Efficient isonitrile hydration through encapsulation within a hexameric self-assembled capsule and selective inhibition by a photo-controllable competitive guest

Article abstract of DOI:10.1039/c3cc42233j

Catalytic hydration of neutral isonitriles to yield the corresponding N-formylamides was achieved by reversible encapsulation in a self-assembled hexameric resorcin[4]arene capsule. Encapsulation of a photochromic dithienylethene bis-cation provides different levels of competitive inhibition depending on the geometry assumed by the cationic inhibitor. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc42233j

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Efficient isonitrile hydration through encapsulation
within a hexameric self-assembled capsule and
selective inhibition by a photo-controllable
competitive guest†
Cite this: Chem. Commun., 2013,
4
9, 5322
Received 27th March 2013,
Accepted 15th April 2013
DOI: 10.1039/c3cc42233j
Giulio Bianchini, Giorgio La Sorella, Nicol o´ Canever, Alessandro Scarso* and
Giorgio Strukul*
www.rsc.org/chemcomm
Catalytic hydration of neutral isonitriles to yield the corresponding Brønsted acids. The catalytic activity can be modulated using a
N-formylamides was achieved by reversible encapsulation in a self- photo-controllable cationic guest as a competitive substrate.
assembled hexameric resorcin[4]arene capsule. Encapsulation of a
Hexameric resorcin[4]arene 3 with long alkyl chains can be easily
photochromic dithienylethene bis-cation provides different levels prepared which spontaneously self-assembles in apolar, water satu-
of competitive inhibition depending on the geometry assumed by rated solvents like chloroform and benzene. The assembly is a
the cationic inhibitor.
spherical hexameric capsule 3
6
Á(H
2 8
O) held together by 60 hydrogen
15
bonds formed from micromolar concentrations with a cavity of
1
3 16
17
Isonitriles 1 are valuable intermediates in organic synthesis that have about 1375 Å . Thanks to extended cation–p interactions, suitable
18
received less attention because of their limited commercial availabi- guests for this assembly are quaternary ammonium compounds.
lity and extremely repellent odour that discourages manipulation. Other guests, used less frequently, comprise neutral species like
They are neutral molecules wherein the NC function can be described carboxylic acids, aminoacids and polyols capable of hydrogen
with either the zwitterionic form with positive N and negative C, or bonding, especially when they are present in a large excess with
19
the predominantly carbenic electronic structure. Overall, a linear respect to the hexameric host.
geometry results from the significant energetic stabilization of the We observed that addition of ten equivalents of cyclohexyl iso-
nitrogen lone pair p donation. The carbon atom in isonitriles nitrile 1a to a solution of the self-assembled capsule 3 O in a
Á8H
behaves either as an electrophile or as a nucleophile which has led water saturated chloroform-d led to the unexpected encapsulation of
2
6
2
3–5
to their employment in multi-component reactions. Several exam- the neutral guest. The appearance of new up-field shifted broad
6
1
ples of naturally occurring isonitriles exist, and they have been resonances in the H NMR spectrum in the range 0.1 to À0.7 ppm
7,8
applied in total syntheses. Recent approaches for the synthesis of (Fig. 1B and C) separate from the signals of free isonitrile in solution
isonitriles make use of alcohols as starting materials, but they have (Fig. 1A) confirmed the encapsulation. The same results were obser-
9
been traditionally synthesized by the reaction of primary amines with ved with other aliphatic and aromatic isonitriles. Smaller isonitriles
10
dichlorocarbene or by dehydration of N-formyl secondary amides.
like isopropyl isonitrile 1b, t-butyl isonitrile 1c and larger ones
The reverse reaction, isonitrile hydration forming N-formylamides 2,
is usually carried out in strongly acidic aqueous media, care should
1
11
be taken to avoid polymerization. Typical catalysts are acetic and
12
13
trifluoroacetic acid, HCl in H O–1,4-dioxane or polymer-supported
p-toluenesulfonic acid. In particular, high temperatures and low
concentrations favour N-formylamide formation.
2
14
5
Here we present an example of unexpected isonitrile encap-
sulation within the hexameric capsule 3
sequent hydration to the corresponding N-formylamides
6
Á8H
2
O and the con-
mediated by the supramolecular host in the absence of strong
Dipartimento di Scienze Molecolari e Nanosistemi, Universit a` Ca’ Foscari di
Venezia, Calle Larga S. Marta 2137, 30123, Venezia, Italy. E-mail: alesca@unive.it;
Fax: +39-041-2340517; Tel: +39-041-2348569
1
Fig. 1 H NMR spectra in water saturated chloroform-d: (A) 1a (60 mM); (B) 1a
†
Electronic supplementary information (ESI) available: Experimental details and
(60 mM) and 3 (36 mM); (C) 1a (120 mM) and 3 (36 mM); (D) 3 (36 mM).
encapsulation spectra. See DOI: 10.1039/c3cc42233j
encapsulated substrate,
N-formylamide product.
5
322 Chem. Commun., 2013, 49, 5322--5324
This journal is c The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
11–13,20
C atom followed by water addition.
Accordingly, it is likely that
the catalytic effect imparted by the capsule relies on the stabilization
of the cationic intermediate by means of interaction with the electron-
rich, concave internal surfaces of the resorcin[4]arene units. In order
to demonstrate unambiguously that the catalytic activity is a con-
sequence of the encapsulation of substrate 1a, we performed control
experiments repeating the hydration reaction in the presence of an
1
8
excess of (NEt
4
)(OTf) 4 (60 mM) as a competitive cationic guest.
2
1
Three molecules of 4 are concomitantly hosted within the capsule
and almost no product was formed (ESI,† Table S1, entry 3). The
reaction in the presence of resorcinol (pK > 9) as a partially acidic
a
and strongly H-bonding molecule in solution did not provide any
formation of the N-formylamide 2a. This provides evidence that the
hydration reaction is not promoted by the weak Brønsted acidity of
the resorcinol residues present in 3 but rather by the capsule itself.
The catalytic activity was highly dependent on the size and
electronic nature of the isonitrile substrates 1a–e as summarized in
Table 1. The smaller 1b bearing an i-propyl residue showed only
reduced conversion to the corresponding N-formylamide 2b, while the
slightly larger t-butyl isonitrile 2c was poorly reactive (Table 1).
Benzylisonitrile 1d was a very good substrate since it was quantitatively
converted into 2d within 18 h. The sterically demanding aromatic
isonitrile 1e led to the corresponding hydration product in 65% yield.
In abiotic catalytic systems, allosteric regulation remains a little
2
2,23
explored application.
Regulation has been achieved by the addi-
24
tion of orthogonal chemical entities as well as light of proper
Scheme 1 Structures of isonitrile substrates 1a–e and the corresponding hydra-
25,26
tion product N-formylamides 2a–e, resorcin[4]arene 3 and capsule 3
competitive guests tetraethyl ammonium triflate 4 and bis-cationic photo- moieties with unprecedented photo-fatigue that make them inter-
controllable inhibitor 5o (open form) and 5c (closed form).
Á(H
6 2
O)
8
,
wavelength.
Dithienylethenes are known as photomodulable
27
28
esting for the development of photomodulable enzyme mimics. We
29
prepared the bis-cationic dithienylethene derivative 5o bearing two
30–32
such as benzyl isonitrile 1d and 2,6-dimethylphenyl isonitrile methyl-pyridinium units
e (Scheme 1) were taken up (see ESI,† Fig. S2–S5). In particular,
(ESI†) that can be converted to the
1
aliphatic isonitriles 1b showed several resonances for the
encapsulated substrates in the range À0.3 to À0.7 ppm, while
Table 1 Hydration reaction of 1a–e mediated by 3
6
Á8H
2
O
a
#
1
Substrate
Product
Yield (%)
1
c showed a major single and relatively sharp resonance at
À0.62 ppm, corresponding to an upfield shift of Dd À2.07 ppm.
Benzyl substrate 1d showed shielded aromatic resonances
experiencing Dd À0.8 to À1.2 ppm and 1e showed a similar
behavior with the corresponding shielded aromatic resonances
that appeared shifted upfield with a Dd of about À1.6 ppm,
while the methyl groups of 1e were shifted by about À2.0 ppm.
>
98a
b,c
0
3
c,d
9
20
0
o5
b
d
2
3
The encapsulation of isonitriles within 3
6
Á8H
2
O is an unexpected
result since those are neutral molecules with minimal hydrogen
2
bonding properties. As recently described, their electronic distribu-
>98
0
b
tion has to be considered predominantly carbenic with substantial
nitrogen lone pair donation thus explaining the electrophilic char-
acter of the C atom. It is possible that the high electron-density
d
8
5
provided by the concave aromatic surfaces of 3
6
Á8H
2
O provides
>
>
98
b
stabilization of the carbenic-like structure of the substrate. While 1a
was stable in water saturated chloroform-d at 60 1C for >18 h (ESI,†
Table S1, entry 1), under the same conditions, complete conversion of
4
5
0
d
98
1a into the corresponding N-formylamide 2a was achieved by simply
65
0
adding 3 (36 mM) as a supramolecular catalyst (ESI,† Table S1,
entry 2). The formation of the N-formylamide 2a was confirmed by
GC-MS analysis and by the appearance of a new resonance at
b
d
48
[
1a–e] = 60 mM, [3] = 36 mM, water saturated chloroform-d 0.5 mL,
T = 60 1C, time 18 h. Determined using GC. No 3 added. Determined
8.09 ppm attributed to the formyl proton. The accepted mechanism
a
b
c
1
d
for isonitrile hydration occurs via protonation of the carbenic like by H NMR. [1a–e] = 120 mM.
This journal is c The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5322--5324 5323

View Article Online
ChemComm
Communication
closed more rigid isomer 5c by UV irradiation at 365 nm. We
In conclusion, we described an example of supramolecular
envisioned that competitive guests for the capsule having geometries catalysis where the hexameric capsule 3
6
Á8H
2
O unexpectedly
that can be regulated by means of light of different wavelengths hosts neutral non-hydrogen bonding isonitrile substrates and
would allow different degrees of co-encapsulation of isonitrile sub- catalyzes their conversion into the corresponding N-formyla-
strates and thus different catalytic activities. Both open and closed mides in the presence of water under mild experimental con-
inhibitors were suitable guests for the capsule (ESI†). The resonances ditions. Inhibition by a competitive bis-cationic guest whose
of the free cations completely disappeared upon addition of six geometry can be regulated by irradiation with a proper wave-
equivalents of 3. For 5o broad resonances for the encapsulated length was possible even though the process was not reversible.
inhibitor are observed at 6.7 ppm for the aromatic residues, and at
Notes and references
about À0.6 ppm for the aliphatic moieties. Cation 5c cannot be easily
generated in chloroform-d by UV irradiation; instead it was obtained
1
2
3
G. Gokel, G. Ltidke and I. Ugi, in Isonitrile Chemistry, ed. I. Ugi,
Academic Press, New York, 1971, p. 145.
R. Ramozzi, N. Ch ´e ron, B. Bra ¨ı da, P. C. Hiberty and P. Fleurat-
Lessard, New J. Chem., 2012, 36, 1137–1140.
Multicomponent Reactions, ed. J. Zhu and H. Bienaym ´e , Wiley-VCH,
Weinheim, Germany, 2005, pp. 1–468.
in acetonitrile-d upon 1 h irradiation with an UV lamp. The product
3
was only sparingly soluble in chloroform-d but it was completely
dissolved in this solvent upon addition of 3. Again, only very broad
resonances for the hosted cationic inhibitor 5c were apparent. NMR
experiments carried out in the range À20 1C to 50 1C did not provide
spectra that were better-resolved.
4
5
6
X. Li and S. J. Danishefsky, J. Am. Chem. Soc., 2008, 130, 5446.
J. G. Polisar and J. R. Norton, Tetrahedron, 2012, 68, 10236.
P. J. Scheuer, Acc. Chem. Res., 1992, 25, 433.
Catalytic isonitrile hydration tests were performed as presented in
Table S1 (ESI†) in the presence of one equivalent of open 5o and
closed 5c inhibitors with respect to the capsule (ESI†). It is evident
that the reaction with the open competitive guest 5o allowed a much
lower conversion with respect to the reaction carried out in the
absence of the inhibitor (ESI,† Fig. S6, 10% and 55% yield of 2a after
7 T. Wang and S. J. Danishefsky, J. Am. Chem. Soc., 2012, 134, 13244.
8
T.-h. Fu, W. T. McElroy, M. Shamszad and S. F. Martin, Org. Lett.,
012, 14, 3834.
2
9
(a) Y. Kitano, K. Chiba and M. Tada, Tetrahedron Lett., 1998,
39, 1911; (b) Y. Kitano, K. Chiba and M. Tada, Synthesis, 2001,
4
37; (c) I. Okada and Y. Kitano, Synthesis, 2011, 3997.
0 A. Porcheddu, G. Giacomelli and M. Salaris, J. Org. Chem., 2005,
0, 2361 and references therein.
1
1
7
3
h, respectively). Conversely, in the presence of 5c the reaction was 11 (a) H. Prawat, C. Mahidol, S. Wittayalai, P. Intachote,
T. Kanchanapoom and S. Ruchirawat, Tetrahedron, 2011, 67, 5651;
b) J. S. Simpson and M. J. Garson, Org. Biomol. Chem., 2004, 2, 939.
2 D. Zhang, X. Xu, J. Tan and Q. Liu, Synlett, 2010, 917.
not particularly inhibited, giving 33% of 2a after 3 h. Initial reaction
rates were calculated and showed that the open inhibitor 5o led to an
(
almost 10 fold rate reduction compared to the closed 5c. After 18 h 13 A. Alimardanov, A. Nikitenko, T. J. Connolly, G. Feigelson,
A. W. Chan, Z. Ding, M. Ghosh, X. Shi, J. Ren, E. Hansen, R. Farr,
M. MacEwan, S. Tadayon, D. M. Springer, A. F. Kreft, D. M. Ho and
J. R. Potoski, Org. Process Res. Dev., 2009, 13, 1161.
3
3% of 2a was observed with 5o and 68% with 5c. The two isomeric
inhibitors have almost identical molecular volumes with a packing
33
coefficient of only 0.24 within the hexamer, similar to that of the 14 J. Azuaje, A. Coelho, A. El Maatougui, J. M. Blanco and E. Sotelo,
21
ACS Comb. Sci., 2011, 13, 89.
encapsulation of three molecules of 4. This implies that room for
some substrate or solvent molecules is available in the remaining
1
1
5 L. R. MacGillivray and J. L. Atwood, Nature, 1997, 389, 469.
6 E. S. Barrett, T. J. Dale and J. Rebek Jr., J. Am. Chem. Soc., 2008, 130, 2344.
space within the cavity to fit the best packing coefficient of 0.45–0.55 17 D. A. Dougherty, Acc. Chem. Res., 2013, 46, 885.
3
3
18 A. Shivanyuk and J. Rebek Jr., Proc. Natl. Acad. Sci. U. S. A., 2001, 98, 7662.
typical of supramolecular encapsulation phenomena. The higher
1
9 (a) Y. Aoyama, Y. Tanaka, Y. H. Toi and H. Ogoshi, J. Am. Chem. Soc.,
inhibition provided by the open 5o isomer with respect to the closed
1988, 110, 634; (b) For an example of encapsulation of a Au(I)
5
c is likely dependent on the higher flexibility of the former species
complex and its application in alkyne hydration reaction see:
A. Cavarzan, A. Scarso, P. Sgarbossa, G. Strukul and J. N. H. Reek,
J. Am. Chem. Soc., 2011, 133, 2848.
0 (a) Isonitrile hydratase: M. Lakshminarasimhan, P. Madzelan, R. Nan,
N. M. Milkovic and M. A. Wilson, J. Biol. Chem., 2010, 285, 29651;
that fits better the space available within the cavity while 5c, being
more rigid and planar, occupies the cavity diameter. This leaves more
space close to the internal aromatic surfaces and allows the substrate
to experience the stabilizing effect of the aromatic surfaces that is
responsible for the catalytic effect imparted by the capsule. A similar
inhibition effect was observed with the smaller substrate 1b that
provided the corresponding hydration product 2b in 15% and 26%
yield after 2 h with 5o and 5c, respectively, and 50% and 59% yield
with 5o and 5c after 18 h (ESI,† Table S2). It is worth noting that at the
end of the reaction in the presence of the 5c isomer, partial (35%)
thermal formation of the open isomer 5o was observed. This is due to
2
2
(b) Iron containing isonitrile: K. Hashimoto, H. Suzuki, K. Taniguchi,
T. Noguchi, M. Yohda and M. Odaka, J. Biol. Chem., 2008, 283, 36617.
1 L. C. Palmer, A. Shivanyuk, M. Yamanaka and J. Rebek Jr., Chem.
Commun., 2005, 857.
2 L. Kovbasyuk and R. Kramer, Chem. Rev., 2004, 104, 3161.
3 U. L u¨ ning, Angew. Chem., Int. Ed., 2012, 51, 8163.
4 (a) M. S. Masar III, N. C. Gianneschi, C. G. Oliveri, C. L. Stern, S. B. T.
Nguyen and C. A. Mirkin, J. Am. Chem. Soc., 2007, 129, 10149; (b) H. J.
Yoon, J. Kuwabara, J.-H. Kim and C. A. Mirkin, Science, 2010, 330, 66.
5 (a) R. S. Stoll and S. Hecht, Angew. Chem., Int. Ed., 2010, 49, 5054;
2
2
2
2
(
b) J. Xuan and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828.
the intrinsically higher thermal lability of the closed isomer because 26 B. M. Neilson and C. W. Bielawski, J. Am. Chem. Soc., 2012,
1
34, 12693.
of the presence of two electron-withdrawing groups like the pyridi-
nium moieties. The difference in inhibition activity is better seen
2
7 S. Kawauchi, H. Yoshida, N. Yamashina, M. Ohira, S. Saeda and
M. Irie, Bull. Chem. Soc. Jpn., 1990, 63, 267.
29b
in experiments carried out with 5o and 5c at room temperature for 28 D. Wilson and N. R. Branda, Angew. Chem., Int. Ed., 2012, 51, 5431.
2
3
3
3
9 (a) M. Irie and K. Uchida, Bull. Chem. Soc. Jpn., 1998, 71, 985–996;
seven days with 38% and 67% yields for 2b, respectively, with about
0% of 5o present when starting with the 5c species. Unfortunately,
attempts to directly photo-isomerize the encapsulated 5o to 5c by UV
irradiation and the opposite re-opening of 5c to 5o were unsuccessful
probably because of steric clashes in the capsule or by its quenching
effect on the excited state of the diarylethene moiety.
(
b) M. Irie, Chem. Rev., 2000, 100, 1685.
1
0 V. A. Migulin, M. M. Krayushkin, V. A. Barachevsky, O. I. Kobeleva,
T. M. Valova and K. A. Lyssenko, J. Org. Chem., 2012, 77, 332.
1 W. R. Browne, J. J. D. de Jong, T. Kudernac, M. Walko, L. N. Lucas,
K. Uchida, J. H. van Esch and B. L. Feringa, Chem.–Eur. J., 2005, 11, 6430.
2 S. L. Gilat, S. H. Kawai and J.-M. Lehn, Chem.–Eur. J., 1995, 1, 275.
33 S. Mecozzi and J. Rebek Jr., Chem.–Eur. J., 1998, 4, 1016.
5
324 Chem. Commun., 2013, 49, 5322--5324
This journal is c The Royal Society of Chemistry 2013