Quantification of a CH-π interaction responsible for chiral discrimination and evaluation of its contribution to enantioselectivity

Article abstract of DOI:10.1002/anie.200903281

Good things come in small interactions: The high chiral discrimination displayed by a new receptor with ammonium salts of aromatic a-amino acid methyl esters is mainly the result of one of the weakest noncovalent interactions, the CH-π interaction (see pi

Full text of DOI:10.1002/anie.200903281

Angewandte
Chemie
DOI: 10.1002/anie.200903281
Noncovalent Interactions
Quantification of a CH–p Interaction Responsible for Chiral
Discrimination and Evaluation of Its Contribution to
Enantioselectivity**
Romen Carrillo, Matꢀas Lꢁpez-Rodrꢀguez, Victor S. Martꢀn, and Tomꢂs Martꢀn*
Dedicated to Professor Julius Rebek, Jr. on the occasion of his 65th birthday
The CH–p interaction, in which the CH group is aliphatic, is
one of the weakest known interactions. However, this
interaction is very important,[1] as it contributes significantly
to the overall stability of protein structures,[2] the selective
recognition and binding affinity between proteins and
ligands,[3] the conformational preference of DNA,[4] the
stereoselectivity of organic reactions,[5] and molecular recog-
nition.[6] Therefore, the measurement of its strength and scope
is very important. Such CH–p interactions have been inves-
tigated qualitatively through protein mutation studies,[7] IR[8]
and NMR[9] spectroscopy, X-ray crystallographic analysis,[10]
and by computational methods.[11] However, the quantifica-
tion of such a weak interaction is usually not easy and thus
there are only a few reports of studies in this area.[12]
Remarkable contributions to this field are Wilcoxꢀs torsion
balance,[13] the carbohydrate–p interaction within a b-hairpin-
peptide[14] and dangling-ended DNA[15] model systems, and
cyclohexylphenyl recognition in the center of a DNA
duplex.[16] It is even more difficult to evaluate the contribution
of a single noncovalent interaction that is involved in a
specific biological or chemical event, particularly for the weak
interactions. Therefore, the development of simple molecular
models in order to assess the contribution of a CH–p
interaction in chiral recognition processes is extremely
important. Herein, we show the key role of a CH–p
interaction in a remarkably high chiral discrimination dis-
played by a new synthetic receptor. Furthermore, we use this
new receptor as a useful model for the quantification of the
interaction and for an unprecedented evaluation of its
contribution to the whole chiral recognition process.
During our search for new chiral cation receptors using
the cis-2-oxymethyl-3-oxy-tetrahydropyran unit as a key
motif,[17] we found that receptor 1[18] displayed high associa-
tion constants with ammonium salts of a-amino acid methyl
esters (Scheme 1).[19] The association constants were distinc-
Scheme 1. Chemical structures of receptors 1, 1F, and the ammonium
salts of a-amino acid methyl esters.
tively higher with the d enantiomers of the amino acids, and
chiral discrimination was conserved using either different
solvents or different anions (Table 1 and Table S1 in the
Supporting Information). Particularly high enantioselectivity
was shown for those amino acids that bear aromatic side
chains. Tryptophan (Trp), which has the most effective donor
aromatic side chain, displays the highest association constant
for the d enantiomer and the best chiral discrimination, which
reached values of up to KD/KL = 33.78 ꢀ 0.90 (DDG0 = (8.72 ꢀ
0.07) kJmolꢁ1) for Trp-OMeNO3 in CD3CN (Table S1 in the
Supporting Information). These data suggest that the aro-
matic side chain is likely to be involved in the origin of the
enantioselectivity.[20]
[*] Dr. T. Martꢀn
Instituto de Productos Naturales y Agrobiologꢀa, CSIC
Francisco Sꢁnchez, 3, 38206 La Laguna, Tenerife (Spain)
Fax: (+34)922-260-135
E-mail: tmartin@ipna.csic.es
Dr. R. Carrillo, Prof. Dr. M. Lꢂpez-Rodrꢀguez, Prof. Dr. V. S. Martꢀn,
Dr. T. Martꢀn
Instituto Universitario de Bio-Orgꢁnica “Antonio Gonzꢁlez”
Universidad de La Laguna
Francisco Sꢁnchez, 2, 38206 La Laguna, Tenerife (Spain)
To gain insight into the causes of this remarkably high
chiral recognition, a detailed NMR-based study of the
geometry of the complexes in solution was carried out.
Complexation-induced chemical shifts (CISs) derived from
1H NMR titration of the receptor 1 with both enantiomers of
alanine (Ala), leucine (Leu), phenylalanine (Phe), and
tryptophan picrate (Pic) salts[21] in CD3CN were analyzed,
and a great deal of information about their binding was
obtained (Figure 1). The signals for protons in positions 3, 6
(equatorial), 7, 11, and 12 are shifted markedly downfield
[**] The authors thank Dr. K. Hirose and Dr. J. M. Sanderson for
providing the titration isotherm curve fitting program, Dr. Eze-
quiel Q. Morales for TOC graphic design, and Dr. David Tejedor and
Dr. Fernando Garcꢀa-Tellado for helpful discussions. This research
was supported by the Spanish MEC (CTQ2005-09074-C02-01 and
02), the MICINN-FEDER (CTQ2008-03334/BQU and CTQ2008-
06806-C02-01/BQU), FICIC, the MSC ISCIII (RETICS RD06/0020/
1046). R.C. thanks the Spanish MEC for an FPU fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903281.
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Table 1: Association constants (Ka), enantioselectivity, Gibbs free-energy
complexes indicates that the aromatic residue in the amino
acids that bear an aromatic side chain (indole for Trp or
phenyl for Phe) does not overlap the pyridine ring. Thus, the
possibility of a p–p interaction between the aromatic side
chain and the pyridine on the receptor was discarded.
Conversely, significant upfield shifts of protons 9 and 10
from the diethyleneglycol spacer can be observed, and these
chemical shifts are quite similar for both enantiomer of all
guests except from complexes with d-Phe-OMe+ and d-Trp-
OMe+, which showed larger upfield shifts than the rest of the
complexes for these proton signals (Figure 1d,e).
This behavior can easily be explained when it is consid-
ered that the complexed structure of 1 is folded. Indeed, the
X-ray structure of receptor 1 shows that it is already folded in
its free form (Figure 2).[23] Several important features can be
found by analyzing this structure. Firstly, the cis tetrahydro-
pyran units are in the optimal conformation for complexation
(with the 3-oxy group in the axial position).[17] Secondly, one
of the carbonyl groups is directed outward from the cavity and
the other is directed inward. As a consequence of this
orientation, the pyridine ring is quite close to the diethylen-
glycol spacer. Finally, the distance between one proton in
position 10 and the pyridine aromatic plane is around 2.73 ꢁ.
This observation clearly indicates the presence of an intra-
molecular CH–p interaction in the
changes (ꢁDG0), and DDG0 calculated from ꢁDG0 for the complexation
of the host 1.
Guest (G+Picꢁ) Ka [mꢁ1 [b,c]
]
KD/KL
1.80
ꢁDG0 [kJmolꢁ1
]
DDG0
1.46
2.97
3.75
5.80
[d]
d-Ala-OMe+
l-Ala-OMe+
d-Leu-OMe+
L-Leu-OMe+
d-Phe-OMe+
l-Phe-OMe+
d-Trp-OMe+
l-Trp-OMe+
25990ꢀ1050
14410ꢀ990
29100ꢀ950
8760ꢀ220
25.19ꢀ0.10
23.73ꢀ0.17
25.47ꢀ0.08
22.50ꢀ0.06
25.56ꢀ0.17
21.81ꢀ0.25
27.85ꢀ0.20
22.05ꢀ0.08
3.32
30230ꢀ2100
6640ꢀ680
4.55
76190ꢀ6260
7330ꢀ230
10.39
[a] Recorded in CHCl3 at 298 K. [b] The association constants were
determined on the basis of differential UV/Vis spectroscopy at three
wavelengths (380, 385, and 390 nm) by the typical nonlinear least-
squares method (1:1 simulation) and the uncertainty is given by the
standard deviation. [c] These values are the average of at least three
independent measurements. [d] KD/KL =enantioselectivity.
compared with their respective chemical shifts in the spec-
trum of free receptor 1. These shifts imply that O-1, O-8, the
oxygen atom from the ester, and the nitrogen atom from
pyridine participate in the complex formation.[22] Also, the
downfield shifts observed for the pyridine proton signals in all
solid phase.[24] Additionally, the tem-
perature-dependent 1H NMR spec-
trum of the complex 1 with d-Trp-
OMePic in CDCl3 was also recorded
(Figure S1 in the Supporting Infor-
mation). At room temperature,
some signals are broad, which sug-
gests a dynamic effect. However, at
low temperatures, these signals split
into two peaks of equal intensity,
which indicates a slow intermolecu-
lar face-to-face guest exchange on
the NMR timescale.[18] In order to
assign all the signals, COSY, HSQC,
and HMBC experiments were per-
formed at 223 K, and 1D and 2D
ROESY were performed at 223 K.
The intramolecular ROEs were
observed between protons in posi-
tions 10 and 10’ with pyridine pro-
tons 11 and 11’, respectively. The
ROE cross peak between pyridine
proton 11’ and axial proton 5’ is in
agreement with the folded structure
found in the X-ray crystal structure
of the free receptor 1 (Figure 3a,b),
which is quite similar to the structure
in solution of its complex with d-
Trp-OMe+. However, complexation
induces conformational changes in
the receptor 1. The intramolecular
1
Figure 1. Sections of H NMR spectra (500 MHz) of the complexes of host 1 with various chiral a-
amino acid methyl ester ammonium picrate salts in CD3CN (9.1 mm) at 298 K. a) Host 1, b) d-Ala-
OMePic·1, c) d-Leu-OMePic·1, d) d-Phe-OMePic·1, e) d-Trp-OMePic·1, f) l-Ala-OMePic·1, g) l-Leu-
OMePic·1, h) l-Phe-OMePic·1, i) l-Trp-OMePic·1.
ROEs between protons in posi-
tions 3 and 3’ with protons 7 and 7’,
respectively, indicate that the oxygen
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1.35 ppm), which is the proton that displays intermolecular
ROEs with the indole ring of the guest (Figure 3c). All the
above data is clear evidence that this proton lies especially
close to the indole group. Alternatively, the intramolecular
ROEs in ROESYexperiments in CDCl3 at room temperature
of complex l-TrpOMePic·1 reveal a folded receptor geome-
try, which is similar to that found for complex d-Trp-
OMePic·1, however, intermolecular ROEs were not
observed.[18,22]
All these geometrical data suggest an appropriate con-
formation for a putative intermolecular CH–p interaction
between one proton in position 9 and the aromatic side chain
of Trp. The interaction occurs only in the d-enantiomer of the
Trp, therefore it could be responsible for the great enantio-
selectivity displayed. Moreover, the chiral discrimination
increased when the solvent was changed from CHCl3 to
CD3CN (Table 1 and Table S1 in the Supporting Informa-
tion). The biggest enhancement was for Phe-OMePic (2.54
times), whilst the enhancement was less than twofold for Trp-
OMePic (1.73), Leu-OMePic (1.70), and Ala-OMePic
(1.56).[25] These results support the putative intermolecular
CH–p interaction. Based on the molecular surface electro-
static potential, the hydrogen-bond donor character for
acetonitrile is less than that for chloroform, so acetonitrile is
a less competitive solvent than chloroform for CH–p inter-
actions.[26] A stronger interaction in acetonitrile for the
d enantiomers of Phe-OMePic and Trp-OMePic, and there-
fore a better chiral recognition, is expected. Nonetheless, this
behavior is only clearly observed for Phe-OMePic, which is in
agreement with the presence of the best donor aromatic
residue in the Trp-OMePic and therefore the CH–p inter-
action with the indole group is less sensitive to solvent
changes.
However, further evidence is needed to support the
existence of a putative intermolecular CH–p interaction. One
such proof is to exchange the hydrogen atom thought to be
involved in the interaction by a fluorine atom. The fluorine
atom has a similar size to the hydrogen atom, so there will be
no steric effects, but has a high electronegativity that inhibits
the interaction with the aromatic chain.[27] With that aim in
mind, we synthesized receptor 1F in which the protons in
position 9 had been replaced by fluorine atoms.[18] If our
hypothesis of a CH–p interaction is correct, a decrease in
chiral discrimination for 1F would be expected. The associ-
ation constants for this receptor are shown in Table 2.[28] At
first glance, we can see how the value of the association
constants decreased drastically as a consequence of the
inductive effect exerted by the fluorine atoms on the adjacent
oxygen atoms.[29] However, the most important information
displayed in Table 2 is that, even though a slight preference
for the d series still remained, the chiral discrimination was
reduced for all substrates especially for tryptophan. We have
verified that the structures of the complexes with the
fluorinated receptor 1F are quite similar to those found
with receptor 1 (see below), thus, these results confirm that
the CH–p interaction does not occur in the fluorinated
receptor.
Figure 2. Front and top view of the X-ray structure of receptor 1.
C gray; H white; N blue; O red.
Figure 3. Three-dimensional structure of complex 1 with d-Trp-OMe+
based on NMR studies. Intramolecular ROEs shown in blue and
intermolecular ROEs shown in red. a) Front view without d-Trp-OMe+,
b) top view without d-Trp-OMe+, and c) structure of complex 1 with d-
Trp-OMe+. The indole group is shown in green.
atoms in positions 8 and 8’ move into the cavity to create a
hydrophilic concave face with six oxygen atoms and the
nitrogen atom directed toward the center of the cavity
(Figure 3b). This geometry is ideally suited for the complex-
ation of ammonium salts and the folding of the receptor
increases once the guest is complexed. This extra folding
makes the pyridine ring lie closer to the diethylenglycol chain,
and thus induces an upfield shift of these protons in all
complexes. Moreover, the further upfield shifts for the
d enantiomers of the amino acids that bear an aromatic side
chain suggest that the phenyl and indole groups are situated
over the diethylenglycol spacer. The intermolecular ROE
effect on complex d-Trp-OMePic·1 confirm that the indole
group overlaps the diethyleneglycol spacer (Figure 3c). Addi-
tionally, in the 1H NMR spectrum of the complex d-Trp-
OMePic·1 at 223 K (Figure S1 in the Supporting Informa-
tion), the protons in positions 9 and 9’ are shifted upfield,
which is consistent with the expected chemical shielding effect
from the p electron clouds of the pyridine and the indole
residue. Both protons in position 9 and one proton in
position 9’ show a moderate shift (d9 = 2.78 ppm, 3.29 ppm
and d9’ = 2.70 ppm). A particularly remarkable upfield shift
was observed for the other proton in position 9’ (d =
By considering all the above evidence, it can be confirmed
that a CH–p interaction occurs between one proton in
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1F) and the guest (d-Trp-OMe+!d-Leu-OMe+) respectively.
Thus, the difference between the stabilities of complexes C
and D provides a direct measurement of the changes in the
ammonium-hydrogen-bond strength and in other secondary
interactions associated with the A!B mutation, and it is
possible to extract the thermodynamic contribution of the
CH–p interaction from all of the other interactions present in
complex A. This thermodynamic relationship can be
expressed as:
Table 2: Association constants (Ka) and enantioselectivity for complex-
ation of the receptor 1F.[a]
Guest
Ka [mꢁ1
]
KD/KL
1.29
1.25
1.47
d-Trp-OMePic
l-Trp-OMePic
d-Leu-OMePic
l-Leu-OMePic
d-Ala-OMePic
l-Ala-OMePic
400ꢀ30
310ꢀ40
800ꢀ60
640ꢀ20
1030ꢀ60
700ꢀ20
[a] Calculated from UV/Vis titrations in CHCl3 at 298 K. Values are the
average of at least three independent measurements and the uncertainty
is given by the standard deviation.
DDGCHꢁp ¼ ðDGAꢁDGBÞꢁðDGCꢁDGDÞ
ð1Þ
In order to apply the proposed chemical double-mutant
cycle, two assumptions have to be made: 1) The substituents
on the mutants do not interact. This assumption is valid as the
fluorine atoms should not interact either with the indole ring
in complex B or with the isopropyl group in complex D, and
there should not be any interaction between diethylenglycol
and the d-Leu-OMe+ side chain in complex C;[31] and 2) there
are no major conformational changes in the structures of all
used complexes. This assumption has to be verified.
position 9 and the aromatic ring of the amino acids, and that
the interaction is especially strong for Trp. It has also been
shown that the interaction is exclusive for the d enantiomers,
and consequently it plays a key role in the chiral discrim-
ination process.
At this stage, a quantification of the CH–p interaction is
desirable. As receptor 1F lacks this interaction, we could
tentatively measure the strength of the interaction as the
difference between the stabilities of complexes A and B
(Scheme 2). However the value is perturbed by changes in the
The X-ray analysis of the free fluorinated receptor 1F
reveals a structure that is very similar to that of the free
receptor 1 (Supporting Information, Figure S2). For com-
plex B, the ROESY experiment displays only intramolecular
ROEs, which confirm the correct conformation for the
complexation of the cis tetrahydropyran units. Also, some
very important information can be obtain by comparing the
1H NMR spectra of the free fluorinated receptor 1F and the
complex d-Trp-OMePic·1F (complex B), where downfield
shifts of the pyridine proton signals and the upfield shifts of
protons in on C-10 indicate that the indole group overlaps the
diethylenglycol spacer.[18] The structure of complex C was
confirmed by ROESY experiments. Intramolecular ROEs
reveal a folded geometry of the receptor skeleton and the
intermolecular ROEs show the proximity between the leucine
residue and the diethylenglycol spacer.[18] For complex D,
ROESY experiments confirm that the cis tetrahydropyran
units are in the correct conformation. By comparing the
1H NMR spectra of the free fluorinated receptor 1F, complex
d-Leu-OMePic·1F (D), and the guest alone, a pattern of
chemical shift changes that is similar to those observed for the
rest of the complexes is revealed, thus indicating that all
complexes adopt similar three-dimensional structures.[18] The
slight downfield shifts of the leucine residue with respect to
the free substrate reveal that the isopropyl group is situated
away from the pyridine ring most of the time.[32]
Scheme 2. Schematic representation of the chemical double-mutant
cycle.
Subsequently, by using the association constants obtained
in CHCl3 by UV/Vis spectroscopic titration, we calculated the
free-energy values for each complex involved in the chemical
double-mutant cycle (Figure S3 in the Supporting Informa-
tion). By applying Equation (1), we determined that the
energy value of (ꢁ4.09 ꢀ 0.34) kJmolꢁ1 for the CH–p inter-
action between the indole group of d-Trp-OMePic and the
hydrogen atom in position 9. This value is in agreement with
theoretical and experimental reported data.[1]
ammonium-hydrogen-bond strength and in other secondary
interactions associated with the change made from com-
plex A to complex B, which will be referred to as the A!B
mutation. In these cases, a double-mutant cycle is very useful
because it overcomes this problem as the secondary free-
energy effects of the mutations cancel in a pairwise fashion in
the thermodynamic cycle.[30] The secondary effects can be
quantified by using complexes C and D where the CH–p
interaction has been removed by means of a mutation in the
guest (d-Trp-OMe+!d-Leu-OMe+) and both in the host (1!
We next tried to evaluate the contribution of the CH–p
interaction to the chiral discrimination. We can consider that
the association constant for each complex with a different
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[7] a) Y. Nakagawa, K. Irie, R. C. Yanagita, H. Ohigashi, K. Tsuda,
enantiomer as guest is composed of the sum of different
attractive and repulsive terms, so that the chiral discrimina-
tion is the sum of all these energetic differences between both
complexes. In this study, we have already calculated the value
of (ꢁ5.80 ꢀ 0.22) kJmolꢁ1 (Table 1) for the chiral discrimina-
tion as the difference in free energy between complexes of 1
with d-Trp-OMePic and l-Trp-OMePic. But, even more
importantly, we have also specifically measured one of the
energetic differences between the complexes of both enan-
tiomers to be (ꢁ4.09 ꢀ 0.34) kJmolꢁ1 for a CH–p interaction
exclusive to the d enantiomer. Thus, a remarkable (70.5 ꢀ
6.4)% of this chiral recognition process is the consequence of
a single CH–p interaction. Only one CH–p interaction is
mainly responsible for the chiral discrimination observed.
In summary, we have shown that a CH–p interaction is
involved in the remarkably high chiral recognition displayed
by a new synthetic receptor based on cis-2-oxymethyl-3-oxy-
tetrahydropyran. We also quantified the interaction through a
chemical double-mutant cycle that provides a value of
ꢁ4.09 kJmolꢁ1 for the interaction with tryptophan, which is
in agreement with theoretical and experimental reported
data. Finally, an assessment of the contribution of this single
interaction to the whole chiral discrimination process was
performed. This evaluation yielded that a single CH–p
interaction causes a 70% of the enantioselection. Thus, for
every selective recognition process or asymmetric reaction
where aromatic and aliphatic groups are involved, we should
take into account that a weak noncovalent interaction, such as
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ꢁ
the CH p bond, is likely to contribute to or even govern the
[18] See the Supporting Information for details.
whole process.
[19] For pioneering work on the chiral recognition of ammonium
salts of a-amino acid esters, see: a) R. C. Helgeson, J. M. Timko,
P. Moreau, S. C. Peacock, J. M. Mayer, D. J. Cram, J. Am. Chem.
Soc. 1974, 96, 6762 – 6763; b) Y. Chao, D. J. Cram, J. Am. Chem.
Soc. 1976, 98, 1015 – 1017.
[20] The fundamental bonding interaction between the ammonium
salt of the a-amino acid methyl ester and the macrocycle 1 is
tripodal hydrogen bonding. In addition, at least two secondary
attractive or repulsive interactions must be present to produce
the different stability of the diastereoisomeric complexes that
cause the chiral discrimination. X. X. Zhang, J. S. Bradshaw,
R. M. Izatt, Chem. Rev. 1997, 97, 3313 – 3362, and references
therein.
Received: June 17, 2009
Published online: September 8, 2009
Keywords: chiral discrimination · CH–p interactions ·
.
molecular recognition · noncovalent interactions · receptors
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[21] The choice of picrate salts is due to their higher solubility in
CD3CN and because their complexation can be followed by
1H NMR spectroscopy. We are currently investigating the causes
of the different enantioselectivity when different anions are
used. However, preliminary studies reveal that the anions
appear to play no role in the structure of the complexes as we
can infer from the similarities in the 1H NMR spectra for all
complexes (see the Supporting Information). The observed
differences could be related to the ion-pair strength of the salts
employed.
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[22] In the complex l-Trp-OMePic·1, the signals of the equatorial
protons in position 6 are shifted upfield, which may be inter-
preted in terms of magnetic anisotropy induced by the indole
group. This result clearly indicates that the indole group in the
complex l-Trp-OMePic·1 is in a different orientation that in the
complex d-Trp-OMePic·1.
[23] Unfortunately all attempts to crystallize complexes of receptor 1
with any ammonium salts were not successful.
[24] In a CH–p interaction, the distance between the hydrogen atom
and the p surface is around 2.5–2.9 ꢁ. See Reference [10].
[4] Y. Umezawa, M. Nishio, Nucleic Acids Res. 2002, 30, 2183 – 2192.
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 7807

Communications
[25] The lower association constants recorded in CD3CN can be
reference [7a]; d) K. Mꢂller, C. Faeh, F. Diederich, Science 2007,
317, 1881 – 1886.
[28] In order to obtain highly reliable binding constants with the
receptor 1F, UV/Vis titrations in CHCl3 were carried out instead
of 1H NMR titrations in CD3CN, because only very small
changes in the chemical shifts were observed.
[29] T.-Y. Lin, W.-H. Lin, W. D. Clark, R. J. Lagow, S. B. Larson, S. H.
Simonsen, V. M. Lynch, J. S. Brodbelt, S. D. Maleknia, C.-C.
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[31] Dispersion interactions are always possible; however these
interactions are similar on both sides of the cycle, therefore, the
free energy differences must be canceled out in the analysis.
[32] We have verified that use of either CDCl3 or CD3CN as solvent
makes no difference to the structure of the complexes. However
the NMR structural studies of complexes involved in the
chemical double-mutant cycle were performed in CD3CN at
298 K because receptor 1F displays low association constants
and therefore it is unable to sufficiently solubilize the ammo-
nium picrate salts of the a-amino acid methyl esters in CDCl3 to
obtain a suitable concentration for the NMR studies.
explained because CD3CN better solvates the ammonium
cation, which competes much more than CHCl3 with receptor
1 for the guest. A lower association constant is expected for both
guest enantiomers, and an even lower value is expected for the
less-preferred guest, because its complex is more sensitive to
changes in the conditions. Thus, association constants for the
l series decreased even more than for the d series, and therefore
a general increase of the chiral discrimination was observed.
[26] Hunter has calculated a series of parameters, for common
functional groups and solvents, based on the molecular surface
electrostatic potential, which allow them to obtain a scale of
hydrogen-bond strength. The values of hydrogen-bond-donor
constant (a) for acetonitrile and chloroform are 1.7 and 2.2,
respectively. C. A. Hunter, Angew. Chem. 2004, 116, 5424 – 5439;
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C. J. Urch, R. Ford, ChemBioChem 2004, 5, 657 – 665; c) see
7808 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 7803 –7808