Guest inding drives reversible atropisomerism in cavitand hosts

Article abstract of DOI:10.1002/chem.200900695

A novel class of cavitand bowl structures carrying rim substituents were developed that can reversibly switch from inwardly- to outwardly-directed orientations. It was found that a preference for either form can be established through purely physical mean

Full text of DOI:10.1002/chem.200900695

DOI: 10.1002/chem.200900695
Guest Binding Drives Reversible Atropisomerism in Cavitand Hosts
Thanh V. Nguyen, David J. Sinclair, Anthony C. Willis, and Michael S. Sherburn*[a]
Cramꢀs cavitand bowls are rigid host compounds derived
from resorcinarenes.[1] These hosts have enjoyed widespread
application in supramolecular chemistry,[2] particularly as
building blocks for double cavitand molecules such as hemi-
carcerands[3] and more recently, for larger covalent struc-
tures.[4] Single cavitand bowls generally bind guests weakly
on their shallow, concave, p-basic surface. Indeed, solution-
phase binding between simple cavitand bowls and (solvent)
guests has only been detected by taking advantage of the
hydrophobic effect, that is, employing water-soluble cavi-
tands in aqueous environments.[5] Landmark contributions
from Dalcanale[6] demonstrated that placement of a fixed,
inwardly-directed phosphonate binding substituent on a cav-
itand bowl leads to a sensor host capable of much stronger
and more selective, two-point guest binding. In elegant stud-
ies, Rebek has introduced deep cavity cavitands carrying
fixed “introverted functionality”,[7] which exhibit unprece-
dented behavior by virtue of the shielding afforded to a
bound guest from the bulk phase. Herein, we introduce a
new class of cavitand bowl structures carrying rim substitu-
ents that can reversibly switch from inwardly- to outwardly-
directed orientations. We show that a preference for either
form can be established through purely physical means, and
we demonstrate that this system provides—for the first
time—a means of measuring relative solvent guest binding
affinities without recourse to the hydrophobic effect.
ditions, isolated yields for the 2,2’,6-trisubstituted biaryl
products 4 and 5 are in the 60–85% range.[9] Reactions lead-
ing to the ortho-bromophenyl (4c/5c) and 1-naphthyl substi-
tuted cavitands (4b/5b) took considerably longer than the
others. Intriguingly, all but two of these reactions furnish
mixtures rich (83–99%) in the inside atropisomer 4. We at-
tribute the kinetic preference for the inside stereoisomer in
the cross-coupling reaction to steric hindrance at play in the
biaryl bond-forming step (Table 1). Thus, in the three-cen-
tered transition state of the reductive elimination step, the
[PdACHTNURTGNEUGN(Pfu3)2] group will occupy the less sterically hindered
outside position and the R substituent will avoid the phos-
phine ligands, thereby adopting an orientation that leads to
inside isomer 4. A similar mechanism has been put forward
to explain p-facial selectivities in Suzuki coupling reactions
involving (arene)chromium complexes.[10] Irrespective of the
mechanism, the kinetic inside stereoselectivity appears to be
a general feature of these reactions: in the two systems fur-
nishing mixtures rich in the outside cavitand isomer 5
(Table 1, entries d and g), the inside isomer 4 is atropisomer-
ically unstable under the reaction conditions.
The inside and outside atropisomers were readily separat-
ed by chromatography and the stereochemistry of each was
assigned through 1H NMR chemical shifts, NOE experi-
ments, X-ray crystallographic analysis (of 5 f[11]), and the re-
sults of interconversion experiments (see below). Informa-
1
Mono-aryl cavitands 4 and 5 are readily prepared by
Suzuki–Miyaura coupling of cavitand mono-boronate ester
2[8] with ortho-iodoarenes 3 (Table 1). Under optimized con-
tive regions of H NMR spectra of selected compounds are
reproduced in Figure 1. All protons associated with the sub-
stituents of inside atropisomers of the methyl (4d), ethyl
(4e), and n-propyl (4 f) esters display upfield chemical
shifts, by virtue of their close proximity to the shielding
zone of the aromatic cavity. The upfield shift is greatest with
the ethyl (4e) and n-propyl (4 f) esters, the terminal methyl
protons of which resonate at d ꢀ2.05 and ꢀ2.71 ppm, re-
spectively, some 3–3.5 ppm upfield of the usual chemical
shift for such protons. Surprisingly, the inside isomer of the
corresponding n-butyl ester (4g) shows only small upfield
chemical shifts. Presumably, whereas the ethyl and n-propyl
groups are close to the ideal size to reach to the bottom of
the cavity, the n-butyl group is prohibitively large for a snug
fit. The inside isomer of the isobutyl ester (4h) can be
[a] T. V. Nguyen,+ Dr. D. J. Sinclair, Dr. A. C. Willis,++
Prof. M. S. Sherburn+
Research School of Chemistry, Australian National University
Canberra, ACT 0200 (Australia)
Fax : (+61)2-6125-8114
E-mail: sherburn@rsc.anu.edu.au
[+] ARC Centre of Excellence for Free Radical Chemistry and Biotech-
nology (Australia)
[
++] Correspondence author for crystallographic data
(willis@rsc.anu.edu.au)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900695.
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Chem. Eur. J. 2009, 15, 5892 – 5895

COMMUNICATION
Table 1. Synthesis of mono-aryl cavitands.[a]
Figure 1. Pertinent sections of 1H NMR spectra of inside and outside
esters, 4d–h and 5d–g, respectively (300 MHz, CDCl3, 258C).
the ortho-CO2Me-phenyl-substituted cavitand 4d/5d is con-
verted into an equilibrium mixture at ambient temperature
overnight, whereas the two atropisomers of the ortho-bro-
mophenyl-cavitand (4c/5c) are kinetically stable at 1008C
for several days. A substituentꢀs influence upon the relative
atropisomeric stability of an arylated cavitand (order of sta-
bility: ortho-Br phenyl > 1-naphthyl > ortho-Me phenyl @
ortho-CO2R phenyl) is broadly consistent with substituent
effects observed during racemization studies with chiral bi-
phenyls.[13] Nevertheless, within the ester substituent family,
a curious atropisomeric stability order CO2Et > CO2nPr @
CO2Me > CO2nBu is witnessed.
Entry
R
Total isolated yield [%]
Kinetic ratio
inside/outside (4/5)[b]
a
b
c
d
e
f
Me
70
70
85
75
60
70
70
65
86:14
97:3
98:2
1-naphthyl[c]
Br
CO2Me
CO2Et
CO2nPr
CO2nBu
CO2iBu
25:75[d]
83:17
83:17
5:95[d]
99:1
g
h
Further unexpected and unprecedented properties begin
to emerge during more detailed investigations into the ther-
modynamic equilibration of these compounds (Table 2). In
general, the thermodynamically more stable isomer in tolu-
ene is the outside form. The exceptions are the CO2Et and
CO2nPr compounds (Table 2, entries e and f), which favor
the inside isomer. Interestingly, the equilibrium ratios of
atropisomers are temperature dependent: the majority of
derivatives examined (Table 2, entries c–g) display an en-
hanced preference for the inside isomer as the temperature
is increased.[14] At even higher temperature, something re-
markable happens with the methyl ester atropisomers 4d/
5d: the inside isomer becomes dominant (inside 4d/outside
5d thermodynamic ratio at 2008C in [D8]toluene 54:46).[15]
Thus, it is possible to prepare a mixture rich in either atrop-
isomer by simply holding a solution of the mixture at a par-
ticular temperature.
[a] a) nBuLi (1.1 equiv), THF, ꢀ788C; then B
! 258C; then pinacol (1.1 equiv), MgSO4 (4.1 equiv), CH2Cl2, 258C,
18 h. b) Iodoarene (3.0 equiv), Ag2CO3 (2.0 equiv), [Pd2A(dba)3]
(0.12 equiv), P(2-furyl)3 (0.50 equiv), THF, 258C, 18–72 h. [b] Average of
two NMR runs, difference between runs = ꢁ1%. [c] The cavitand sub-
stituent is a 1-naphthyl group in this case. [d] Not kinetic ratios: in these
cases, interconversion between inside and outside forms occurs under the
reaction conditions.
G
3
ACHTUNGTRENNUNG
viewed as a hybrid of the ethyl and n-propyl esters. This de-
rivative is undergoing rapid interconversion between “ethyl”
down and “propyl” down conformations at room tempera-
ture.[12] Interestingly, a higher upfield shift is evident for the
“ethyl” CH3 than the “propyl” CH3, a result we interpret as
a win for the ethyl over the propyl group as the more readi-
ly accommodated substituent.
Atropisomeric stability varies considerably throughout
the series of compounds prepared (Table 2). Thus, in
[D8]toluene solution, a pure sample of either atropisomer of
These results are best explained by the equilibrium de-
picted in Table 3, which takes into account the influence of
solvation upon the relative stabilities of the inside and out-
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M. S. Sherburn et al.
Table 2. Temperature and substituent effects on atropisomer ratio.
At first glance, the atropisomeric stability order CO2Et >
CO2nPr @ CO2nBu > CO2Me (Table 2, t1/2) appears curi-
ous. If steric effects alone were determining the barrier to-
wards rotation about the biaryl bond, one would expect that
as the size of the ester substituent is increased, atropisomer-
ic stability would increase. We suggest an additional (Goldi-
locks) factor at play here, which relates to how well the
ester substituent fits into the cavity: the methyl ester is too
small for the cavity and the n-butyl is too large, whereas the
ethyl and n-propyl esters are within the correct size range
(but the ethyl fits best of all). Evidently, the self-fulfilling[7c]
nature of the inside ethyl and n-propyl groups causes a
ground-state stabilization which increases the barrier to-
wards biaryl bond rotation. The methyl and n-butyl groups
have a lower interconversion barrier since the inside isomers
lack such a high degree of stabilization.
Entry
R
t1/2 at 658C[a] Equil. ratio Equil. ratio Isomer
in/out (4/5) in/out (4/5) favored at
at 658C[b]
at 1008C[b] higher T
a
b
c
d
e
f
Me
28 h
13:87ꢁ3
28:72ꢁ1
6:94ꢁ2
outside
outside
1-naphthyl[c] 400 h
17:83ꢁ2
[d]
Br
–
20:80[e] ꢁ2 29:71[f] ꢁ1 inside
CO2Me
CO2Et
CO2nPr
CO2nBu
5 min
50 min
40 min
10 min
30:70ꢁ2
83:17ꢁ2
75:25ꢁ1
16:84ꢁ2
43:57ꢁ2
86:14ꢁ1
77:23ꢁ2
23:77ꢁ2
inside
inside
inside
inside
The complementary fit of the ethyl and n-propyl substitu-
ents in the cavitand bowl not only affects the barrier to-
wards atropisomerism, it is sufficiently strong to override
the usual thermodynamic preference for the outside form in
toluene (Table 2, in/out equilibrium ratios).
g
[a] Outside atropisomer. [b] in/out ratios are the average of 4–8 runs and
standard deviations are quoted. [c] The cavitand substituent is a 1-naph-
thyl group in this case. [d] No measurable change after 1000 h at 658C.
[e] Equil. ratio at 1208C. [f] Equil. ratio at 1408C.
This unique system[16] offers a very convenient method for
the measurement of relative solvent–guest binding strengths
(Table 3). Evidently, this remarkable solvent influence upon
inside/outside atropisomer ratio is the result of competition
between the ortho-CO2Et substituent and the solvent for the
cavitand bowl cavity. In the absence of solvent or in poorly
binding solvents, the equilibrium is dominated by inside
isomer 4e. In contrast, a solvent that binds in the bowl well
(i.e., ethyl acetate) is signaled by an equilibrium dominated
by the outside isomer 5e. The equilibrium ratio in a particu-
lar solvent is, therefore, a direct measure of relative solvent–
guest binding affinity for cavitands. A simple explanation of
different atropisomer ratios resulting from solvent polarity
effects can be ruled out, since there is no correlation be-
tween atropisomer ratios and solvent dipoles or dielectric
constants.[17] In contrast, the relative solvent-binding affini-
ties recorded here through switchable in/out cavitand 4e/5e
display an excellent correlation with association constants
reported by Sherman, in studies employing an ammonium
phosphate-derivatized cavitand.[5,18] The ability of this new
method to measure relative[19] guest binding strengths of or-
ganic solvents in an operationally straightforward manner,
that is, by simply measuring atropisomer ratios, and without
recourse to the hydrophobic effect, clearly demonstrates its
unprecedented simplicity and sensitivity.
side atropisomers. The cavity of the inside isomer 4 is occu-
pied by the ortho-substituent of the aryl group, which pre-
cludes guest (i.e., solvent) binding. In contrast, the outside
isomer 5 is free to serve as a host for a complementary
guest molecule. The increased preference for the inside
isomer 4 at higher temperatures (Table 2) now becomes evi-
dent: outside ! inside switching leads to the expulsion of a
guest molecule, an entropically driven process.
Table 3. Relative guest binding affinities measured through atropisomer
ratios.
Solvent
Equil. ratio in/out (4e/5e) at 508C[a]
no solvent[b]
Me2NCHO
CCl4
PhMe
Me2CO
PhH
CHCl3
Me2SO
EtOAc
99:1
98:2
85:15
81:19
80:20
76:24
73:27
69:31
41:59
Experimental Section
Typical procedure: Under nitrogen, an oven-dried round-bottom flask
was charged with C-pentyltribromocavitandboronate pinacolyl ester 2
(100 mg, 84 mmol), 2-iodotoluene (55.4 mg, 254 mmol, 3.0 mol equiv),
silver carbonate (46 mg, 170 mmol, 2.0 mol equiv), tris(dibenzylideneace-
tone)dipalladium(0) (10 mg, 10 mmol, 0.12 mol equiv), and tri-2-furyl-
phosphine (10 mg, 42 mmol, 0.5 mol equiv). The flask was evacuated and
refilled with nitrogen three times then dry tetrahydrofuran (5 mL) was
added. The reaction mixture was stirred at 258C in the dark for 18 h then
[a] Average of three NMR runs, difference between runs
[b] The solid 4e/5e mixture was heated to 508C, then immediately dis-
solved in CDCl3 at 258C and a 1H NMR spectrum was recorded.
=
ꢁ1%.
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Reversible Atropisomerism in Cavitand Hosts
COMMUNICATION
filtered through a short plug of celite and the solvent was evaporated to
afford the crude product. 1H NMR analysis of the crude product indicat-
ed an 86:14 mixture of inside/outside isomers. The crude product was pu-
rified by flash chromatography (100 g silica, 6:4 dichloromethane/hexane
then 50 g silica, 1:9 ethyl acetate/hexane) to give inside isomer 4a (58 mg,
60%) and outside isomer 5a (9 mg, 10%).[17]
[9] The procedure described herein was, in our hands, superior to re-
ported Suzuki-coupling protocols for aryl cavitand formation: a) C.
von dem Bussche-Hꢂnnefeld, R. C. Helgeson, D. Bꢂhring, C. B.
Knobler, D. J. Cram, Croat. Chem. Acta 1996, 68, 447–458; b) S.
Ma, D. M. Rudkevich, J. Rebek, Jr., J. Am. Chem. Soc. 1998, 120,
4977–4981; c) L. Sebo, F. Diederich, V. Gramlich, Helv. Chim. Acta
2000, 83, 93–113; d) K. Kobayashi, K. Ishii, S. Sakamoto, T. Shirasa-
ka, K. Yamaguchi, J. Am. Chem. Soc. 2003, 125, 10615–10624; e) K.
Kobayashi, Y. Yamada, M. Yamanaka, Y. Sei, K. Yamaguchi, J. Am.
Chem. Soc. 2004, 126, 13896–13897; f) T. Haino, M. Kobayashi, M.
Chikaraishi, Y. Fukazawa, Chem. Commun. 2005, 2321–2323;
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h) H. Jude, D. J. Sinclair, N. Das, M. S. Sherburn, P. J. Stang, J. Org.
Chem. 2006, 71, 4155–4163; i) M. Yamanaka, K. Ishii, Y. Yamada,
K. Kobayashi, J. Org. Chem. 2006, 71, 8800–8806; j) O. Hass, A.
Schierholt, M. Jordan, A. Lꢂtzen, Synthesis 2006, 519–527; k) C.
Ihm, K. Paek, Tetrahedron Lett. 2007, 48, 3263–3266.
Acknowledgements
Funding from the Australian Research Council (ARC) is gratefully ac-
knowledged. We thank Dr. Michael Carland and Ms. Jessica Rowley for
conducting preliminary experiments.
Keywords: atropisomerism · cavitands · host–guest systems ·
molecular recognition
[10] K. Kamikawa, M. Uemura, Synlett 2000, 938–949.
[11] See the Supporting Information for details. CCDC 700914 contains
the supplementary crystallographic data for compound 5 f. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] The triplet at d=ꢀ0.5 ppm and doublet at d=ꢀ1.1 ppm are the
result of an averaging of the up and down conformations of the
“ethyl” CH3 and the “propyl” CH3 groups. The rate of interconver-
sion between these two forms is too rapid, even at ꢀ908C, to ob-
serve discrete conformations. See the Supporting Information for
details.
[13] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, New York, 1994, p. 1144.
[14] The exceptions to this trend are the o-tolyl (4a/5a) and 1-naphthyl
(4b/5b) substituted cavitands. An explanation of the behavior of
these two compounds eludes us but we note the similarity of the
cavitand aryl substituents to the solvent used in the study.
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[15] See the Supporting Information for van’t Hoff analysis.
[16] For elegant studies with Trçgerꢀs base systems capable of measuring
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[17] See the Supporting Information for details.
[18] We observe the same relative binding strengths: PhMe < PhH <
CHCl3 < EtOAc. Sherman obtained a much lower binding affinity
for acetone, a result that we ascribe to competitive H-bonding by
water in his system. Since such competitive H-bonding is absent in
the present system, we believe that this new data provides a better
value for the binding affinity of acetone.
[19] This in/out cavitand system offers an operationally simple method
for relative guest affinities. We are investigating the use of related
systems to provide equilibrium constants for host–guest binding
events.
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[8] Prepared using selective mono-lithiation chemistry: a) J. L. Irwin,
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Received: March 18, 2009
Published online: May 12, 2009
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