Asymmetric catalysis of Diels-Alder reactions with in situ generated heterocyclic ortho -quinodimethanes

Article abstract of DOI:10.1021/ja206517s

The Diels-Alder reaction is probably the most powerful technology in the synthetic repertoire for single-step constructions of complex chiral molecules. The synthetic power of this fundamental pericyclic transformation has greatly increased with the emerg

Full text of DOI:10.1021/ja206517s

ARTICLE
pubs.acs.org/JACS
Asymmetric Catalysis of DielsꢀAlder Reactions with in Situ Generated
Heterocyclic ortho-Quinodimethanes
Yankai Liu,† Manuel Nappi,† Elena Arceo,† Silvia Vera,† and Paolo Melchiorre*,†,‡
†ICIQ - Institute of Chemical Research of Catalonia, Avenida Països Catalans 16, 43007 Tarragona, Spain
‡ICREA - Instituciꢀo Catalana de Recerca i Estudis Avanc-ats, Passeig Lluís Companys 23, 08010 Barcelona, Spain
S Supporting Information
b
ABSTRACT: The DielsꢀAlder reaction is probably the most
powerful technology in the synthetic repertoire for single-step
constructions of complex chiral molecules. The synthetic power
of this fundamental pericyclic transformation has greatly in-
creased with the emergence of asymmetric catalytic variants,
and research aimed at further expanding its potential is still
exciting and fascinating the chemical community. Here, we
document the first asymmetric catalytic DielsꢀAlder reaction of
in situ generated heterocyclic ortho-quinodimethanes (oQDMs),
reactive diene species that have never before succumbed to a catalytic approach. Asymmetric aminocatalysis, that uses chiral amines
as catalysts, is the enabling strategy to induce the transient generation of indole-, pyrrole- or furan-based oQDMs from simple
starting materials, while directing the pericyclic reactions with nitroolefins and methyleneindolinones toward a highly stereoselective
pathway. The approach provides straightforward access to polycyclic heteroaromatic compounds, which would be difficult to
synthesize by other catalytic methods, and should open new synthetic pathways to complex chiral molecules using nontraditional
disconnections.
’ INTRODUCTION
designing a catalytic asymmetric strategy mainly depends on
the necessity of generating the highly reactive and unstable
oQDMs dienes in situ, in the presence of the trapping reactant
(the dienophile).5,6 Generally, the dearomatization process that
leads to these species (intermediate I in Figure 1a) requires harsh
reaction conditions and high temperatures, which are not com-
patible with the action of a chiral catalyst.
The DielsꢀAlder reaction1 is considered to be the most
powerful and reliable synthetic strategy for achieving structural
and stereochemical complexity. This is testified to by its many
applications in total synthesis.2 As anticipated a decade ago,3
further advances in the scope and utility of this transformation
were to come, and investigations into further improvement are
still a highly active area of modern organic chemistry research.
The emergence of catalytic asymmetric variants4 has even in-
creased the synthetic potential of this pericylic reaction. Many
combinations of dienes and dienophiles have been rendered
highly stereoselective, providing a predictable and single-step
access, from simple starting materials to stereochemically dense
cyclohexenyl rings adorned with different molecular architec-
tures. Although the scope of the asymmetric DielsꢀAlder re-
action has greatly expanded, one highly useful class of dienes,
ortho-quinodimethanes (oQDMs),5 has never been used for a
catalytic enantioselective approach. This notable lack stands in
sharp contrast to the synthetic utility of oQDMs and their hetero-
cyclic counterparts, since those highly reactive dienes provide direct
access to complex polycyclic (hetero)aromatic compounds with
multiple stereocenters. Indeed, heterocyclic oQDMs6 have been
extensively studied over the last 40 years in order to design intra- and
intermolecular DielsꢀAlder reactions for synthesizing target com-
plex molecules, including steroids, alkaloids, and anthracyclines.7,8
To date, the sporadic examples of enantioselective DielsꢀAlder
reactions of oQDMs described in the literature require (over)-
stoichiometric amounts of chiral inducers.9,10 The challenge of
In the 1980s, Magnus and colleagues published a series of
inspiring studies on the DielsꢀAlder process of heterocyclic
oQDMs. These works illustrated the directness and versatility of
this approach for the stereocontrolled annulations of indole
systems (Figure 1b).11 The so-called indole-2,3-quinodimethane
strategy,12 designed for the synthesis of indole alkaloids, was
based on the mild generation of the indole-2,3-quinodimethane
intermediate III from a preformed imine. The key tautomeriza-
tion event was driven by the increased acidity of the proton at the
2-methyl indole moiety, induced by nitrogen quaternarization
with methyl chloroformate to form an iminium ion intermediate
II. Despite the rather mild reaction conditions, the implementa-
tion of an enantioselective synthesis of the cis-fused tetracyclic
products was based upon the use of chiral auxiliaries.13,14
One fascinating aspect of chemical research, and scientific
progress at large, is that the accumulated knowledge and resulting
techniques often provide new tools for attacking longstanding
problems using pre-existing strategies.15 One example is asymmetric
Received: July 18, 2011
Published: August 15, 2011
r
2011 American Chemical Society
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Figure 1. ortho-Quinodimethanes (oQDMs) as dienes of the DielsꢀAlder reaction. (a) Traditional methods for the generation of oQDM intermediates
I generally require harsh reaction conditions, high reaction temperatures, and difficult-to-make starting materials, that is, 1,4-eliminations, flash vacuum
pyrolysis (FVP) of cyclohexene-fused heterocycles, thermal ring-opening of aryl-cyclobutene derivatives, and cheletropic extrusion of sulfur dioxide.
(b) Original annulation developed by Magnus and colleagues in 1981, based on the indole-2,3-quinodimethane intermediate III formation through
imine tautomerization. (c) Design blueprint for an asymmetric catalytic DielsꢀAlder reaction with in situ generated indole-2,3-quinodimethane using
aminocatalysis as the enabling strategy. Het, heteroaromatic; DA, DielsꢀAlder; E, electron-withdrawing group; H-X, acid.
aminocatalysis,16 which exploits the ability of chiral amine cata-
lysts to reversibly condense with carbonyl compounds.17,18 Ex-
ploitingfundamental and well-established mechanistic patterns,19
and mainly using the chemistry of simple enamine and iminum
ion intermediates,20 this approach has greatly expanded the
chemist’s ability to asymmetrically functionalize unmodified car-
bonyl compounds.21 We recently wondered whether the syn-
thetic plan engineered by Magnus and co-workers11ꢀ14 could be
brought to fruition by capitalizing on this modern perspective,
after 30 years of chemistry progress and innovation. Could the
underlying principle of the indole-2,3-quinodimethane strategy
(Figure 1b) be used to design a catalytic asymmetric DielsꢀAlder
reaction, using enantioselective aminocatalysis as the enabling
strategy? Specifically, we sought to generate in situ the desired
diene derivative V directly from a simple starting material, such as
an easily available β-indolyl unsaturated aldehyde of type 1 and a
chiral secondary amine catalyst (Figure 1c). To meet this chal-
lenge, we recognized two critical issues. We needed to identify a
chiral catalyst that, upon condensation with enal 1 and the
formation of the expected electrophilic iminum ion intermediate
IV, (i) could facilitate the tautomerization toward the reactive
species V, (ii) while selectively directing the [4 + 2] cycloaddition
reaction with a suitable dienophile toward a highly enantioselec-
tive pathway.
allows direct access to functionalized tetrahydrocarbazoles22 with
three stereogenic centers with extremely high regio-, diastereo-,
and enantio-control, and can be extended to the synthesis of
polycyclic pyrrole- or furan-based compounds.
’ RESULTS
In our initial experiments, we examined the reactivity of N-Boc
protected 3-(2-methyl-indol-3-yl)acrylaldehyde 1a toward the
[4 + 2] cycloaddition with the electron-deficient trans-β-nitro-
styrene 2a. We chose compound 1, a 2-methylindole bearing an
α,β-unsaturated aldehyde substitution pattern in position 3,
instead of the 2-methylindole 3-carboxaldehyde used by Magnus
as the imine precursor.23 This is because we wished to make the
strategy catalytic. The amine, following the Magnus approach, is
consumed by becoming part of the product as a substituent in the
DielsꢀAlder adduct (from intermediate III, Figure 1b). Con-
versely, in our design plan, the use of the α,β-unsaturated aldehyde
1, after activation by a chiral amine catalyst, would afford a
cycloadduct (from intermediate V, Figure 1c) bearing an ena-
mine substituent. This would subsequently release the amine
through iminium ion hydrolysis, providing the necessary condi-
tion for the catalyst turnover. Pursuing this prospect, we inves-
tigated the effect of different chiral secondary amine catalysts in
the model reaction. Extensive optimization studies are reported
in Tables S1ꢀ5 in the Supporting Information, with selected
results summarized in Table 1. There was no background re-
action when aldehyde 1a and nitrostyrene 2a were combined
without any catalyst, indicating an inherent lack of reactivity
Herein, we document how this design blueprint was translated
to experimental reality, leading to the development of the first
asymmetric catalytic DielsꢀAlder reaction of in situ generated
heterocyclic oQDMs with two distinct classes of olefinic dieno-
philes, nitroolefins and methyleneindolinones. The chemistry
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Table 1. Optimization of the Asymmetric Catalytic DielsꢀAlder
Table 2. Generality of the DielsꢀAlder Reaction with Ni-
troolefin Substratesa
Reaction of in Situ Generated Indole-2,3-quinodimethanea
entry
R
R1
R2
3
yield [%]b
drc
eed [%]
1
Boc
H
Ph
a
b
c
76
84
80
80
0
16:1
11:1
17:1
17:1
93
92
90
92
2
Boc OMe Ph
3
Boc Cl
Ph
Ph
Ph
benzoic acid
4
Me
H
H
H
H
H
H
H
H
H
H
H
d
entry catalyst [mol %] t [h] T [°C] yield [%]b drc 3a ee [%]d
5
1
15
15
15
15
15
15
40
40
40
40
40
40
40
40
40
40
40
60
70
70
80
70
<5
<5
19
6
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
p-MeC6H4
p-ClC6H4
e
f
72
83
54
88
96
55
64
22
>20:1
>20:1
>20:1
10:1
92
92
93
92
92
92
92
92
2
proline
7
3
A
B
A
A
A
A
A
A
4:1
90
8
p-MeOC6H4
p-NO2C6H4
o-BrC6H4
g
h
i
9e
10
11
12
13
4
20
20
20
20
20
20
20
10
<5
33
5
12:1
15:1
15:1
16:1
16:1
15:1
15:1
91
93
94
93
92g
90
92
11:1
6e
7e
8e
9e
10e
44
2-furanyl
j
17:1
69f
76f
75f
76f
65f
3-thiophenyl
k
>20:1
CH2CH2Ph
l
14:1
a General reaction conditions: reactions performed on a 0.1 mmol scale
using 20 mol % amine A, 20 mol % benzoic acid, 1.5 equiv of 1, and [2]0 =
0.5 M in toluene at 70 °C over 40 h. Results represent the average of two
runs per substrate. All the reactions have also been performed using
(R)-A as the catalyst to afford the opposite enantiomer of compounds 3;
see Table S8 in the Supporting Information for details. b Yield of the
isolated compound 3. The yields reflect the degree of conversion.
11e Ah
a Boc: tert-butyloxycarbonyl. General reaction conditions: unless other-
wise specified, reactions were carried out on a 0.1 mmol scale using 1.2
equiv of 2a and [1a]0 = 0.5 M in toluene. b Yield determined by 1H NMR
using 1,3,5-trimethoxybenzene as the internal standard. c Diastereomeric
ratios (dr) were determined by means of 1H NMR analysis of the crude
mixture. d Enantiomeric excess (ee) values were determined after
NaBH4 reduction of compound 3a to the corresponding alcohol and
HPLC analysis on commercially available chiral stationary phases.
e Reactions carried out on a 0.1 mmol scale using 1.5 equiv of 1a and
[2a]0 = 0.5 M in toluene. f Yield of the isolated product 3a. g The (R)
enantiomer of amine A was used, leading to the opposite antipode of
product 3a. h Reaction performed over 64 h using 10 mol % of catalyst A.
1
c Diastereomeric ratios (dr) were determined by H NMR analysis of
the crude mixture. d Enantiomeric excess (ee) values were determined
after NaBH4 reduction of compounds 3 to the corresponding alcohols
and HPLC analysis on commercially available chiral stationary phases.
e The reaction required 16 h for completion.
the high enantioselectivity (entry 5). The use of an excess of
aldehyde 1a (1.5 equiv) further increased the reactivity of the
catalytic system (entry 6).26b Evaluation of the reaction media
confirmed that the catalytic process performed better in toluene.
Other solvents such as chloroform, tetrahydrofuran, ethyl ace-
tate, and acetone significantly diminished the chemical yield (see
Table S2 in the Supporting Information for further details).
Importantly, the reaction temperature increased the catalyst
turnover while minimally affecting the stereoselectivity of the
cycloaddition process (entries 7ꢀ10). The best compromise
between the chemical yield and the stereocontrol was achieved
when performing the DielsꢀAlder reaction at 70 °C, using
20 mol % of both the amine A and benzoic acid in toluene as
the solvent (entry 8). Under the optimized conditions, the
tetrahydrocarbazole 3a was isolated after 40 h in 76% yield, with
excellent diastereoselectivity (dr 16:1) and very high enantio-
selectivity (93% ee). The (R) enantiomer of the catalyst A showed
the same catalytic profile and stereochemical outcome, securing
access to each product enantiomer individually (entry 9).
Lowering the catalyst loading down to 10 mol % resulted in
longer reaction times (65% yield after 64 h), although the stereo-
control in the cycloaddition reaction was preserved (entry 11).
These results further consolidate the unique ability of catalyst A
to modulate the equilibrium between the iminium ion intermediate,
between the chosen reagents (Table 1, entry 1). Among the
catalysts tested (entries 2ꢀ4), only the diphenylprolinol silyl-
ether A (20 mol %, reaction carried out in toluene), indepen-
dently developed by Jørgensen et al.24 and Hayashi et al.25 in
2005, afforded the desired product 3a, albeit in less than 20%
yield after 15 h and with a rather poor diastereomeric ratio (dr).
The level of enantioselectivity (enantiomeric excess, ee = 90% for
the major diastereoisomer), however, prompted us toward further
optimizations. We thus chose catalyst A as the most suitable
candidate for inducing the in situ generation of ortho-quinodi-
methane intermediate of type V while securing high levels of
stereocontrol.
Further optimizations of the standard reaction parameters
revealed that the nature of the acidic additive and the stoichio-
metry of the reagents were the crucial factors for improving the
catalysis.26 When the reaction was carried out in the presence of
benzoic acid as additive (20 mol %, equimolar amount with
respect to the amine A),26a both reactivity and diastereoselec-
tivity were positively influenced, leading to the DielsꢀAlder
product 3a with a 15:1 diastereomeric ratio, while maintaining
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Figure 2. Methyleneindolinones as dienophiles in the DielsꢀAlder reaction: construction of tetrahydrocarbazole spirooxindoles. General reaction
conditions: reactions performed on a 0.1 mmol scale using 20 mol % amine A, 20 mol % benzoic acid, 1.2 equiv of 1, and [4]0 = 0.5 M in DCE at room
temperature (rt). Yields refer to the sum of the isolated diastereoisomers. The yields reflect the degree of reaction conversion. Selected reactions have
been also performed using (R)-A as the catalyst to afford the opposite enantiomer of compounds 5; see Table S9 in the Supporting Information for
details. Compound 5h was prepared at 40 °C in toluene using trimethylacetic acid (TMAA) as the acidic additive. The endo and exo pure isomers were
individually isolated by additional chromatography purification in 32% and 28% yield, respectively. See the Supporting Information for further details.
†Reaction leading to compound 5l was conducted using TMAA as the acidic additive.
which is formed upon condensation with polyunsaturated enals,
and the nucleophilic extended enamines (dienamine27 and tri-
enamine28intermediates). The resulting transmission of electro-
nic effects through a conjugated π-system29 was recently used to
design catalytic asymmetric DielsꢀAlder transformations27,28
exploiting vinylogous nucleophilicity in extended enamines.30,31
Adopting the conditions described in Table 1, entry 8, the ge-
nerality of the method was demonstrated by evaluating a variety
of indole moieties 1 and nitroalkenes 2. As highlighted in Table 2,
there appears to be significant tolerance toward structural and
electronic variations of both precursors to enable access to a
variety of complex tetrahydrocarbazoles (3aꢀl) having three
stereocenters with very high diastereomeric ratio and optical
purity. Different substituents on the indole core of enal 1 are well
tolerated, since electronic modification of the aromatic ring can
be accomplished without affecting the efficiency of the system.
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Substitution at the 5-position efficiently provided diene precur-
sors for the highly stereoselective DielsꢀAlder reaction with nitro-
styrene (entries 1ꢀ3, Table 2). A substituent with a different
electronic nature at the N-position did not alter the reactivity:
N-methylindole-derived aldehyde, in which the electron-with-
drawing Boc group was replaced by an electron-donating alkyl
group, reacted smoothly with nitrostyrene, to afford the product
3d in high optical purity (entry 4). However, the N-unprotect-
ed indole-derived enal remained unchanged under the reaction
conditions (RdH, entry 5). This could be attributed to a
tautomerization process32 in which a more stable species is
generated by proton transfer from the free NH moiety within
the transiently generated ortho-quinodimethane to the vicinal
methylene group, which results in a trans disposition of the electron-
rich conjugated diene, disabling the system for DielsꢀAlder
reactivity (where a cis disposition is required).
Concerning the scope of nitroolefinic derivatives, different
substituents at the aromatic moiety are well-tolerated, regardless
of their electronic properties. The corresponding adducts 3 were
obtained in good to high yield and very high stereocontrol. Both
electron-donating and electron-withdrawing functionalities at the para
position were fully compatible with the method (entries 6 to 9),
while substitution at the ortho position of the phenyl ring afforded
product 3i with high yield (96%) and stereocontrol (dr 11:1; 92%
ee). The generality of the reaction was also verified by using
nitroolefins with heteroaromatic β-substituents, including 2-[(E)-
2-nitrovinyl]furan and 2-[(E)-2-nitrovinyl]thiophene (entries 11 and
12), and even with the less reactive aliphatic olefin (entry 13).
To further explore the potential of our approach to rapidly
build up complex frameworks from simple starting materials, we
investigated the reactivity of in-situ-generated indole-2,3-quino-
dimethanes toward electron-deficient olefins bearing the oxin-
dole moiety. The DielsꢀAlder reaction with methyleneindolinone
derivatives 4 provided direct access to spirocyclic oxindole
scaffolds, which feature in a large number of natural33,34 and un-
natural compounds35ꢀ37 with important biological activities. Ad-
vances have been made recently in the stereocontrolled synthesis of
Figure 3. Extending the scope of the DielsꢀAlder reaction to pyrrole-
and furan-based ortho-quinodimethanes. (a) Reaction performed on a
0.1 mmol scale using trimethylacetic acid (TMAA) as the additive, 1.2
equiv of the aldehyde precursor, and [4]0 = 0.5 M in DCE. (b) Reaction
performed on a 0.1 mmol scale using benzoic acid as the additive, 1.2
equiv of the aldehyde precursor, and [4]0 = 0.5 M in DCE.
Figure 4. Rationalization of the stereochemical outcome of the DielsꢀAlder reaction with nitroolefins and methyleneindolinones. X-ray structures
showing the spatial arrangement of the substituents in the newly formed cyclohexane ring (some parts of the molecule have been removed for clarity).
ORTEP drawing at 50% probability. The complete information on the crystallographic structural determination can be found in the Supporting
Information.45
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spirooxindoles,38 mainly based on catalytic asymmetric cyclo-
addition39ꢀ41 and cascade strategies.42,43 However, it remains
highly relevant and far from easy to efficiently install the chal-
lenging spiro-quaternary stereocenter in a chemo-, regio-, and
stereocontrolled manner. As shown in Figure 2, our DielsꢀAlder
approach provides an easy and reliable entry to highly enan-
tioenriched compounds 5. These are complex molecular scaf-
folds, in which two biologically relevant and privileged molecular
units22,38 (a tetrahydrocarbazole and a spirooxindole) are
merged. The chemistry reported in Figure 2 may thus be useful
for synthesizing nature-inspired compound collections that may
find application in other scientific domains such as medicinal
chemistry and chemical biology research.44
The complete progress toward the optimized conditions for
the DielsꢀAlder reaction of indole derivatives 1 with methyle-
neindolinones 4 is detailed in Tables S6, S7, and S9 in the
Supporting Information. Dichloroethane (DCE) emerged as the
most appropriate solvent for this transformation. As depicted in
Figure 2, the reaction proceeds at room temperature in the pre-
the nitro group and the silyloxy group of the diene.48 In addition,
our results conform to the exo selectivity observed in DielsꢀAlder
reactions of nitroolefins28c with enamines generated from aldehydes
and chiral secondary amines.49,50
’ CONCLUSION
Asymmetric aminocatalysis has allowed us to develop the
hitherto elusive catalytic asymmetric DielsꢀAlder reaction of
in situ generated ortho-quinodimethane intermediates. The in-
dole-2,3-quinodimethane strategy, originally conceived for the
straightforward synthesis of indole alkaloids more than 30 years
ago, can now be made catalytic with the chiral amine A. This
strategy can then be used to synthesize a structurally diverse
range of complex nitrogen and spirooxindole-containing tetra-
hydrocarbazoles with high chemical yield and excellent stereo-
selectivity. Demonstration that this new strategy can be easily
extended to access complex pyrrole- and furan-based hetero-
cyclic compounds while using mild and simple reaction condi-
tions may provide for the rapid application of this chemistry in
synthetic and medicinal arenas.
sence of the catalytic salt A benzoic acid (20 mol %), affording a
3
wide variety of complex tetrahydrocarbazole spirooxindoles 5aꢀp
with almost perfect stereocontrol.
’ ASSOCIATED CONTENT
The general applicability of a chemical strategy is a crucial
parameter for evaluating its usefulness for future endeavors to
synthesize complex chiral molecules. To expand the scope of our
DielsꢀAlder approach, we explored the possibility of using the
chiral amine catalyst A to induce the generation of different
heteroaromatic-based oQDMs from simple starting aldehydes,
while directing the pericyclic reactions with methyleneindoli-
nones 4 toward a highly stereoselective pathway. The results
summarized in Figure 3 illustrate the potential of the chemistry
for the stereoselective preparation of chiral spirocyclic oxindoles
bearing a pyrrole (product 6) or a furan moiety (7).
S
Supporting Information. Complete ref 37, experimental
b
procedures, optimization studies, compound characterization,
HPLC traces, and NMR spectra (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
pmelchiorre@iciq.es
’ ACKNOWLEDGMENT
’ DISCUSSION
This work was supported by the Institute of Chemical
Research of Catalonia (ICIQ) Foundation and by MICINN
(Grant CTQ2010-15513 and Consolider Ingenio 2010, Grant
CSD2006-0003). Y.L. is grateful for a Marie Curie fellowship
(Grant FP7-PEOPLE-2010-IIF no.: 273088). The authors also
thank Eduardo Escudero-Adꢀan for X-ray crystallographic analysis
and Grace Fox for proofreading the manuscript.
Crystals from compounds 8 and 9, directly derived from
cycloadducts 3a and 5d, respectively, were suitable for X-ray
analysis. This established the stereochemical outcome of the
reaction as well as the absolute configuration.45 The high stereo-
control of these transformations can be rationalized as follows
(Figure 4): DielsꢀAlder additions are governed by steric effects
and electronic interactions between the interacting diene and
dienophile π-electronic systems.46 In both systems (reaction
with nitroolefins 2 and with oxindole-derived dienophiles 4), the
chiral catalyst selectively provides face shielding of the generated
ortho-quinodimethane intermediate inducing the π-facial-selec-
tivity and securing high enantiomeric excess, while the regio-
selectivity is dictated by an optimum HOMO(oQDM)-LUMO-
(electron-deficient olefin) orbital overlap.47 The reaction with
nitroolefins proceeds with exo selectivity relative to the nitro
group (alignment of the two reacting components in the transi-
tion state, interpreted by the Alder rules). This is the opposite
selectivity pattern to the endo approach (relative to the oxindole
moiety) observed for the methyleneindolinones dienophiles 4.
A common property of the DielsꢀAlder cycloaddition, whether
thermal or catalyzed, is its endo diastereoselectivity. In contrast,
examples of the DielsꢀAlder reaction displaying exo selectivity
occur less frequently, at least in an intermolecular context. The
uncommon stereochemical outcome of the reaction with nitro-
olefins was first noticed in the cycloaddition with Danishefsky’s
diene and explained by unfavorable electrostatic repulsion between
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Journal of the American Chemical Society
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