Enantiomeric recognition of racemic 4-aryl-1,4-dihydropyridine derivatives via chiralpak AD-H stationary phases

Article abstract of DOI:10.1002/chir.22083

The chromatographic chiral resolution of two new series of racemic 4-substituted-1,4-dihydropyridine derivatives was studied on a commercial Chiralpak AD-H column. Analytes without 5,5-dimethyl substituents (1-15) are more efficiently resolved than analyt

Full text of DOI:10.1002/chir.22083

CHIRALITY (2012)
Enantiomeric Recognition of Racemic 4-Aryl-1,4-dihydropyridine
Derivatives via Chiralpak AD-H Stationary Phases
*
ZHI DAI, CHARLES U. PITTMAN JR., AND TINGYU LI
Department of Chemistry, Mississippi State University, Mississippi State, Mississippi, USA
ABSTRACT
The chromatographic chiral resolution of two new series of racemic 4-substituted-
1,4-dihydropyridine derivatives was studied on a commercial Chiralpak AD-H column. Analytes
without 5,5-dimethyl substituents (1–15) are more efficiently resolved than analytes with 5,5-
dimethyl groups (16–30). The AD-H column discriminated between enantiomers through both
hydrogen bonding attractions and p–p interactions. This interpretation is in accord with plots of
the logarithm of separation factors, log(a), versus s (Hammett–Swain substituent parameter)
and s+ (Brown substituent constant) plots. By elucidating the effects of the remote substituents
on these chiral separations, it was shown that the influence of p–p interaction forces increase when
steric bulk effects act to decrease the hydrogen bonding attractive forces on the AD-H column.
Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: 1,4-dihydropyridine; chiral separation; Chiralpak AD-H column
INTRODUCTION
on 3-aminopropyl silanized silica.25 AGP26 and ES-OVM27
are made from a1-acid glycoprotein and ovomucoid on
silica, respectively.
1,4-Dihydropyridines are a well-known class of biologically
active heterocycles.1–3 For example, cardiovascular agents nifed-
ipine, nicardipine, amlodipine, and other related dihydropyridyl
derivatives are effective for the treatment of hypertension.4
4-Aryl-1,4-dihydropyridines have also been explored for their
calcium channel activity, and these heterocyclic rings are found
in a variety of other bioactive compounds such as bronchodila-
tors, antiatherosclerotics, antitumor agents, vasodilators, anti-
diabetic compounds, and heptaprotective agents.5,6 Moreover,
these compounds exhibit other diverse medical functions, acting
as neuroprotectants, platelet antiaggregators, cerebral anti-
ischemic agents, and chemosensitizers.7,8 The 1,4-dihydropyridines
are also analogs of NADH coenzymes.9,10 They are used as
hydride sources in a wide variety of organocatalytic asymmetric
reductions.11–13
An asymmetric carbon often exists at position 4 of the
dihydropyridine ring in many dihydropyridine drugs, and these
drugs are generally formulated as racemic mixtures. In many
cases, chiral and/or unsymmetrical 1,4-dihydropyridines have
exhibited higher activities or, in the case of enantiomers, an
opposite pharmacological activity.14,15 Although enantiomeri-
cally pure 1,4-dihydropyridines have great biological impor-
tance, a general methodology for resolving the enantiomers
and then evaluating them remains difficult. High-performance
liquid chromatography (HPLC) separation of enantiomers on
chiral stationary phases (CSPs) is a convenient and accurate
method for the determination of the enantiomeric purity of chi-
ral compounds.16,17 The direct resolutions of dihydropyridine
enantiomers using a CSP in LC are now reaching an advanced
stage.18 Several types of CSPs have been developed including
the amide-urea, ligand-exchange, host–guest, protein, and
polysaccharide types.19 For example, dihydropyridine separa-
tions by polysaccharide type CSPs predominate. Cellulose tris
(4-methylbenzoate) coated on silica gel (Chiralcel OJ)20–22 and
Chiralpak AD,23,24 consisting of amylose tris(3,5-dimethylphe-
nylcarbamate), have often been used for dihydropyridine
resolutions. OA-4500,25 AGP,26 and ES-OVM27 CSPs have
also been employed. OA-4500 is a p-donor type chiral phase
consisting of (S)-1-a-naphthyl ethylamine with (S)-proline
Recently, a series of new 4-substituted-1,4-dihydropyridine
derivatives was synthesized by using various substituted
benzaldehydes, 1,3-cyclohexanedione or 5,5-dimethyl-1,3-
cyclohexanedione, ethyl acetoacetate, and ammonium
acetate under different reaction conditions.28 However, these
4-substituted-1,4-dihydropyridine derivatives were all obtained
as racemic mixtures, which have not been resolved. The avail-
able Chiralpak AD-H (AD) commercial column was investi-
gated in this work in order to help elucidate aspects of the
chiral resolution mechanism for asymmetric 1,4-dihydropyridine
compounds. Thirty 1,4-dihydropyridine compounds, 1–30,
were synthesized and purified for this purpose in this current
work by using the method pioneered by Ko and Yao28 (Fig. 1).
Chiralpak AD-H has a CSP composed of amylose that has been
derivatized by 3,5-dimethylphenylcarbamate functions as shown
in Figure 2.
MATERIALS AND METHODS
Materials and Equipment
Amino acid derivatives were purchased from NovaBiochem (San Diego,
CA, USA). All other chemicals and solvents were purchased from Sigma-
Aldrich (Milwaukee, WI, USA), Fluka (Ronkonkoma, NY, USA), or
Fisher Scientific (Pittsburgh, PA, USA). Hexanes (from Fisher scientific)
were a mixture of hexanes (86.1% n-hexane, 9.7% methylcyclopentane,
4.2% various methylpentanes). Solvents were purchased from Fisher
(Springfield, NJ, USA) or Sigma-Aldrich. An Agilent 1100 HPLC system
(Agilent, Wilmington, DE, USA) consisting of a vacuum degasser, a
quaternary pump, an autosampler, and a multiple wavelength detector was
used to evaluate the columns.
Additional Supporting Information may be found in the online version of this article.
Contract grant sponsor: NIH; Contract grant numbers: R15 GM 83326–
01.3R15GM083326-01 S1.
*Correspondence to: Charles Pittman Jr., Department of Chemistry, Box 9573,
Mississippi State University, Mississippi State, MS 39762, USA.
E-mail: CPittman@chemistry.msstate.edu
Received for publication 03 April 2012; Accepted 11 May 2012
DOI: 10.1002/chir.22083
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

DAI ET AL.
Et
OMe
Cl
N
MeO
O
OMe
O
O
O
O
O
O
O
4
O
O
5
6
O
O
O
O
O
O
3
2
O
O
O
O
O
O
O
O
N 1
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
1
2
4
6
3
5
8
7
Br
F
NO2
NO2
CF3
NO2
NO2
O
NO2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
9
11
10
12
14
13
16
15
Et
Cl
OMe
N
Br
MeO
O
OMe
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
N
H
N
N
H
N
H
H
H
21
17
20
19
18
23
22
24
CF3
NO2
F
NO2
NO2
NO2
O
NO2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
H
N
H
N
H
26
27
30
29
25
28
Fig. 1. Structures of the racemic 4-substituted-1,4-dihydropyridine derivatives (1–30) synthesized and used in this study.
and t0 is the void time. The separation factor (a) equals k2/k1, the ratio of
the retention factors of the two enantiomers. The resolution factor (Rs)
was calculated using the equation Rs = 2 ꢀ (tr2 ꢁ tr1)/((w)1 + (w)2), where
(w)1 and (w)2 are the peak widths. The void time t0 was measured with
1,3,5-tri-t-butylbenzene as the void volume marker. This compound was con-
veniently used for several chiral HPLC.30,31 A flow rate of 1 ml/min was
used. Each analyte was resolved in 15% isopropanol in hexanes, and the
concentrations were 1 mg/ml. The injected volume was 10 ml. Each analyte
was repeated at least two times at 25ꢂC.
The Synthesis of 4-Substituted-1,4-dihydropyridine
Derivatives
4-Substituted-1,4-dihydropyridine derivatives 1–30 were each synthe-
sized in our laboratory by adapting a literature procedure.29 A typical
experimental procedure for the preparation of 4-substituted-1,4-dihydropyridine
derivatives is described as follows: a 10-ml round-bottomed flask was charged
with the specific aldehyde (1.0 mmol), either 1,3-cyclohexanedione or 5,5-
dimethyl-1,3-cyclohexanedione (1.0 mmol), ammonium acetate 4 (1.0 mmol),
ethyl acetoacetate (1.0 mmol), and iodine (0.3 mmol), followed by 2 ml of
ethanol. The mixture was then stirred at room temperature until the reaction
was completed (monitored by thin layer chromatography). Typical reaction
times were 3–4 h. The reaction mixture was treated with brine solution
and extracted with ethyl acetate (2 ꢀ 20 ml). After evaporation of the solvent,
the crude product was recrystallized from ethanol to give a solid product
in each case. The isolated yields and the NMR resonance spectra and
mass spectrometry data confirming the structures of 1–30 are given in the
Supporting Information.
RESULTS AND DISCUSSION
Thirty racemic 4-substituted-1,4-dihydropyridine analytes
were synthesized using substituted benzaldehydes, 1,3-
cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione, ethyl
acetoacetate, and ammonium acetate (Fig. 1). The numbering
system used throughout is shown on compound 1 in Figure 1.
The commercial Chiralpak AD-H column was investigated
in this work in order to provide some insight into the poten-
tial separation mechanism for the 1,4-dihydropyridine enantio-
mers (Fig. 2).
Chromatographic Measurements
The commercial AD-H column with 5 mm particle size is 250 ꢀ 4.6 mm.
The retention factor (k) equals (tr ꢁ t0)/t0, where tr is the retention time
The ability to resolve racemic 4-substituted-1,4-dihydropyridine
derivatives was studied on the commercial Chiralpak AD-H
column. The separation factor (a), resolution factor (Rs), and
retention factor (k) were determined for each of the 30
analytes on Chiralpak AD-H columns (Table 1). The average
separation and resolution factors for all 30 analytes on this
CSP are all summarized in Table 2. Representative chromato-
grams for the resolution of analyte 6 using Chiralpak AD-H
are illustrated in Figure 3.
OR
O
O
RO
R=
OR
N
O
H
n
The commercial Chiralpak AD-H column resolved 29 of the
30 analytes with an average separation factor of 2.30, an aver-
age resolution factor of 5.36 using a 15% isopropanol in
Slica-gel
Fig. 2. Structures of chiral stationary phases of Chiralpak AD-H.
Chirality DOI 10.1002/chir

CHIRAL SEPARATION OF RACEMIC 1,4-DIHYDROPYRIDINE VIA CHIRALPAK AD-H
TABLE 1. Resolution of analytes 1–30 on Chiralpak AD-H
columna
efficiently align in the CSP’s chiral cavities in ways that allow
strong hydrogen bonding. Therefore, they may manifest their
p–p interactions as a relatively larger fraction of the total
attractive interactions. In addition, other inclusion or steric
fitting interactions of a racemate with the chiral selector may
contribute. For racemic 4-substituted-1,4-dihydropyridines
on the Chiralpak AD-H column, all the aforementioned
interactions are occurring. All racemic 4-substituted-1,4-
dihydropyridines studied contain the carbonyl (CO) group.
The CO group can form hydrogen bonds with the stationary
phase’s NH groups and dipole–dipole interactions with the
CSP CO groups. The 5,5-dimethyl groups of 16–30 increased
the bulkiness of these molecules. Phenyl groups both
increase the steric bulk of the analytes and also interact via
p–p interaction forces with the 3,5-dimethylphenylcarbamate’s
phenyl group of the CSP.
The 30 analytes were divided into two categories. Analytes
1–15 were made from 1,3-cyclohexanedione while 16–30
were derived from 5,5-dimethyl-1,3-cyclohexanedione. Thus,
16–30 each have a larger steric bulk than 1–15, when
comparing the analogs which contain the same phenyl substit-
uent at the 4-position. The average separation factors for
the Chiralpak AD-H column are 2.34 for analytes 1–15 and
2.25 for 16–30. Overall, analytes with 5,5-dimethyl groups
(16–30) are found to be less efficiently resolved than
analytes without 5,5-dimethyl groups (1–15) on Chiralpak
AD-H columns. Possibly, analytes with 5,5-dimethyl groups
have sufficient bulk to less efficiently align in the CSP’s chiral
cavities in ways that allow strong hydrogen bonding. There-
fore, they may manifest their attractive p–p interactions as a
relatively larger fraction of the total attractive interactions.
Although analytes with 5,5-dimethyl substituents (16–30)
generally are less efficiently resolved on the Chiralpak AD-H
column than analytes without 5,5-dimethyl groups, some 5,5-
dimethyl-containing analytes are more efficiently resolved
than analytes without 5,5-dimethyls. Examples include analytes
with 4-(p-methylphenyl) (2 vs 17), 4-(p-methoxylphenyl) (3
vs 18), 4-(p-isopropylphenyl) (5 vs 20), 4-(p-ethylphenyl)
(6 vs 21), and 4-(p-dimethylaminophenyl) (7 vs 22) substitu-
ents, respectively. It is interesting to note that each of these
molecules had p-substituents that were electron donating
groups. Since Chiralpak AD-H columns have both hydrogen
bonding and p–p attractive forces that facilitate resolution,
increasing analyte bulk may reduce the attractive hydrogen
bonding forces. That would induce less efficient resolution for
most analytes relative to those with less steric bulk. However,
electron donating groups on the phenyl rings will induce
stronger p–p interactions, thereby assisting chiral separation
for analytes with 5,5-dimethyl substituents. These interactions
become relatively more important as the hydrogen bonding
forces decrease.
AD-H
Rs
Analyte
a
k1
1
1.73
1.65
2.75
1.11
1.94
2.05
2.66
3.26
3.18
3.05
1.43
1.72
2.83
2.23
3.49
1.53
2.32
3.05
1
2.28
2.53
3.28
3.02
3.00
2.49
1.36
1.44
1.60
1.87
3.03
4.43
4.96
9.13
0.84
4.17
5.98
7.80
7.24
6.97
6.62
3.20
5.20
8.90
7.07
4.91
2.78
5.87
8.63
0
3.19
4.86
9.45
7.18
7.35
5.07
2.90
2.78
3.05
4.67
5.37
0.938
1.09
2
3
1.688
1.603
0.781
0.961
1.289
0.92
0.978
0.882
1.553
1.34
1.745
2.426
0.691
0.796
0.748
1.152
1.168
0.493
0.657
0.997
0.882
0.943
0.874
1.42
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
1.221
1.732
1.385
0.63
aa is the separation factor. Rs is the resolution factor. The mobile phase constitu-
ents is 15% isopropanol in mixed hexanes. Chiralpak AD-H column dimensions,
250 ꢀ 4.6mm ID. Flow rate, 1.0ml/min; UV diode array detector (DAD).
hexanes mobile phase at 1 ml/min. Furthermore, 28 of the
test compounds were baseline-resolved. This is the first
report of these new racemic 4-substituted-1,4-dihydropyridine
derivatives being resolved by HPLC using a CSP. These
results clearly indicate that the AD-H column efficiently
resolved racemic 4-substituted-1,4-dihydropyridines.
Polysaccharide CSPs are widely applicable for enantiomer
separations of various types of solutes. However, the molecu-
lar recognition mechanisms with which they distinguish
between enantiomers remain mostly concealed because of
the structural complexity of polymeric selectors. The deriva-
tized amylose chiral selectors of the Chiralpak AD-H column
form chiral helical cavities composed from tris(3,5-dimethyl
phenylcarbamate)-D-glucose units (Fig. 2). These cavities
discriminate enantiomers through attractive hydrogen
bonding forces and also p–p interaction forces.32–35 The 3,5-
dimethyl phenylcarbamate groups have sufficient bulk to less
The effect of substituted phenyl groups on the resolution of
this class of analytes was also examined. Various electron
donating and electron withdrawing substituents were studied.
Some substituents on analytes with or without 5,5-dimethyl
TABLE 2. Summary of the chromatographic behavior of the AD-H column
Average of all 30 analytes Average of the analytes 1–15 Average of the analytes 16–30
Analytes
resolved
Column
AD-H
Rs > 1.5
a
Rs
a
Rs
a
Rs
29
28
2.30
5.36
2.34
5.83
2.25
4.88
Chirality DOI 10.1002/chir

DAI ET AL.
Fig. 3. Resolution of analyte 6 on Chiralpak AD-H. Mobile phase: isopropanol/
hexanes (15:85, v/v).
Fig. 5. Dependence of the logarithm of separation factors, log(ah, for 4-aryl-1,
4-dihydropyridines on the Brown substituent constants s+ on a Chiralpak AD-H
column: (a) analytes 1–15 without 5,5-dimethyl substituents and (b) analytes
16–30 with 5,5-dimethyl substituents.
TABLE 3. The value of Hammett parameter s and Brown
a
substituent constants s+
Substituent group
s
s+
p-N(CH3)2
p-OCH3
p-CH3
p-C2H5
p-Isopropyl
p-H
ꢁ0.83
ꢁ0.27
ꢁ0.17
ꢁ0.15
ꢁ0.15
0
ꢁ1.7
ꢁ0.78
ꢁ0.31
ꢁ0.3
ꢁ0.28
0
p-F
p-Cl
0.06
0.23
ꢁ0.07
0.11
p-Br
m-NO2
p-NO2
0.23
0.71
0.78
0.15
0.79
Fig. 4. Dependence of the logarithm of separation factors, log(a), for 4-aryl-1,
4-dihydropyridines on the modified Hammett–Swain parameter s on a Chiralpak
AD-H column: (a) analytes 1–15 without 5,5-dimethyl substituents and (b) analytes
16–30 with 5,5-dimethyl substituents.
aHammett parameter
s are obtained from Ref. 36. Brown substituent
constants s+ are obtained from Ref. 38.
be due to steric effects. There are no obvious trends for
electronic effects on the resolution of any of these less
sterically bulky analytes (1–15) on the Chiralpak AD-H
column. In contrast, electronic effects were manifested for
analytes with 5,5-dimethyl substituents (16–30) on the
Chiralpak AD-H column.
group have similar resolution responses on Chiralpak AD-H
columns. For instance, introduction of a 4-trifluoromethyl
group on the benzene ring led to improved chiral separation,
possibly due to increasing the hydrogen bonding interactions.
However, 2-NO2, 2,4-diNO2, and 3,5-dimethoxyl substitution
on the benzene ring induced less chiral separation. This might
Chirality DOI 10.1002/chir

CHIRAL SEPARATION OF RACEMIC 1,4-DIHYDROPYRIDINE VIA CHIRALPAK AD-H
In order to elucidate the effect of the phenyl ring substituents
AD-H constitute a complex set of attractions. A variety of
dipole–dipole, Van der Waal interactions, p–p attractions,
etc., are occurring between the analytes and the CPS, as
well as the competing interactions of the analytes and the
CSP with the eluting solvent. Isolating specific effects is
difficult, especially in the presence of different steric effects.
Therefore, our explanations and observed correlations are
clearly simplifications of the more complex reality being
observed. However, the series of analytes 1–30 does provide
a somewhat unique opportunity to hold the general molecular
shape/structure constant while searching for substituent
electronic effects-over a 30 compound set.
on resolution, the dependence of the logarithm of separation
factor on typical electron donating and electron withdrawing
groups was studied for resolutions on the Chiralpak AD-H
column. Some substituents, such as 2-NO2, 2,4-diNO2, 3,5-
dimethoxyl, and 4-trifluoromethyl substitution were excluded
because of the combination of steric bulk and hydrogen bond-
ing effects. The modified Hammett–Swain parameter s36,37
and the Brown substituent constants s+ 38,39 were selected to
see if correlations existed. The modified Hammett–Swain
parameter s is defined by field and resonance effects, F and
R, which are dependent on the individual substituent. These
constants depend on the set of Hammett substituent param-
eters corresponding to the molecular structure (sm, sp,
etc.).36 The electrophilic substituent constant, Brown substitu-
ent constants s+, were derived from the relative rate constants
of the solvolysis of substituted alpha-cumyl chlorides in an
acetone/water solvent mixture in the original work by Brown
and Okamoto.38 These constants exhibit a strong resonance
stabilizing or destabilizing effect when the system is subjected
to a strong electron demand. Substituent effects were probed
by plotting the logarithm of separation factors, log(a), versus
the Hammett parameter s and Brown substituent constants
s+ (Figs. 4 and 5). The values of the Hammett s and Brown
s+ substituent constants for the substituents used in this
work are all shown in Table 3. Also, a short introduction to
the use of s and s+ substituent constants and linear free energy
relationships is given in the Supporting Information as
suggested by a reviewer.
The correlation coefficient of the logarithm of separation
factors, log(a), versus the Hammett parameter s for analytes
1–15 without 2-NO2, 2,4-diNO2, 3,5-dimethoxyl, and 4-
trifluoromethyl substitution is 0.038, and the correlation
coefficient of these same plots for analytes 16–30 (without
2-NO2, 2,4-diNO2, 3,5-dimethoxyl, and 4-trifluoromethyl
substitution) is 0.653 in Figure 4. The correlation coefficient
of the logarithm of separation factors, log(a), versus the
Brown substituent constants s+ for analytes 1–15 is 0.111,
and the correlation coefficient of these plots for analytes
16–30 is 0.601 in Figure 5. It is clear that the logarithm of
separation factors of analytes 1–15 (without 5,5-dimethyl
substitution) do not correlate with, and are not dependent
on, the electronic nature of the substituents on the phenyl
ring (Figs. 4a and 5a). Thus, we conclude that the logarithm
of separation factors of analytes 1–15 do not correlate
with the electron donating or withdrawing nature of these
substituents. Overall, the log(a) values are not sensitive to
the substituents, indicating that the p–p interaction forces
have a smaller influence on the resolution of analytes without
5,5-dimethyl substitution.
CONCLUSIONS
Two new series of 4-aryl-1,4-dihydropyridine derivatives were
synthesized and resolved for the first time on a Chiralpak AD-H
column. The AD-H stationery phase efficiently resolved most of
the racemic 4-aryl-1,4-dihydropyridine derivatives. Analytes with
5,5-dimethyl groups (16–30) are less efficiently resolved
than the corresponding analytes without 5,5-dimethyl groups
(1–15). A hypothesis that is in accord with a correlation that
we observed between the logarithm of separation factors, log
(a), versus Hammett–Swain s substituent constant and Brown
substituent constants s+ for 16–30 was suggested to explain
these observations. Bulky analytes with 5,5-dimethyl substitu-
tion may not fit the chiral pocket of the CSPs as well as their less
bulky analogs with the 5,5-dimethyl group. This leads to a
reduction in the net hydrogen bonding attractive forces
between the analytes and the CSP. The Chiralpak AD-H column
can apparently recognize these analytes by additional p–p-type
interactions. This p–p-type attraction becomes relatively more
important with a reduction in hydrogen bonding. This suggests
that the AD-H column discriminates enantiomers through both
attractive hydrogen bonding and the p–p interaction forces.
Upon observing the effects on resolution of electron donating
and attracting substituents, remote from the asymmetric center,
it seems reasonable to interpret the results for the AD-H column
in terms of p–p interaction forces. The relative contribution of
these forces to resolution increases when steric bulk serves to
decrease the hydrogen bonding attractive forces.
ACKNOWLEDGMENTS
The financial support from NIH (grant numbers R15 GM
83326–01 and 3R15GM083326-01 S1) is greatly appreciated.
We also appreciate the assistance and helpful discussions
with Professor Gerald Rowland, who also provided generous
access to, and use of, HPLC instrumentation in his laboratory.
LITERATURE CITED
In contrast to analytes 1–15, the logarithm of separation
factor of analytes 16–30, with 5,5-dimethyl groups, are
somewhat dependent on the electron donating/withdrawing
nature of the phenyl substituents. Analytes 16–30, containing
5,5-dimethyl groups, are more sensitive to the electron
donating or withdrawing effects of these phenyl substituents
than analytes 1–15. This is evident from the log(a) versus
Hammett parameter s and Brown substituent constants s+
plots in Figures 4b and 5b. This relative influence of p–p
interaction appears to increase as steric bulk effects get larger,
perhaps due to a decrease the hydrogen bonding attractions.
The interactions of analytes 1–30 with the 3,5-dimethyl-
phenylcarbamate-derivatized amylose CPS of Chiralpak
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