Reactivity of N-nitrosoamides in confined spaces

Article abstract of DOI:10.1016/j.tetlet.2010.11.030

The thermal rearrangement of several N-nitrosoamides was studied by ¹H NMR in the context of reversible encapsulation. The N-nitrosoamide guests were isolated from the bulk solvent in a hydrogen-bonded dimeric host capsule which prevented their rearrangement. The guests appear to be preserved in their ground state conformations by the pressure exerted by the host. The conformations of the free and bound N-nitrosoamides are of comparable relative energies as determined by DFT calculations.

Full text of DOI:10.1016/j.tetlet.2010.11.030

Tetrahedron Letters 52 (2011) 2100–2103
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactivity of N-nitrosoamides in confined spaces
⇑
Aaron C. Sather, Orion B. Berryman, Dariush Ajami, Julius Rebek Jr.
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla CA 92037, United States
a r t i c l e i n f o
a b s t r a c t
The thermal rearrangement of several N-nitrosoamides was studied by 1H NMR in the context of revers-
ible encapsulation. The N-nitrosoamide guests were isolated from the bulk solvent in a hydrogen-bonded
dimeric host capsule which prevented their rearrangement. The guests appear to be preserved in their
ground state conformations by the pressure exerted by the host. The conformations of the free and bound
N-nitrosoamides are of comparable relative energies as determined by DFT calculations.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Available online 18 November 2010
Dedicated to Harry Wasserman on the
happy occasion of his 90th birthday.
Keywords:
Hydrogen bonding
Reversible encapsulation
N-Nitrosoamides
The thermal decomposition of N-nitrosoamides was
bulk solvent—they exhibit unique behavior and reactivity.6a–k
These hosts have been used as reaction flasks7 and as protective
containers for reactive species.8a–d For the case at hand we chose
cylindrical capsule 1 with a cavity of ꢀ1.7 nm in length.9 The cap-
sule is flexible along its equator where breaking hydrogen bonds
allows guests to enter and exit, but much more rigid at its cova-
lently bound and tapered ends. We chose N-nitrosoamide 2
(Scheme 1), which appeared to fit snugly within the host to study
the effect physical restriction has on its decomposition.
ð1Þ
In solution, N-nitrosoamides decompose at a range of tempera-
tures depending on the steric bulk of R0.10a,b The benzoic acid deriv-
atives decompose at convenient rates on gentle warming; for
example, the thermal decomposition of 2 was followed by 1H
NMR at 35 °C in the absence of 1 (Fig. 1).
Equation: The mechanistic pathway for the thermal decomposition
of N-nitrosoamides:
discovered more than a century ago,1a,b and extensive subsequent
mechanistic studies2a–i led to a sequence of steps shown in the equa-
tion. Diazoester intermediate (I) is formed in the rate-determining
step and its N–O bond breaks, generating an ion pair. The subsequent
distribution of reaction products depends on solvent, temperature
and, the nature of the R group, but generally the products include
the ester and the acid/olefin pair. The initial N to O migration of the
acyl group—a reaction that has counterparts in O to N migrations of
the Mumm rearrangement3a,b and in the reaction of acids with carbo-
diimides4—may involve a four-membered intermediate in the first
step or no intermediate at all5 but whatever the path, rearrangement
lengthens the molecule as two new atoms are inserted in the original
amide bond to give the diazoester intermediate. We were intrigued
by the consequences of performing this reaction in a confined space,
and report herein our observations.
The same reaction was followed by 1H NMR in the presence of
host 1. The addition of one equivalent of 2 to host 1 in mesitylene-
d12 followed by brief sonication and mild heating gives the encapsu-
lated complex.11 Figure 2 shows the upfield region of the 1H NMR
spectrum, indicating that the guest remains intact inside the
capsule. To confirm that the upfield signals belonged to the N-nitr-
osoamide and not to the product ester, an authentic sample of the
ester was prepared and encapsulated in 1; the encapsulated ester
showed different chemical shifts (see Supplementary data).
A longer guest, N-hexylnitrosoamide 3 was studied next in a
similar manner. Guest 3 fits inside 1, although it is not as good a
guest as 2. After warming at 35 °C for 72 h all of the free guest res-
onances disappeared and new signals appeared in the upfield re-
gion (Fig. 3). These represent the product ester, as established by
encapsulation of authentic hexylester (see Supplementary data).
At first glance, the reaction of a longer nitrosoamide inside the
capsule is incomprehensible, but we found that the reaction takes
place outside the capsule. In the presence of 1 equiv of 3 only
A multitude of synthetic hosts are known to accommodate
guests in a limited space, where—temporarily isolated from the
⇑
Corresponding author.
E-mail address: jrebek@scripps.edu (J. Rebek).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.030

A. C. Sather et al. / Tetrahedron Letters 52 (2011) 2100–2103
2101
Scheme 1. Two molecules (left) come together in solution to form hydrogen-bonded dimeric host 1 (cartoon representation) which accommodates N-nitrosoamide guests.
MM1 minimization of encapsulated 2 within 1 (right).
Figure 1. The thermal decomposition of N-nitrosoamide 2. The lower red trace shows the starting material. After 67 h at 35 °C all the starting material is gone, giving the
corresponding ester as shown in the purple trace.
Figure 2. The thermal decomposition of N-nitrosoamide 2 in the presence of 1. The lower red trace shows the encapsulated starting material. After ꢀ67 h at 35 °C the starting
material remains and little or no ester is observed.
ꢀ35% becomes encapsulated within host 1. The remaining free
guest decomposes into the product ester, which displaces the nitr-
osoamide. The difference in length between guests 2 and 3 is two
atoms, just the difference between an N-nitrosoamide and its dia-
zoester rearrangement product (I). This suggests that there is en-
ough space for butyl guest 2 to rearrange to the diazoester yet
no reaction was observed. If diazoester intermediate (I) does in-
deed form, there must not be enough room for fragmentation of
the N–O bond and subsequent SN2 attack on the diazonium ion.
It appears that either the pressure exerted by host 1 on the guest
is preserving the starting material or a stable conformation of the
guest is enforced upon encapsulation. We turned to DFT calcula-
tions to address this question.12
The ground state conformation of N-nitrosoamide 2 is the trans
form where the N–O bond is directed away from the carbonyl car-
bon (Fig. 4 left). In the cis form the N–O bond is directed near the
carbonyl carbon, which is the conformation that must be achieved
for the rearrangement to take place. DFT calculations at the (HF/6-
31G*) level give a difference in energy between the two conforma-
tions of 6.8 kcal, in favor of the trans form.
The DFT calculations were also performed for the encapsulated
complexes to compare the relative energies of the trans and cis
N-nitrosoamide conformations within host 1 (Fig. 5). Again, the
calculations give a difference in energy between the two conforma-
tions of 6.9 kcal in favor of the trans form. Accordingly, the relative
energies of the ground state conformation for the free and bound

2102
A. C. Sather et al. / Tetrahedron Letters 52 (2011) 2100–2103
Figure 3. The thermal decomposition of N-nitrosoamide 3 at 35 °C. Due to the poor fit of guest 3, the reaction takes place in the presence of 1.
Figure 4. Ab initio gas phase energy minimization at the Hartree–Fock (HF) level
(HF/6-31G*) of N-nitrosoamide 2 in both the trans and cis conformations.
guests are calculated to be comparable, suggesting that the pres-
sure exerted by the host on the guest is preserving the starting
material.
We also prepared N-benzylnitrosoamide 4 to study its behavior
inside 1. It is known that N-benzyl nitrosoamides form stable ben-
zylic cations when decomposed.13a,b If there is enough room in 1 to
form an ion pair the resulting benzylic cation should recombine
with the carboxylate fragment after N2 escapes the host. The reac-
tion was first followed in the absence of host; as shown in Figure 6
the decomposition reaction is approximately 70% complete after
144 h at 35 °C in mesitylene-d12
.
Once again, upon encapsulation of 4 no reaction takes place
(Fig. 7). Even though the mode of decomposition for 4 differs from
2 and 3, the restrictive environment of host 1 prevents the rear-
rangement from occurring.
Figure 5. Ab initio gas phase energy minimization at the Hartree–Fock (HF) level
(HF/6-31G*) of encapsulated N-nitrosoamide
2 in both the trans and cis
conformations.
To return reactivity to the N-nitrosoamides we were able to free
the guests from their restrictive host (1) with the addition of
MeOD-d4. The methanol disrupts the hydrogen-bonding seam that
holds the host together, destroying the complex. Upon addition of
30 L of MeOD-d4 to a solution of encapsulated guest 2 all up field
l
Figure 6. The thermal decomposition of N-nitrosoamide 4 at 35 °C followed by 1H NMR in mesitylene-d12
.

A. C. Sather et al. / Tetrahedron Letters 52 (2011) 2100–2103
2103
Figure 7. The thermal decomposition of N-benzylnitrosoamide 4 in the presence of 1. All starting material remains after 144 h at 35 °C. Free guest 4 is indicated by a red
circle.
1973, 95, 8107; (e) White, E. H.; Stuber, J. J. Am. Chem. Soc. 1963, 85, 2168; (f)
White, E. H. J. Am. Chem. Soc. 1955, 77, 6014; (g) White, E. H.; Aufdermarsh, C. A.
J. Am. Chem. Soc. 1958, 60, 2597; (h) White, E. H.; Aufdermarsh, C. A. J. Am.
Chem. Soc. 1961, 83, 1179; (i) White, E. H.; Elliger, C. A. J. Am. Chem. Soc. 1967,
signals disappear as the guest is released to the bulk solution (see
Supplementary data). After heating at 35 °C for ꢀ63 h all of the
signals corresponding to the guest disappear from the 1H NMR
89, 165.
spectrum and signals corresponding to ester can be observed
3. (a) Mumm, O.; Hesse, H.; Yolquarts, H. Ber. 1915, 48, 379; (b) Schwarz, J. S. P.
(see Supplementary data).
J. Org. Chem. 1972, 37, 2906.
In conclusion, encapsulated N-nitrosoamides behave differently
than those in bulk solution. Inside the capsule, the host restricts
the elongation of the guests and prevents the rearrangement reac-
tion. Guest 2 does not react inside the capsule although there is
enough room to accommodate the longer (by two carbon atoms)
hexyl guest 3. The physical constraints of the capsule either pre-
vent the breakdown of the diazoester intermediate (I) or, more
likely, keep it from forming altogether. We were able to free encap-
sulated guests by the addition of methanol, restoring their reactiv-
ity. Guest 4 also shows no reactivity while encapsulated in 1, as
was the earlier case with dibenzoyl peroxide.14 By surrounding
N-nitrosoamides we were able to turn off their reactivity and sta-
bilize them at elevated temperatures.
4. De Tar, D. F.; Silverstein, R. J. Am. Chem. Soc. 1966, 88, 1013.
5. Jones, G. O.; Li, X.; Hayden, A. E.; Houk, K. N.; Danishefsky, S. J. Org. Lett. 2008,
10, 4093.
6. (a) Canceill, J.; Lacombe, L.; Collet, A. J. Am. Chem. Soc. 1986, 108, 4230; (b)
MacGillivary, L. R.; Atwood, J. L. Nature 1997, 389, 469; (c) Avram, L.; Cohen, Y.
J. Am. Chem. Soc. 2004, 126, 11556; (d) Shivanyuk, A.; Rebek, J., Jr. J. Am. Chem.
Soc. 2003, 125, 3432; (e) Sherman, J. C. Tetrahedron 1995, 51, 3395; (f) Fiedler,
D.; Leung, D. H.; Bergman, R. G.; Raymond, K. N. Acc. Chem. Res. 2005, 38, 349;
(g) Kerckhoffs, J. M. C. A.; ten Cate, M. G. J.; Mateos-Timoneda, M. A.; van
Leeuwen, F. W. B.; Snellink-Ruël, B.; Spek, A. L.; Kooijman, H.; Crego-Calama,
M.; Reinhoudt, D. N. J. Am. Chem. Soc. 2005, 127, 12697; (h) Liu, S.; Gibb, B. C.
Chem. Commun. 2008, 32, 3709; (i) Kobayashi, K.; Ishii, K.; Sakamoto, S.;
´
Shirasaka, T.; Yamaguchi, K. J. Am. Chem. Soc. 2003, 125, 10615; (j) Gonza lez, J.
J.; Ferdani, R.; Albertini, E.; Blasco, J. M.; Arduini, A.; Pochini, A.; Prados, P.; de
Mendoza, J. Chem. Eur. J. 2000, 6, 73; (k) Scarso, A.; Pellizzaro, L.; De Lucchi, O.;
Linden, A.; Fabris, F. Angew. Chem., Int. Ed. 2007, 46, 4972.
7. Yoshizawa, M.; Klosterman, J. K.; Fujita, M. Angew. Chem., Int. Ed. 2009, 48,
3418.
8. (a) Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem., Int. Ed. 1991, 30, 1024;
(b) Warmuth, R.; Marvel, M. A. Angew. Chem., Int. Ed. 2000, 39, 1117; (c)
Iwasawa, T.; Hooley, R. J.; Rebek, J., Jr. Science 2007, 317, 493; (d) Mal, P.;
Breiner, B.; Rissanen, K.; Nitschke, J. R. Science 2009, 324, 1697.
9. Heinz, T.; Rudkevich, D.; Rebek, J., Jr. Nature 1998, 394, 764.
10. (a) Huisgen, R.; Ruchardt, C. Justus Liebigs Ann. Chem. 1956, 601, 1; (b) White, E.
H.; Dolak, L. A. J. Am. Chem. Soc. 1966, 88, 3790.
11. Usually, guests are added to a suspension of the capsule and heated to give a
solution. However in this case, the guests are sensitive to heat, so the
suspensions were sonicated for about 30 min and then placed in an oil bath
between 30 and 35 °C overnight. After this period of time the suspensions
became solutions and all of the guest was taken up by the host. During this
brief induction period, the guest that is in the bulk solution can react giving
rise to a small background reaction.
Acknowledgments
We are grateful to the Skaggs Institute for support. A.C.S. is a
Skaggs Pre-doctoral Fellow. O.B.B. thanks the NIGMS (GM 27953)
for financial support. A postdoctoral fellowship for O.B.B. was
provided by NIH (F32GM087068).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.030.
12. DFT calculations were performed with the Gaussian 09, Revision A.1 program
using Ab initio gas phase energy minimization at the Hartree–Fock (HF) level.
(HF/6-31G*) was carried out on each structure, with ‘tight’ convergence
optimization criterium.
References and notes
13. (a) Darbeau, R. W.; White, E. H.; Song, F.; Darbeau, N. R.; Chou, J. C. J. Org. Chem.
1999, 64, 5966; (b) White, E. H.; De Pinto, J. T.; Polito, A. J.; Bauer, I.; Roswell, D.
F. J. Am. Chem. Soc. 1988, 110, 3708.
14. Körner, S. K.; Tucci, F. C.; Rudkevich, D. M.; Heinz, T.; Rebek, J., Jr. Chem. Eur. J.
2000, 6, 187.
1. (a) Chancel, M. F. Bull. Soc. Chim. Fr. 1895, 13, 125; (b) Pechmann, H. V. Ber.
1898, 31, 2640.
2. (a) White, E. H. J. Am. Chem. Soc. 1954, 76, 4497; (b) White, E. H. J. Am. Chem. Soc.
1955, 77, 6008; (c) White, E. H. J. Am. Chem. Soc. 1955, 77, 6011; (d) White, E. H.;
McGirk, R. H.; Aufdermarsh, C. A.; Tiwari, H. P.; Todd, M. J. J. Am. Chem. Soc.