Helicity induction in a bichromophore: A sensitive and practical chiroptical method for absolute configuration determination of aliphatic alcohols

Article abstract of DOI:10.1021/ol0268079

(equation presented) A practical method for the determination of the absolute configuration of aliphatic secondary alcohols, based on the circular dichroism of the readily available N-(1,8-naphthaloyl)-2-aminobenzoyl (NAB) derivative, is presented. The or

Full text of DOI:10.1021/ol0268079

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4185-4188
Helicity Induction in a Bichromophore:
A Sensitive and Practical Chiroptical
Method for Absolute Configuration
Determination of Aliphatic Alcohols
Jacek Gawron´ski,* Marcin Kwit, and Krystyna Gawron´ska
Department of Chemistry, A. Mickiewicz UniVersity, Poznan 60 780, Poland
gawronsk@amu.edu.pl
Received August 28, 2002
ABSTRACT
A practical method for the determination of the absolute configuration of aliphatic secondary alcohols, based on the circular dichroism of the
readily available N-(1,8-naphthaloyl)-2-aminobenzoyl (NAB) derivative, is presented. The origin of the induced Cotton effects is traced by ab
initio calculations to the dominant helicity of the NAB π-electron system.
Current stereochemical studies employ two methods for the
absolute configuration determination: either the X-ray dif-
fraction method (Flack parameter)1 or the circular dichroism
(CD) method. In the latter case, exciton-coupled circular
dichroism (ECCD)2 is of particular value, as it allows the
determination of absolute configuration on a microscale,
often without the need to perform tedious theoretical model
calculations. The method requires the presence of two
chromophores with the allowed π-π* transitions; these can
be introduced, when necessary, through suitable derivatiza-
tion of diols, amino alcohols, hydroxy acids, etc. with a
chromophoric derivative, the typical representative being the
benzoate group. Alcohols are among the most abundant chiral
compounds of synthetic and natural origin. If the absolute
configuration of a chiral nonchromophoric alcohol is to be
determined by the ECCD method, a bichromophoric mol-
ecule has to be attached to the hydroxy group. Derivatives
of this type bearing axially chiral 2,2′-binaphthalene-3,3′-
dicarboxylic acid3 or 5,5′-dinitrodiphenic acid4 have been
recently introduced by Hosoi, Ohta, and co-workers. Harada
and co-workers used for this purpose esters of di(1-naphthyl)-
acetic acid.5 An entirely different approach was demonstrated
by Nakanishi, Berova, and co-workers6 and relies on chiral
recognition by a CD-sensitive dimeric zinc porphyrin host.
The guest molecule forms a complex with the zinc porphyrin
host in solution, but the chiral alcohol (or amine) has to be
derivatized with an achiral carrier molecule.
The field of chromophoric derivatives of monoalcohols
has not matured yet and new derivatives with broad sensitiv-
ity to the structural variations of the alcohol molecule and a
convenience of preparation are needed. We reasoned that
the bichromophore, consisting of the benzoate substituted
in the ortho position with the naphthalimide group (the NAB
(3) Hosoi, S.; Kamiya, M.; Ohta, T. Org. Lett. 2001, 3, 3659-3662.
(4) Hosoi, S.; Kamiya, M.; Kiuchi, F.; Ohta, T. Tetrahedron Lett. 2001,
42, 6315-6317.
(5) Ishiya, F.; Ehara, H.; Yoshida, N.; Goto, H.; Monde, K.; Harada, N.
40th Symposium on the Chemistry of Natural Products, symposium papers,
1998; pp 85-90.
(6) (a) Kurta´n, T.; Nesnas, N.; Li, Y.-Q.; Huang, X.; Nakanishi, K.;
Berova, N. J. Am. Chem. Soc. 2001, 123, 5962-5973. (b) Kurta´n, T.;
Nesnas, N.; Koehn, F. E.; Li, Y.-Q.; Nakanishi, K.; Berova, N. J. Am. Chem.
Soc. 2001, 123, 5974-5982.
(1) Flack, H. D. Acta Crystallogr. 1983, A39, 879-881.
(2) (a) Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy-
Exciton Coupling in Organic Stereochemistry; University Science Books:
Mill Valley, CA, 1983. (b) Nakanishi, K.; Berova, N. In Circular
Dichroism-Principles and Applications; Berova, N., Nakanishi, K., Woody,
R. W., Eds.; Wiley-VCH: New York, 2000; pp 337-382.
10.1021/ol0268079 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/08/2002

polarized π-π* transition in the naphthalene ring of the 1,8-
naphthalimide chromophore, and the other at below 226 nm
and presumably due to the benzoate π-π* charge-transfer
transition. The signs of these Cotton effects are solvent-
independent.
Scheme 1
These Cotton effects form a couplet, the sign of which is
clearly related to the difference in size of the R1 and R2
substituents, i.e., to the absolute configuration at the carbinol
atom (Figure 1).
Figure 1. Correlation between the size of R1, R2 (absolute
configuration) and the sign of the NAB Cotton effect.
chromophore), will act as a sensor of the alcohol chirality,
by conformationally induced Cotton effects within its π-π*
absorption bands.
The size of R1, R2 according to the CD data increases in
the order Me < COOR < CH2R < CH(OH)R < CHRR′,
which does not exactly follow the differences in conforma-
tional energies of substituents in monosubstituted cyclohex-
anes. It is of importance to note that the NAB chromophore
has high sensitivity to relatively small differences in sub-
stituent size. The chromophore differentiates two homologous
substituents, the methyl and the ethyl group in 3. Comparable
sensitivity in chirogenesis was reported for a supramolecular
system based on a complex formation between chiral amines
and the ethane-bridged bis(zincporphyrin).8 Noteworthy also
is the sensitivity of the NAB chromophore to γ-substitution
in the cyclohexane skeleton. Thus, NAB derivatives of
cholesterol 14 and 3-epicholesterol 13 differ in the sign and
magnitude of the Cotton effects. The structural differences
between R1 and R2 groups in these molecules appear between
substituents at C1 and C5. The Cotton effects of 13 are
stronger, as the axial C3-O bond brings the NAB chro-
mophore closer to the two stereodifferentiating C1 and C5
groups, compared to the equatorial C3-O bond in 14.
Finally, the strongest Cotton effects (A ca. 30) are observed
for two NAB derivatives significantly differentiated in the
size of substituents in the â position: 12 (CH2 vs CHi-Pr)
and 15 (CH2 vs CMe2). The sensitivity range (∆ꢀ/ꢀ) for the
series of NAB derivatives 3-15 is 1 × 10-4 to 6 × 10-4,
i.e., well within the range easily measured by commercial
dichrographs.
N-(1,8-Naphthaloyl)-2-aminobenzoates of primary and
secondary alcohols (2-15) are readily available from NAB
chloride (1) (Scheme 1).
The UV spectra of the NAB derivatives display two
intense maxima at 332 nm (ꢀ 13500-14000) and at 232 nm
(ꢀ 45000-50000) in acetonitrile solution. These absorption
maxima are clearly associated with the π-π* transitions of
the 1,8-naphthalimide chromophore;7 the benzoate absorption
is apparently hidden under the envelope of the absorption
bands between 240 and 200 nm. The 232 nm band is CD
active: in the CD spectra of derivatives 3-15 (Table 1) there
are observed two opposite-sign Cotton effects (see also
Figure 4), one at 240 ( 5 nm, associated with the long-axis
Table 1. CD Data for NAB Derivatives 3-15 in Acetonitrile
Solution
R1
R2
∆ꢀ (nm)
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Et
+5.7 (240), -2.4 (226)
+7.0 (243), -5.6 (226)
+4.8 (235)a
CH2COOEt
COOEt
(S)-CH2CH(OH)Me +12.5 (240), -4.3 (222)
(S)-CH(OH)Me
COOMe
+7.0 (243), -1.9 (220)
-5.5 (240), +3.5 (216)
-1.8 (244), +4.3 (224)
-7.9 (241), +10.9 (213)
CH2Ph
CH2COOMe COOMe
10 (S)-CH(OH)- COOMe
COOMe
To provide an insight into the induction of optical activity
of the NAB chromophore we carried out extensive confor-
mational modeling of the chromophore as well as semiem-
11
12
13
14
15
-6.1 (243), +1.4 (224)
-22.8 (239), +6.0 (225)
-11.0 (242), +2.7 (225)
+4.0 (235)a
+18.3 (238), -13.2 (204)
(7) Gawron´ski, J.; Gawron´ska, K.; Skowronek, P.; Holme´n, A. J. Org.
Chem. 1999, 64, 234-241.
(8) Borovkov, V. V.; Lintuluoto, J. M.; Inoue, Y. J. Am. Chem. Soc.
2001, 123, 2979-2989.
a No distinct second Cotton effect observed.
4186
Org. Lett., Vol. 4, No. 24, 2002

the size of the alkyl ester group). An important conclusion
emerged from the computational study: the angles R and â
are correlated, i.e., they have the same sign for conformers
A and opposite sign for conformers B. Other combinations
lead to a sharp increase of the energy of 2.
Analysis of the X-ray diffraction of crystals 310 provides
additional insight into the structure of the real NAB
molecules. Compound 3 crystallizes in the space group P1
with four independent molecules in the asymmetric unit. This
result is apparently due to molecular flexability of 3. The
four molecules of 3 in the crystal are in the extended A
conformation and differ in the conformation of the (S)-2-
butyl chain as well as in the helicity (torsion angles R, â) of
the NAB chromophore (Table 2).
Figure 2. Extended (A) and folded (B) conformers of the NAB
chromophore.
pirical and ab initio computation of rotational strength of
the chiral conformers of 2.
Conformation of the NAB moiety is described by the two
torsion angles9 R (C1or C1′-N-C2-C3) and â (C2-C3-
C4dO), Figure 2. Angle R determines nonplanarity of the
phenyl and the imide ring system and is within the range 0,
(90°. Angle â determines nonplanarity of the benzoyl group,
and it changes between 0° for the extended (A) conformer
and 180° for the folded (B) conformer.
The conformers of 2 were fully optimized by the DFT
b3lyp/3-31g(d) method. At the b3lyp/6-31g/(d) level non-
planar conformers A and B were obtained as the energy
minima. The minimum-energy conformer A was found for
R ) 80°, â ) 10°; the energy of the molecule raised
significantly for |R| < 75° and |â| > 20° (Figure 3). Folded
Table 2. Torsion Angles (deg) R and â of NAB Chromophore
in Four Independent Molecules of 3 in Crystal
(S)-2-butyl chain
conformation
R
â
trans
-75.3
-73.7
+71.1
+79.7
-41.6
-29.6
+44.2
+34.4
gauche (-)
gauche (+)
gauche (+)
The NAB chromophores form either an M helix (negative
R and â values) or a P helix (positive R and â), from the
carbonyl group of the benzoate to the carbonyl group of the
imide, but there is no preference toward one or the other in
the crystal of 3.
The excited states of the NAB chromophore have been
initially computed by the ZINDO method for a number of
chromophore geometries in 2, systematically varying mag-
nitudes of angles R and â. Variations of the oscillator strength
(f) and of the electronic transition energies were observed,
but the salient features, i.e., the presence of an allowed
transition at 300-350 nm and a set of strongly allowed
transitions at below 250 nm, were present in all of the
computed spectra. The spectrum computed by the ZINDO
and the ab initio CIS/6-31g(d)11 methods for R ) 70°, â )
10° is shown in Figure 4.
The computed pattern of the most intense transitions
correlates reasonably well with the experimental UV spec-
trum of the NAB chromophore. The computed rotational
strengths of the transitions for R ) 70°, â ) 10° are in good
agreement with the CD spectrum of 12. The allowed
transition at 350 nm does not show significant rotational
strength. On the other hand, the 240 nm transition displays
a large negative rotational strength for a P-helical NAB
chromophore, just as is observed in the CD spectrum of 12
(Figure 4). According to computations, variations of angle
â between 0° and 40° had little effect on R; negative R values
Figure 3. Molecular energy of the extended (A) conformer of 2
as a function of angles R and â. Insert shows the energy minimum
(R ) 80°, â ) 10°).
conformers B are of higher energy, but their energy profile
as a function of R and â (not shown) is quite similar: a
minimum obtained for |R| ) 85°, â ) 180° is 0.66
kcal‚mol-1 above the conformer A energy minimum (the
energy difference between B and A conformers rises with
(9) Additional conformational parameter is the spatial relation of the
carbinol C-H bond to the benzoyl CdO bond; this is invariably syn, as in
Figure 2.
(10) Rychlewska, U. Unpublished data; e-mail: urszular@amu.edu.pl.
(11) The computed wavelengths of the transitions were multiplied by a
factor 1.35 to account for electron correlation.
Org. Lett., Vol. 4, No. 24, 2002
4187

Figure 5. ZINDO method computed rotational strength R of the
240 nm transition of the NAB chromophore in 2 as a function of
angles R and â.
Accordingly, the Cotton effect at around 240 nm is positive,
as observed experimentally for the alcohol of the S config-
uration (Figure 1).
Figure 4. Computed oscillator strengths f (upper panel, vertical
bars) and rotational strengths R (lower panel, vertical bars) for the
electronic transitions of the NAB chromophore in 2 (R ) 70°, â )
10°). Overlaid are the UV and CD spectra of 12.
In summary, we have developed a sensitive and practical
method for determination of the absolute configuration of
aliphatic secondary alcohols. The method is based on the
induced helicity of the NAB chromophore, which in turn
determines the sign of the observed Cotton effects in the
250-200 nm range. The NAB derivatives are readily
obtained from the cheap commercial substrates.
were computed for all R values between 90° and 60° (Figure
5). The computed rotational strength of the shorter-
wavelength transitions (below 230 nm) were positive, again
in agreement with the signs of the Cotton effects of 12 below
230 nm.
Acknowledgment. This work was supported by the
Committee for Scientific Research (KBN), grant PBZ 6.06.
The computations provide a model of induction of optical
activity of the NAB chromophore. For R2 > R1 in an
extended A conformation (Figure 2) angle R is negative as
a result of the interaction between R2 and the nearest carbonyl
group of the 1,8-naphthalimide chromophore. To release the
strain due to the imide CdO/benzoyl CdO group interaction,
the latter is rotated in the direction of negative angle â,
resulting in the NAB chromophore of dominant M helicity.
Supporting Information Available: Experimental pro-
cedure for the preparation of NAB derivatives and charac-
terization of compounds, details of computation procedures,
and numerical data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0268079
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Org. Lett., Vol. 4, No. 24, 2002