) and 219 nm (second CE). A negative torsion angle as in (R,R)-136 between the interacting moments results in a negative first CE and a positive second CE, the couplet termed a negative exciton coupled Cotton effect (ECCE); a positive torsion angle results in a positive ECCE. Since in a N-alkylbenzamide the transition moment analogous to that of the 230 nm band in the benzoate group is also nearly parallel to the C N bond of the amine moiety, it was anticipated and in fact found that the dibenzoate chirality rule could be applied to vicinal amino alcohols and vicinal diamines, and both (R,R)-N,O-dibenzoyl- 2-aminocyclohexanol [(R,R)-137] and R -trans-N,N0 -dibenzoyl-1,2-cyclohexanediamine [(R,R)-138] show negative ECCE, similar to that shown by (R,R)-136123.

R1

R2

[(R,R)-136] R1 = R2 = OBz [(R,R)-137] R1 = OBz, R2 = NHBz [(R,R)-138] R1 = R2 = NHBz

Exciton coupling can also occur between the benzamide chromophore and other - electron systems, and S -N-benzoyl-˛-(2-furfuryl)alkylamines [ S -139] show positive ECCE spectra62 with a bisignate CE couplet centered at about 228 nm. For the enantiomers the ECCE spectra are negative62. Similarly the p-bromobenzoyl group linked to the N-terminus of a helical peptide chain is useful as a CD probe in the determination of the relationship between the C ˛ -configuration of coded and noncoded ˛-amino acids and peptide helix screw sense in solution, the bisignate CE center around 238 nm the result of the interaction between the p-bromobenzamido chromophore and the peptide chromophores124.

(1R,2R)-2-p-Chlorobenzamido-1-phenyl-1-cyclohexanol [(1R,2R)-140] also shows an ECCD spectrum, but with only a single negative CE above 205 nm. The latter is

3. Chiroptical properties of amino compounds

143

	C6H5
	H
	OH
	C R
O	NHCOC6H4Cl-p
	NHCOC6H5
[(S)-139] R = CH3, CH2CH2CH3 or CH2CH(CH3)2 [(1R,2R)-140]

associated with a transition of the p-chlorobenzamido chromophore and its sign is the result of chirality of the exciton coupling of the transition moment of the chromophore

with the	!	Ł transition moment below 200 nm of the phenyl group at C-1 in the
		125
cyclohexane ring .
The principle of exciton coupling between					vicinal benzoate chromophores has
been extended		to	other aromatic	carboxylic	acid derivatives126, including those
of ring-substituted			benzoic acids,	9-anthranoic	acid (141) and p-methoxycinnamic

acid (142). These derivatives have been widely used for the determination of the absolute stereochemistry in polyol natural products127. The circular dichroism of the N-p-bromobenzoyl group combined with various O-, O,O0 -di- and O,O0 ,O00 -tri-(p- bromobenzoyl) derivatives of 2-amino-2-deoxygalactopyranoside128 and an N-anthranoyl group combined with tri-, tetraand penta-p-methoxycinnamoyl derivatives of acyclic 1-amino polyols129 were studied to improve and develop microscale CD methods for the structural study of amino sugars.

CO2R

CO2R

CH3O

(141)

(142)

The ECCD method was extended to determination of the absolute configurations and conformations of chiral organic molecules containing chromophores which are either preexistent in the molecule or introduced through derivatization by O- or N-acylation and also incorporating a tertiary amino group130. This latter group was derivatized through quaternary ammonium salt formation using p-phenylbenzyl chloride130. Thus the trifluoroacetate (TFA) salt of the O-p-methoxycinnamoyl-N-p-phenylbenzyl derivative R -143 of R -3-quinuclidinol [ R -144] gives an ECCD spectrum with a negatively split exciton couplet in agreement with the R configuration for 143, the same configuration previously established by X-ray diffraction for 144131. The use of a chromophoric derivative for tertiary amino groups should find substantial application in the establishment of the absolute configurations of other natural products incorporating a tertiary amino group.

D. N-Nitrosamines

As a continuation of the interest in the electronic circular dichroism (ECD) of the chiral nitrosamines, the ECD of the N-nitroso derivatives of chiral 4-, 5- and 6-membered cyclic

144	Howard E. Smith

OCH3

O

N+

HO

TFA−

OH

N

H

[(R)-143]

[(R)-144]

amines, including N-nitroso-L-proline (L-145) and a number of ring-substituted N-nitroso- L-prolines, were measured132. The effect of the nitrosamine group conformation, pyrrolidine geometry, different perturbing substituents and hydrogen bonding on the sign and magnitude of the n ! Ł CD band centered around 350 nm were discussed132. A negative CD band due to the ! Ł transition was observed for all N-nitrosamines having the L- proline configuration at C-2 regardless of the nitroso group conformation. As an extension of this work, the ECD spectra of several 2- and 3-substituted N-nitrosopyrrolidines were studied in solvents of varying polarity133. 2-Substituted nitrosopyrrolidines such as S-2- methyl-N-nitrosopyrrolidine [S-146], as shown by their 1H NMR spectrum, prefer the

R2

CH3

N

NO

(L-145)

CO2H

(−)

O (−)

N	R1	N
N		N
O		O
[(E)-(S)-146] R1 = CH3, R2 = H
[(E)-(S)-147] R1 = H, R2 = CH3		[(Z)-(S)-147]

(+)

N

(−) (Signs refer to upper sectors.)

N

(+)

(148)