Encapsulated reagents for nitrosation

Article abstract of DOI:10.1021/ol0342195

(Matrix presented) A novel class of stable, mild, and size-shape-selective nitrosating agents for secondary amides is introduced. These are based on reversible entrapment and release of reactive nitrosonium species by calix[4]arenes. The NO⁺ encapsulation controls the reaction selectivity.

Full text of DOI:10.1021/ol0342195

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1253-1256
Encapsulated Reagents for Nitrosation
Grigory V. Zyryanov and Dmitry M. Rudkevich*
Department of Chemistry & Biochemistry, UniVersity of Texas at Arlington,
Arlington, Texas 76019-0065
rudkeVich@uta.edu
Received February 6, 2003
ABSTRACT
A novel class of stable, mild, and size−shape-selective nitrosating agents for secondary amides is introduced. These are based on reversible
entrapment and release of reactive nitrosonium species by calix[4]arenes. The NO+ encapsulation controls the reaction selectivity.
Among the challenges of modern synthetic chemistry are
the control of kinetics and selectivity of reactions and the
creation of reagents that modify a portion of a molecule
without protecting other reactive sites. “Molecule-within-
molecule”, or encapsulation complexes,1 offer an exciting
breakthrough here as they can at will entrap and release guest
species, under subtle chemical or physical control. For such
complexes, stabilization of reactive species within the
interiors,2 controlled chemical reactivity,3 and catalysis4 have
been impressively demonstrated. For example, a self-
assembling capsule was used to entrap dicyclohexylcarbo-
diimide (DCC) and dibenzoyl peroxide (DBPO).5 The
chemical stability of these reagents was greatly improved
within the shielded interior. Controlled release and displace-
ment of reactants within a capsule resulted in autocatalysis
in the amide bond formation.3c,d
We define encapsulated reagents as highly reactive species
reversibly entrapped within the host cavity that can be
released into the reaction mixture under subtle control. The
cavity offers protection from the bulk environment and thus
controls the reaction rates. Chemical transformations with
encapsulated reagents may occur either within the cavity
interior, or outside, upon release.2-4 As far as the delicate,
noncovalent forces holding the molecule-within-molecule
complex together are concerned, temperature, solvent polar-
ity, and substrate-cavity size-shape complementarity are
the critical factors responsible for the reagent release and
the occurrence of the reaction. In this communication, we
introduce a novel class of encapsulated reagents, stable, mild
and selective nitrosating reagents, that are based on reversible
encapsulation of reactive nitrosonium species by calixarenes.
In organic chemistry, nitrosation holds a special place.
Alkylnitrites (RO-NO), nitrosoamines/amides, and nitro-
sothiols are used in biomedicine as NO-releasing drugs.6 In
total synthesis, -NdO is an important activating group,
(1) (a) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew. Chem.,
Int. Ed. 2002, 41, 1488-1508. (b) Fujita, M.; Umemoto, K.; Yoshizawa,
M.; Fujita, N.; Kusukawa, T.; Biradha, K. Chem. Commun. 2001, 509-
518. (c) Rudkevich, D. M. In Calixarene 2001; Asfari, Z., Bo¨hmer, V.,
Harrowfield, J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht,
2001; pp 155-180. (d) Rudkevich, D. M. Bull. Chem. Soc. Jpn. 2002, 75,
393-413.
(2) (a) Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1024-1027. (b) Goto, K.; Okazaki, R. Liebigs Ann./Recl
1997, 2393-2407. (c) Warmuth, R. Eur. J. Org. Chem. 2001, 423-437.
(3) (a) Kurdistani, S. K.; Helgeson, R. C.; Cram, D. J. J. Am. Chem.
Soc. 1995, 117, 1659-1660. (b) Yoshizawa, M.; Kusukawa, T.; Fujita, M.;
Yamaguchi, K. J. Am. Chem. Soc. 2000, 122, 6311-6312. (c) Chen, J.;
Ko¨rner, S.; Craig, S. L.; Rudkevich, D. M.; Rebek, J., Jr. Nature 2002,
415, 385-386. (d) Chen, J.; Ko¨rner, S.; Craig, S. L.; Lin, S.; Rudkevich,
D. M.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 2593-2596.
(4) (a) Kang, J.; Santamaria, J.; Hilmersson, G.; Rebek, J., Jr. J. Am.
Chem. Soc. 1998, 120, 7389-7390. (b) Ito, H.; Kusukawa, T.; Fujita, M.
Chem. Lett. 2000, 598-599.
(5) Ko¨rner, S. K.; Tucci, F. C.; Rudkevich, D. M.; Heinz, T.; Rebek, Jr.
J. Chem. Eur. J. 2000, 6, 187-195.
(6) Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk,
A. J. Chem. ReV. 2002, 102, 1091-1134.
10.1021/ol0342195 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/15/2003

Figure 1. Chemical fixation of NO2/N2O4 with calix[4]arenes.
Generation of encapsulated nitrosating reagents.
allowing elegant transformations of amides to carboxylic
acids and their derivatives.7 In addition, nitrosation mimics
interactions between biological tissues and environmentally
toxic NOX gases, NO, N2O3 and NO2/N2O4, which generate
mutagenic nitrosoamines/peptides and nitrosate and deami-
nate DNA.8
We recently reported that simple calix[4]arenes reversibly
interact with NO2/N2O4 and entrap highly reactive NO+
cation within their cavities.9 NO+ is generated from N2O4,
- 10
which is known to disproportionate to NO+NO3 . Stable
calixarene-nitrosonium complexes were quantitatively iso-
lated upon addition of a Lewis acid. Only one NO+ cation
was found per cavity; very high Kass values .106 M-1 were
determined.11
For this project, nitrosonium complex 1 was employed as
an encapsulated nitrosating reagent for secondary amides
(Figure 1). Complex 1 was quantitatively prepared upon
bubbling NO2/N2O4 through the CHCl3 solution of tetrakis-
(O-n-hexyloxy)calix[4]arene 2 in the presence of SnCl4 and
characterized by UV-vis, FTIR, 1H NMR spectroscopy, and
CHN elemental analysis.12
1
Figure 2. Portions of the H NMR spectra (500 MHz, CDCl3,
295 ( 1 K) of (A) calix[4]arene 2; (B) calix[4]arene-nitrosonium
complex 1 prepared from 2, NO2/N2O4, and SnCl4; (C) a mixture
of 2 and NO2/N2O4; and (D) nitrosonium complex, prepared upon
addition of NO+SbF6- to calixarene 2. The residual CHCl3 signals
are marked (b).
Specifically, the UV-vis spectrum showed a broad charge-
transfer13 band at λmax ≈ 578 nm. The complex is deeply
colored. The FTIR spectrum exhibited characteristic13 arene-
NO+ stretching at ν ) 1934 cm-1. The H NMR spectrum
1
of 1 showed new sets of the calixarene signals, different from
2 (Figure 2). In particular, aromatic CH protons of guest-
free 2 were seen as a singlet at 6.95 ppm. In nitrosonium
complex 1, this signal was transformed into a singlet at 7.02
ppm. The methylene bridge CH2 protons of 2 were recorded
as a singlet at 3.73 ppm. In complex 1, this was seen at 3.60
ppm.
(7) (a) White, E. H. J. Am. Chem. Soc. 1955, 77, 6011-6014 and 6014-
6022. (b) Karanewsky, D. S.; Malley, M. F.; Gougoutas, J. Z. J. Org. Chem.
1991, 56, 3744-3747. (c) Kelly, T. R.; Xu, W.; Ma, Z.; Bhushan, V. J.
Am. Chem. Soc. 1993, 115, 5843-5844. (d) Glatzhofer, D. T.; Roy, R. R.;
Cossey, K. N. Org. Lett. 2002, 4, 2349-2352.
(8) Kirsch, M.; Korth, H.-G.; Sustmann, R.; de Groot, H. Biol. Chem.
2002, 383, 389-399.
(9) Zyryanov, G. V.; Kang, Y.; Stampp, S. P.; Rudkevich, D. M. Chem.
Commun. 2002, 2792-2793.
Complex 1 can be cleanly obtained from calixarene 2 and
NO2/N2O4 even without SnCl4 (Figure 2C). Finally, inde-
(10) Bosch, E.; Kochi, J. K. J. Org. Chem. 1994, 59, 3314-3325.
(11) Kochi and Rathore recently described charge-transfer complexes
between NO+ cation and structurally similar calix[4]arenes. The cation was
found encapsulated within the cavity (X-ray analysis). See: Rathore, R.;
Lindeman, S. V.; Rao, K. S. S.; Sun, D.; Kochi, J. K. Angew. Chem., Int.
Ed. 2000, 39, 2123-2127.
solution of 2 (1 equiv) and SnCl4 (1.5 equiv) in CHCl3 at room temperature.
After 1 h, complex 1 was precipitated upon addition of hexanes, filtered,
washed with hexanes, and dried in vacuo: 1H NMR (CDCl3) δ 7.02 (s, 8
H), 3.77 (t, J ) 7.5 Hz, 8 H), 3.60 (s, 8 H), 1.38 (m, 32 H), 1.30 (s, 36 H),
0.92 (t, J ) 7.5 Hz, 12 H); UV-vis (CHCl3) λmax ) 578 nm; FTIR (CDCl3)
ν (NO+) ) 1934 cm-1. Anal. Calcd for C68H104Cl4N2O8Sn: C, 61.04; H,
7.83; N, 2.09. Found: C, 60.96; H, 7.88; N, 2.09.
(12) Complex 1: Procedure 1. NO2/N2O4 gas, generated from copper
wire and concentrated HNO3, was bubbled for 20 s through the solution of
calixarene 2 (25 mg, 2.5 × 10-5 mol) and SnCl4 (3 µL, 2.6 × 10-5 mol)
in dry CHCl3 (1.0 mL). The solvent was evaporated. The dark-blue solid
was dissolved in dry CHCl3 (0.5-1.0 mL) and used for further reactions.
Procedure 2. Stock solution of NO2 (∼3 equiv) in CHCl3 was added to the
(13) Review: Borodkin, G. I.; Shubin, V. G. Russ. Chem. ReV. 2001,
70, 211-230.
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Org. Lett., Vol. 5, No. 8, 2003

Figure 3. N-Nitrosation of amides 3 with encapsulated reagent 1.
pendent structural evidence for 1 came from the complex-
ation experiments between calixarene 2 and commercially
available NO+SbF6- salt (CDCl3, 295 K). The corresponding
UV-vis, FTIR, and 1H NMR complexation-induced changes
were in agreement with the data presented above for complex
1 (Figure 2).
Chemical properties of the encapsulated NO+ are different
from those in bulk solution and are controlled by the cavity.
We found the following:
1. Highly reactive NO+ species are protected from the bulk
environment. Complex 1 is quite stable toward moisture and
oxygen and can be handled, for at least 30 min, without
drybox conditions and/or a nitrogen/argon atmosphere. On
the other hand, it can be decomposed within a few minutes
by addition of H2O or alcohols, recovering free calixarene
2. Such stability of arene-nitrosonium complexes is remark-
able.13
Figure 4. 1H NMR analysis of nitrosation reactions (500 MHz,
CDCl3, 295 ( 1 K): (A) N-nitrosoamides 4b (left) and 4c (right),
independently obtained from 3b,c and NO2/N2O4, respectively; (B)
reaction mixtures 1 + 3b (left) and 1 + 3c (right) after ∼1 h; and
(C) guest-free calixarene 2.
2. Complex 1 acts as a mild nitrosating reagent. When
added to the equimolar solution of amide RC(O)NHR′ 3a-e
in freshly distilled CHCl3, it reacted instantly at room
temperature, yielding N-nitrosoamides 4a-e in 50-95%
(Figure 3, Table 1). Dark-blue solutions of 1 quickly
discharged upon addition of 3a-e, which is a reasonable
disappeared and novel, characteristic signals for N-nitroso-
amides at ∼3.2 ppm (2 H, q for 4a and t for 4b-e, C(O)-
CH2) and ∼3.1 ppm (s, 3 H, N(NO)-CH3) and for
nitrosonium-free calixarene 2 were detected (Figure 4,
Supporting Information).14,15
1
Visual test for the reaction. In the H NMR spectra of the
reaction mixtures, signals for amides 3a-e and complex 1
3. In reaction with a variety of amides 3a-q, only those
possessing N-CH3 substituents were transformed to the
corresponding N-nitrosoamides 4a-e. No reaction occurred
for substrates 3f-q (Table 1, NMR analysis). Accordingly,
no color discharge was observed for these reaction mixtures.
Such delicate selectivity of N-nitrosation by complex 1
was unexpected and may be due to steric effects. Clearly,
the unreacted subtrates were those possessing N-Alk groups
bulkier than CH3.
Table 1. Nitrosation of Amides 3a-q with Encapsulated
Reagent 1. Yields of N-Nitrosoamides 4a-q
compound
R
R′
yield, %
4a
4b
4c
4d
4e
4f
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
50
68
53
95
63
0
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
CH3(CH2)6
C(CH3)3
NO+ is an aggressive electrophile and is typically not
selective.16,17 Mechanistically, nitrosation of secondary amides
and peptides incorporates an electrophilic attack of NO+
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
C2H5
C2H5
C2H5
C2H5
C2H5
CH3(CH2)2
CH3(CH2)2
CH3(CH2)2
CH3(CH2)2
CH(CH3)2
C(CH3)3
CH2C6H5
0
0
0
0
0
0
0
0
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
C2H5
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
CH3(CH2)3
C(CH3)3
(14) Complex 1 (1 equiv) was added to the solution of amide 3a-q
(1-3 equiv) in freshly distilled CHCl3, and the reaction mixture was stirred
at room temperature for 5 h. The solvent was evaporated, and the residue
1
was analyzed by H NMR spectroscopy and, in some cases, separated by
preparative TLC. All runs were performed at least in duplicate.
(15) For spectral comparison, representative N-nitrosoamides 4a-
e,h,l,m,q were quantitatively obtained employing NO2/N2O4 in CHCl3,
similar to the protocol reported in ref 16a. From both methods, the spectral
and TLC data for N-nitroso compounds 4a-e were identical and in
agreement with published data; see ref 16c-e and Supporting Information.
Caution: N-Nitrosoamides are carcinogens and should be treated with
extreme care.
0
0
0
CH3(CH2)3
Org. Lett., Vol. 5, No. 8, 2003
1255

calixarene. For sizable R′, this situation could be sterically
unfavorable, so that the substrate CdO and the encapsulated
NO+ would not reach each other. As for the C(O)R alkyl
group, it is obviously positioned farther away from the
calixarene substituents and does not significantly interfere,
except in the case with bulky amide 3f.18 Once formed, the
O-nitroso intermediate leaves the interior and further col-
lapses in bulk solution, as expected.17 Due to the extremely
strong binding of NO+ by the calixarene, the rate-limiting
formation of the O-nitrosation intermediates should take
place within the cavity, prior to the NO+ dissociation.
Otherwise, all reactions should proceed with roughly the
same rate, and no selectivity should be seen.
In summary, novel nitrosating reagents are now available
that can be obtained upon fixation of NO2/N2O4 with calix-
[4]arenes. These are encapsulated reagents, and their reactiv-
ity is controlled by the host cavity. They are stable, mild,
and size-shape selective. It would be interesting to test the
encapsulated reagents in the synthesis of peptide-based NO-
releasing pharmaceuticals, including chiral derivatives, and
also for regioselective activation of peptides through N-
nitrosation. For this, synthetic modifications of the calix[4]-
arene cavity may be required.
Figure 5. Top: the currently accepted mechanism of N-nitrosation
of secondary amides/peptides.17 Below: a proposed mechanism of
nitrosation with encapsulated reagents.
(generated from NO+-salts, N2O3, or NO2/N2O4) on a
nucleophilic carbonyl oxygen of the substrate, yielding the
corresponding O-nitroso species (Figure 5).17
Rapid deprotonation, rotation around the C-O bond, and
inversion through the nitrogen results in the intermediate,
in which both the nitrogen lone pair and the NO group are
properly oriented for the isomerization to the N-nitrosoamide.
Dimensions and shapes of R and R′ become much more
crucial when encapsulated reagent 1 is employed. Molecules
3 approach the cavity 1, facing it with the carbonyl oxygen
(Figure 5). This places the N-R′ alkyl group in close
proximity to the two t-Bu and two O(CH2)5CH3 groups of
Acknowledgment. Financial support is acknowledged
from the University of Texas at Arlington and from the
donors of the Petroleum Research Fund, administered by the
American Chemical Society.
Supporting Information Available: Procedures and
spectral data for complex 1, amides 3, and nitrosoamides 4
and 1H NMR spectra of amides 3a-q and nitrosoamides 4a-
e,h,l,m,q. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) (a) White, E. H. J. Am. Chem. Soc. 1955, 77, 6008-6010. (b)
Challis, B. C.; Milligan, J. R.; Mitchell, R. C. J. Chem. Soc., Chem.
Commun. 1984, 1050-1051. (c) Garcia, J.; Gonzalez, J.; Segura, R.; Urpi,
F.; Vilarrasa, J. J. Org. Chem. 1984, 49, 3322-3327. (d) Saavedra, J. E. J.
Org. Chem. 1979, 44, 860-861. (e) Kakuda, Y.; Gray, J. I. J. Agric. Food
Chem. 1980, 28, 584-587. (f) Torra, N.; Urpf, F.; Vilarrasa, J. Tetrahedron
1989, 45, 863-868. For rare examples of steric inhibition of N-nitrosation
with crowded amides, see: (g) Garcia, J.; Gonzalez, J.; Segura, R.; Vilarrasa,
J. Tetrahedron 1984, 40, 3121-3127. (h) Evans, D. A.; Carter, P. H.;
Dinsmore, C. J.; Barrow, J. C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett.
1997, 38, 4535-4538.
OL0342195
(18) It is well-known that secondary N-alkyl amides similar to 3 exist
mostly (>98%) as trans isomers; see, for example: Radzicka, A.; Pedersen,
L.; Wolfenden, R. Biochemistry 1988, 27, 4538-4541 and references
1
therein. In our experiments, no cis isomers 3 were detected by H NMR.
Moreover, if the nitrosation proceeded via the cis conformers, there should
not be any preferences in reactivities for amides with different R′-groups,
as they are positioned far away from the calixarene cavity.
(17) Darbeau, R. W.; Pease, R. S.; Perez, E. V. J. Org. Chem. 2002, 67,
2942-2947 and references therein.
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