Reaction of carboxylic acids and isonitriles in small spaces

Article abstract of DOI:10.1021/ja802288k

Reversible encapsulation complexes are applied to the reaction of isonitriles with carboxylic acids. Encapsulation facilitates these reactions by amplifying the concentration of reactants, arranging the acid and isonitrile in the appropriate orientations,

Full text of DOI:10.1021/ja802288k

Published on Web 05/29/2008
Reaction of Carboxylic Acids and Isonitriles in Small Spaces
Jun-Li Hou, Dariush Ajami, and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
Received March 28, 2008; E-mail: jrebek@scripps.edu
Scheme 1
Reversible encapsulation is an ultimate form of molecular
recognition in which a self-assembled host completely surrounds
the guest. The process temporarily isolates the guest from bulk
solution and can provide a safe haven for otherwise labile species.1
When two different guests are coencapsulated, reactions between
them can be accelerated2 and even catalyzed.3 The shape of the
inner space can channel the reaction along one stream rather than
another.4 Here, we apply encapsulation to the reaction of isonitriles
with carboxylic acids and give evidence for the detection of an
elusive intermediate along the pathway.
The reaction of carboxylates with nitrilium ions glows at the
core of the Passerini5 and Ugi6 reactions, much-admired in
combinatorial chemistry. In contrast, the prototypical combination
of acid with isonitrile is a relatively obscure reaction and practically
unknown under ambient conditions.7 Danishefsky8 has recently
applied the reaction in nonprotic solvents (CHCl3) with microwave
heating at 150 °C for 30 min. These conditions lead to formylated
secondary amides in admirable yields (Scheme 1).
The pathway undoubtedly involves the intermediate O-acyl
isoamide (the acyclic version of an azlactone) followed by the
Mumm rearrangement9 of the acyl from O to N. To our knowledge,
no observations of this intermediate from isonitriles and acids are
consistent with spectroscopic data,7b but the analogous intermediate
from substituted nitrilium ions and carboxylates is known9 and can
be intercepted with external nucleophiles such as amines to give
amides or react with another molecule of carboxylic acid to give a
symmetric anhydride. The overall reaction of Scheme 1 is known
to be reversible at high temperatures.9d
How does the capsule 1.1 facilitate this reaction? First, the
capsule amplifies the concentration of reactants since each com-
ponent exists at a 4 M concentration inside the capsule. Second,
the capsule arranges the acid and isonitrile in the appropriate
orientation. The long butyl group of the isonitrile pushes the reactive
centers toward the middle of the capsule where the seam of
hydrogen bond donor and acceptor can stabilize polar transition
states.9 The acyl rearrangement involves a four-membered ring
which creates a great deal of strain, but the n-butyl group is
apparently flexible enough to accommodate the necessary motions
inside.
We next studied the reaction with a bulkier group on the
isonitrile. Treatment of acid 2 with isopropyl isonitrile 7 at 4.0 M
concentration in mesitylene-d12 at 40 °C results in a 40% yield of
formamide 10 after 2 days. Only 1% of the rearrangement product
9 was observed. In the presence of the capsule 1.1, at millimolar
concentrations, immediate formation of a coencapsulation complex
takes place, as shown by the NMR spectra (Figure 3a).
The initial complex is gradually replaced by another one—a
complex that builds up then disappears (Figure 3b-d). It has the
spectroscopic earmarks expected for the elusive intermediate 8; the
signal for the isopropyl group is the furthest upfield shifted,
indicating it is the longest occupant of the capsule. Its rearrangement
appears to be thwarted within the capsule since none of the
formylated secondary amide 9 is produced. Instead, the intermediate
is released to the bulk solution where it reacts with the carboxylic
acid 2 to give 10 and the symmetrical anhydride 6. Together, 10
We studied this reaction in the cylindrical host 1.110 (Figure 1)
by NMR methods. This structure self-assembles only in the presence
of a suitable guest or combinations of different guests11 that properly
fill the space. The aromatic environment in 1.1 causes characteristic
upfield shifts in the NMR spectra, and hydrogens near the ends of
the capsule appear at 0 to -4 ppm.
The combination of p-tolylacetic acid 2 and n-butyl isonitrile 3
provides a single12 encapsulation complex with 1 in which the
isonitrile and the acid groups are located near one another in the
polar middle of the capsule (Figure 2). The 1H NMR spectra show
that the initial coencapsulation complex is replaced by the rear-
rangement product 4 even at room temperature. The intermediate
is not observed to build up in concentration. A small amount of
formamide 5 coencapsulated with acid 2 is also observed on
completion of the reaction. Under mildly elevated temperatures
(40 °C), the reaction was complete over the course of 20 h. Control
experiments at millimolar concentrations at the same temperature
and solvent showed that no reaction could be detected in the absence
of the capsule. However, the same reagents at 4.0 M concentration
and 40 °C result in the formamide 5 and the anhydride 6 after 2
days. No rearrangement product 4 was observed under these
conditions. Accordingly, the reaction takes a different and acceler-
ated course inside the capsule.
Figure 1. Two cavitands self-assemble through hydrogen bonding into a
cylindrical capsule 1.1. Two representations of the capsule are shown. In
the center is the energy-minimized (semiempirical AM1, HyperChem 7)
structure 1.1; the long alkyl chains and CH hydrogen atoms are omitted
for viewing clarity. Right: the cartoon representation.
9
7810 J. AM. CHEM. SOC. 2008, 130, 7810–7811
10.1021/ja802288k CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
result. The complexity of the spectrum for encapsulated 10 reflects
its existence as a mixture of rotamers13 and social isomers.14
Elsewhere, we have described the principles of coencapsulation
of two guests within a host: the congruence of shapes, the
compatibility with lengths, the conformity with volumes, and the
complementarity of surfaces. These features manipulate reactivity
within the rigid capsules15 and contrast with flexible receptors with
more functionality16 or other unimolecular cages.17 The surround-
ings may also be thought of as a solvent cage fixed in place through
synthesis. The adaptation of solvent to the transition state during a
reaction inside a capsule does not incur an entropic price. Some
reactions do not—perhaps cannot—occur inside the confined
environment. In the cases at hand, encapsulation does provide an
alternative to reactions at high temperatures in bulk solution.
Acknowledgment. We are grateful to the Skaggs Institute for
support and Prof. S. J. Danishefsky for stimulating discussions and
sharing data (ref 8) prior to publication. J.H. and D.A. are Skaggs
Postdoctoral Fellows.
1
Figure 2. Partial H NMR spectra show the transformation of acid 2 (20
mM) and isonitrile 3 (6.0 mM) in the presence of capsule 1.1 (2.0 mM) at
300 K. Cartoon representations show the complexes involved in the
transformation. The intermediate within capsule (green) is undetectable in
1H NMR spectrum: (a) t ) 0 h; (b) t ) 7 h; (c) t ) 20 h; (d) 4 (authentic
sample) within capsule 1.1; (e) 5 (authentic sample) and acid 2 within
capsule 1.1.
Supporting Information Available: Reaction pathways and NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
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1
Figure 3. Partial H NMR spectra show the transformation of acid 2 (20
mM) and isonitrile 7 (2.0 mM) in the presence of capsule 1.1 (2.0 mM) at
300 K (/ ) impurities). Cartoon representations show the complexes
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Ironically, the expected but absent rearrangement product 9 is a
better guest (nearly ideal occupancy12) than any of the other
products observed from the reaction in the presence of the capsule,
as revealed by competitive binding experiments. The formation of
8 in the capsule is irreversible since the ratio of the starting
coencapsulation complex to 8 changes (decreases) with time. At
any rate, this capsule prevents the rearrangement, yet provides a
source of reactive 8 that leaks out of the capsule to react with the
acid in bulk solution. The capsule could be regarded as a catalyst
for the formation of the symmetrical anhydride 6 since it is too
large to fit inside the capsule. However, the other product, 10, does
eventually occupy the capsule so classic product inhibition is the
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