Dynamic hemicarcerands and hemicarceplexes.

Article abstract of DOI:10.1021/ol005962p

The reversible nature of the imine bond formation in CDCl(3) solution has been exploited to exchange substituted for unsubstituted m-phenylenediamine (MPD) units in hemicarcerand octaimines. Moreover, acid-catalyzed imine exchange has been shown to provid

Full text of DOI:10.1021/ol005962p

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2411-2414
Dynamic Hemicarcerands and
Hemicarceplexes
Stephen Ro,† Stuart J. Rowan,‡ Anthony R. Pease,† Donald J. Cram,† and
,†
J. Fraser Stoddart*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
405 Hilgard AVenue, Los Angeles, California 90095-1569
stoddart@chem.ucla.edu
Received April 18, 2000
ABSTRACT
The reversible nature of the imine bond formation in CDCl3 solution has been exploited to exchange substituted for unsubstituted
m-phenylenediamine (MPD) units in hemicarcerand octaimines. Moreover, acid-catalyzed imine exchange has been shown to provide a novel
mechanism whereby ferrocene (Fc) can be released as an entrapped guest from the hemicarceplex C B4.Fc dissolved in CDCl3 to give the
2
hemicarcerand C B4 when excess of both MPD and trifluoroacetic acid are present.
2
In 1991, one of us1 reported a new class of container
molecule2 called hemicarcerands. Guests can become im-
prisoned inside these molecular capsules to generate com-
plexes known as hemicarceplexes. Although these complexes
can be isolated under standard laboratory conditions, at
higher temperatures, the “equatorial” portals in the hemi-
carceplexes open up sufficiently to let their imprisoned guests
escape.
which equates with the free energy of complexation and the
other is constrictiVe binding which is commensurate with
the free energy of activation for complex formation:4 it
follows that the sum of these two terms corresponds to the
free energy of activation (∆Gq ) of decomplexation.
d
According to computational studies carried out subse-
quently by Houk,5 the ingression of guests into hemicar-
cerands and their egression out of hemicarceplexes is
controlled by one or other of two slightly different confor-
mational processes, i.e., gating by either a “sliding door” or
“French door” mechanism. More recently, novel gating
One of us1,3 has also identified two free energy terms that
govern the stabilities of hemicarceplexes formed between
hemicarcerands and their guestssone is the intrinsic binding
(4) The concept of constrictiVe binding as it relates to hemicarceplexes
and their hemicarcerands is analogous to the concept of slippage in the
context of pseudorotaxanes and their dumbbell components. See: Ashton,
P. R.; Baxter, I.; Fyfe, M. C. T.; Raymo, F. M.; Spencer, N.; Stoddart, J.
F.; White, A. J. P.; Williams, D. J. J. Am. Chem. Soc. 1998, 120, 2297-
2307.
(5) Houk, K. N.; Nakamura, K.; Sheu, C.; Keating, A. E. Science 1996,
273, 627-629.
(6) Wang, X.; Houk, K. N. Org. Lett. 1999, 1, 591-594.
(7) (a) Conn, M. M.; Rebek, J., Jr. Chem. ReV. 1997, 97, 1647-1668.
(b) de Mendoza, J. Chem. Eur. J. 1998, 4, 1373-1377. (c) Rebek, J., Jr.
Acc. Chem. Res. 1999, 32, 278-286.
† University of California, Los Angeles
‡ Current address: Department of Macromolecular Science, Case Western
Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-7202.
Fax: (216) 368-4202.
(1) (a) Cram, D. J.; Cram, J. M. In Container Molecules and Their Guests;
Stoddart, J. F., Ed.; RSC: Cambridge, 1994; pp 149-216 and references
therein.
(2) Jasat, A.; Sherman, J. C. Chem. ReV. 1999, 99, 931-967 and
references therein.
(3) Cram, D. J.; Blanda, M. T.; Paek, K.; Knobler, C. B. J. Am. Chem.
Soc. 1992, 114, 7765-7773.
10.1021/ol005962p CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/19/2000

mechanisms have also been invoked6 to explain the exchange
of guest molecules in Rebek’s sportsballs,7 e.g., spherical
dimeric supermolecules held together by multiple hydrogen
bonds.8,9
acting as a water scavenger, the MgSO4 is probably also
catalyzing imine bond formation. When we repeated this
reaction in CDCl3 with MgSO4 absent, but in the presence
of a catalytic amount of trifluoroacetic acid (TFA), 1H NMR
spectroscopy indicated a near-quantitative conversion of the
reactants to C2B4 in less than 1 h. The efficiency of this
reaction indicates that, most likely, it is being thermodynami-
cally driven. In support of this hypothesis, we observed that
the product undergoes slow hydrolysis during silica gel
chromatography, leading to 55% yield of the pure C2B4.
Unfortunately, however, the hemicarcerand octaimine, with
phenethyl feet and m-phenylenediimine (B) bridging units,
is not soluble in the millimolar concentration range in CDCl3,
A recent foray we have made into the realm of molecular
capsules was prompted by the notion that yet another
mechanism might operate during the escape of guests from
hemicarceplexes in which two cavitands are held together
by dynamic covalent bonds.10 There are a number of
reversible covalent bond-making and -breaking processes that
lend themselves to doing reactions on molecular compounds
under thermodynamic control. They include olefin meta-
thesis,11 as well as the formation, and sometimes also the
exchange, of acetals,12 borazaaromatic anhydrides,13 disul-
fides,14 esters,15 hydrazones,16 imines,17 and oximes.18 In this
Letter, we describe how imine exchange (1) can be used to
replace 5-substituted-m-phenylenediamine (5-substituted-
MPD) units by unsubstituted ones (MPD) in hemicarcerand
octaimines and (2) provides a “bar-opening/bar-closing”
mechanism whereby ferrocene (Fc), entrapped in a hemi-
carceplex octaimine, can escape imprisonment from behind
the diimine bars.
1
making detailed H NMR spectroscopic analyses difficult.
We decided that it would be more straightforward to address
this problem, not by chemically modifying the feet of the
cavitands but rather by introducing 5-substituted-MPD (A)
bridging units. One of the attractions of using this approach
to increase the solubility of the hemicarcerand is that a
1
suitable H NMR probe can be introduced (Figure 2) into
Previously, one19 of us has described how the hemicar-
cerand octaimine C2B4 can be made in 45% yield by
condensing 2 equiv of the appropriate cavitand tetraaldehyde
with 4 equiv of m-phenylenediamine (MPD) (Figure 1) in
Figure 2. The 5-substituted-MPD employed in the synthesis of
the hemicarcerand C2A4 portrayed as a graphical representation.
the 5-substituent on B to give A. The 5-substituted-MPD
(A), which was prepared21 in two steps in 70% overall yield
from 3,5-dinitrobenzoic acid, was condensed in CHCl3 with
the same cavitand tetraaldehyde as that used in the synthesis
(9) For molecular capsules formed by metal-ion coordination, see: (a)
Fujita, M.; Oguro, D.; Miyazawa, M.; Oka, H.; Yamaguchi, K.; Ogura, K.
Nature 1995, 378, 469-471. (b) Jacopozzi, P.; Dalcanale, E. Angew Chem.
Int, Ed. Engl. 1997, 36, 613-615. (c) Olenyuk, B.; Fechtenko¨tter, A.; Stang,
P. J. J. Chem. Soc., Dalton. Trans. 1998, 1707-1728.
(10) Lehn, J.-M. Chem. Eur. J. 1999, 5, 2455-2463.
Figure 1. The preparation of hemicarcerand C2B4 by eight
successive imine condensations between two molecules of the
cavitand tetraaldehyde with four molecules of MPD.
(11) (a) Marsella, M. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1101-1103. (b) Kidd, T. J.; Leigh, D. A.; Wilson,
A. J. J. Am. Chem. Soc. 1999, 121, 1599-1600.
C5H5N at ∼65 °C for 4 days. On the other hand, Kaifer et
al.20 have isolated C2B4 in 39% yield by carrying out the
same reaction in CH2Cl2 with added MgSO4 at room
temperature for 6 days. It occurred to us that, in addition to
(12) Davies, A. P. Angew. Chem., Int. Ed. Engl. 1997, 36, 591-594.
(13) Comina, P. J.; Philp, D.; Kariuki, B. M.; Harris, K. D. M. Chem.
Commun. 1999, 2279-2280.
(14) Tam-Chang, S.-W.; Stehouwer, J. S.; Hao, J. J. Org. Chem. 1999,
64, 334-335.
(8) For additional recent examples of hydrogen-bonded supramolecular
capsules, see: (a) Ko¨rner, S. K.; Tucci, F. C.; Rudkevich, M.; Heinz, T.;
Rebek, J., Jr. Chem. Eur. J. 2000, 6, 187-195. (b) Grawe, T.; Schrader,
T.; Gurrath, M.; Kraft, A.; Osterod, F. Org. Lett. 2000, 2, 29-32. (c)
Kobayashi, K.; Shirasaka, T.; Yamaguchi, K.; Sakamoto, S.; Horn, E.;
Furukawa, N. Chem. Commun. 2000, 41-42. (d) Prins, L. J.; Huskens, J.;
de Jong, F.; Timmermann, P.; Reinhoudt, D. N. Nature 1999, 398, 498-
502. (e) Shivanyuk, A.; Paulus, E. F.; Bo¨hmer, V. Angew. Chem., Int. Ed.
1999, 38, 2906-2909. (f) Chapman, R. G.; Sherman, J. C. J. Am. Chem.
Soc. 1998, 120, 9818-9826. (g) MacGillivray, L. R.; Atwood, J. L. Nature
1997, 389, 469-472.
(15) (a) Rowan, S. J.; Sanders, J. K. M. Chem. Commun. 1997, 1407-
1408. (b) Brady, P. A.; Sanders, J. K. M. J. Chem. Soc., Perkin Trans. 1
1997, 3237-3253. (c) Rowan, S. J.; Reynolds, D. J.; Sanders, J. K. M. J.
Org. Chem. 1999, 64, 5804-5814.
(16) Cousins, G. R. L.; Poulsen, S.-A.; Sanders, J. K. M. Chem. Commun.
1999, 1575-1576.
(17) (a) Cantrill, S. J.; Rowan, S. J.; Stoddart, J. F. Org. Lett. 1999, 1,
1363-1366. (b) Rowan, S. J.; Stoddart, J. F. Org. Lett. 1999, 1, 1913-
1916.
(18) Polyakov, V. A.; Nelen, M. I.; Nazarpack-Kandlousy, N.; Ryabov,
A. D.; Eliseev, A. V. J. Phys. Org. Chem. 1999, 12, 357-363.
2412
Org. Lett., Vol. 2, No. 16, 2000

of C2B4 in the presence of a catalytic amount of TFA to
afford C2A4 as a pale yellow solid in 45% yield after silica
gel chromatography.
Following addition of 4 equiv of MPD22 to 1 equiv of
C2A4 in CDCl3,23 1H NMR spectroscopy indicates (Figure
3) that imine exchange takes place with time in such a
fact that they arise from the multicomponent mixture of
hemicarcerands shown in Figure 4. Indeed, a FAB mass
Figure 4. Equilibrium established between the different hemicar-
cerands in the series C2A4-nBn, where n ) 0, 1, 2, 3, or 4.
spectrum recorded on the equilibrated reaction mixture
revealed peaks with m/z values of 2418, 2565, 2711, and
2859 for the hemicarcerands C2B4, C2AB3, C2A2B2 (two
regioisomers presumably), and C2A3B with the relative
intensities of 48, 79, 100, and 64, respectively.
To account for these experimental observations, we
propose a mechanism that involves the stepwise opening of
diimine bridging units as a result of imine exchange with
the free diamines present in solution. The first step from C2A4
to C2A3B in this proposed mechanism is shown in Figure 5.
1
Figure 3. Partial H NMR spectra (400 MHz, CDCl3, 300 K)
recorded with time. The exchange of A for B reaches an equilibrium
after 582 h in which some or all of the species shown in Figure 5
are present. The boxed descriptors refer to signals arising from
methoxy and imine protons in the bridging units A and B in the
hemicarcerands C2A4-nBn.
manner that A bridging units in C2A4 are replaced by B
bridging units.24 Initially, peaks for C2A4 are observed at δ
3.36 and 8.53 for the methoxy and imine protons, respec-
tively. After some hours, additional peaks appear centered
on δ 3.39 (well-resolved) and 8.49 (broad) for methoxy (in
free released 5-substituted-MPD) and imine (in hemicar-
cerands containing B bridging units) protons, respectively.
It should be noted that the peaks at δ 3.36 and 8.53 also
become progressively broadened with time, reflecting the
Figure 5. The first step in the proposed imine exchange mechanism
that allows C2A4 to be converted into C2A3B, C2A2B2 (two
regioisomers), C2AB3, and C2B4.
(19) Quan, M. L.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 2754-
2755.
(20) Mendoza, S.; Davidov, P. D.; Kaifer, A. E. Chem. Eur. J. 1998, 4,
864-870.
(21) A solution of 3,5-dinitrobenzoic acid in PhMe was heated under
reflux with diethylene glycol methyl ether in the presence of a catalytic
amount of p-TsOH. The ester was isolated in 85% yield. Subsequent
reduction (H2 over Pd/C in EtOH) of the nitro groups in the ester gave
(82%) the 5-substituted-MPD.
To obtain evidence for such a “bar-opening/bar-closing”
mechanism, we decided to explore if it is operational during
the decomplexation of a hemicarceplex to give a hemicar-
cerand and its previously imprisoned guest. To carry out this
experiment, we selected the known19 hemicarceplex C2B4.Fc
because (1) its decomplexation using a gating mechanism
has been studied previously,19 (2) its pentyl feet enhance its
solubility in CDCl3, and (3) the ferrocene (Fc) proton
resonances, when both complexed and uncomplexed, appear
(22) The final concentration of C2A4 in CDCl3 was always maintained
at 3 mM. All samples were sealed and monitored for their proton signals
on a 400 MHz NMR spectrometer at 300 K.
1
1
as sharp singlets in H NMR spectra at δ 3.66 and 4.16,
(23) The CDCl3 employed in all the H NMR experiments was stored
over K2CO3 for 24 h prior to its use.
respectively. Moreover, the Fc resonance peaks do not
overlap with any signals arising from the hemicarcerand or
hemicarceplex. Previously, one of us reported19 that the half-
(24) No indication of diimine exchange was detected by 1H NMR
spectroscopy when simple anilines, such as p-toluidine and 3,5-di-tert-
butylaniline, were added to CDCl3 solutions of C2A4.
Org. Lett., Vol. 2, No. 16, 2000
2413

life for the escape of Fc from C2B4.Fc is 19.6 h at 112 °C
in C2D2Cl4 while Kaifer et al.20 report a t1/2 of >300 h in
CD2Cl2 at 25 °C.
more and more, and yet more, remote in relation to the other
three bars. It follows that the hemicarceplex can be converted
into the hemicarcerand without any serious risk of the two
cavitands parting company.
In the present investigation, we have observed (Table 1)
In the case of a single bar-opening mechanism, at least
three different processes can be identified. One involves the
simple hydrolysis of one of the imine bonds in C2B4.Fc
with hydronium ions to produce a formyl derivative which
can either revert back to the hemicarceplex or release the
guest Fc to give the hemicarcerand. In this case, the half-
life of C2B4.Fc will depend on the concentration of the
hydronium ion, i.e., the amount of adventitious water which
is inevitably present in the reaction mixture. When MPD is
also present, the formyl derivative will be converted into an
intermediate, similar to that illustrated in Figure 5. Yet
another process would involve direct imine exchange be-
tween C2B4.Fc and MPD to give the bis(m-aminoanilidene)
intermediate. If this direct process is slower than the
hydrolysis-followed-by-imine-exchange process, then the
small decrease in the half-life of C2B4.Fc with an increasing
concentration of MPD or TFA is not unexpected.
In summary, reversible imine exchange and/or reversible
imine hydrolysis make it possible for the diimine bridges
(B) in the hemicarceplex C2B4.Fc to open and close
essentially one at a time, allowing the guest (Fc) to escape
and hence produce the hemicarcerand C2B4. Reversible imine
exchange also provides a means whereby unsubstituted and
substituted m-phenylenediamine (A and B) bridging units
can replace each other essentially one at a time in the
hemicarcerands C2A4 and C2B4. These observations dem-
onstrate the power of dynamic chemistrysi.e., the stepwise
breaking and remaking of dynamic covalent bondss(1) to
convert a hemicarceplex into a hemicarcerand and (2) to
modify the constitution of a hemicarcerand without either
the hemicarceplex or hemicarcerand falling apart into its
component cavitands in the process.
Table 1. A Comparison of the Effects of Different Amounts of
MPD and TFA (1%, v/v, in CDCl3) on the Half-Life (t1/2) of
Escape of Fc from C2B4.Fc at Room Temperature in CDCl3
entry equiv of C2B4.F c equiv of MPD TFA (µL) t1/2 (h)
1
2
3
4
5
6
1
1
1
1
1
1
0
0
0
4
8
4
0
4
8
4
4
8
>4000
1500
1400
380
330
180
a half-life of >4000 h (entry 1) for the decomplexation of
C2B4.Fc in CDCl3 at room temperature in a sealed NMR
tube. When 4 µL (entry 2) and 8 µL (entry 3) of 1% TFA
(v/v) in CDCl3 were added to the C2B4.Fc solution, the half-
life for the decomplexation dropped to 1500 and 1400 h,
respectively. These t1/2 values emerge from a treatment of
the reaction which assumes a mechanism whereby a single
bar is opened as a result of the hydrolysis of one of the eight
imine bonds present in the hemicarceplex. A full kinetic
treatment of the data using Dynafit25 suggest that the
hydrolysis step is rate-limiting. When 4 equiv of MPD and
4 µL of TFA are present in the reaction mixture, a synergistic
effect comes into play and t1/2 falls down (entry 4) to 380 h.
When the amount of MPD is doubled to 8 equiv, then a
further small decrease in the half-life (t1/2 ) 330 h) is
observed (entry 5). Finally, when the amount of acid is
doubled to 8 µL, the half-life of C2B4.Fc drops (entry 6) to
180 h. Once again, a full kinetic treatment of these data
established that the “bar-opening” step, as illustrated in the
graphical abstract, is rate-determining. It follows that the
release of Fc from C2B4.Fc occurs fastest in the presence
of an excess of MPD and an acid catalyst.
Acknowledgment. We are grateful to the NIH and UCLA
for generous financial support.
Supporting Information Available: Experimental pro-
1
cedures, H and 13C NMR spectroscopic and FAB mass
spectrometric data for 5-substituted-MPD and hemicarcerand
C2A4, and kinetic curves fitted for liberation of ferrocene
from hemicarceplex C2B4. This material is available free of
charge via the Internet at http://pubs.acs.org.
If we consider C2B4.Fc to be a four-bar gate, then the
likelihood of more than one bar on the gate being dislodged
at any one time ready for its possible replacement becomes
(25) Kuzmic, P. Anal. Biochem. 1996, 237, 260-273.
OL005962P
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Org. Lett., Vol. 2, No. 16, 2000