Mechanism of the conversion of inverted CB[6] to CB[6]

Article abstract of DOI:10.1021/jo071034t

(Figure Presented) Inverted cucurbit[n]urils (iCB[n]) form as intermediates during the synthesis of cucurbit[n]urils from glycoluril and formaldehyde in HCl (85°C). Product resubmission experiments establish that the diastereomeric iCB[6] and iCB[7] are kinetic products that are less stable thermodynamically than CB[6] or CB[7] (>2.8 kcal mol^-1). When iCB[6] or iCB[7] is heated under aqueous acidic conditions, a preference for ring contraction is noted in the formation of CB[5] and CB[6], respectively. Interestingly, under anhydrous acidic conditions ring size is preserved with iCB[6] delivering CB[6] cleanly. To establish the intramolecular nature of the iCB[6] to CB[6] conversion under anhydrous, but not aqueous, acidic conditions we performed crossover experiments involving mixtures of iCB[6] and its ¹³C=O labeled isotopomer ¹³C₁₂-iCB[6]. An unusual diastereomeric CB[6] with a Moebius geometry (13) is proposed as a mechanistic intermediate in the conversion of iCB[6] to CB[6] under anhydrous acidic conditions. The improved mechanistic understanding provided by this study suggests improved routes to CB[n]-type compounds.

Full text of DOI:10.1021/jo071034t

Mechanism of the Conversion of Inverted CB[6] to CB[6]
†
,‡
,†
Simin Liu, Kimoon Kim,* and Lyle Isaacs*
Department of Chemistry and Biochemistry, UniVersity of Maryland, College Park, Maryland 20742, and
National CreatiVe Research InitiatiVe Center for Smart Supramolecules, and Department of Chemistry,
Pohang UniVersity of Science and Technology, Pohang, 790-784, Republic of Korea
lisaacs@umd.edu; kkim@postech.ac.kr
ReceiVed May 18, 2007
Inverted cucurbit[n]urils (iCB[n]) form as intermediates during the synthesis of cucurbit[n]urils from
glycoluril and formaldehyde in HCl (85 °C). Product resubmission experiments establish that the
diastereomeric iCB[6] and iCB[7] are kinetic products that are less stable thermodynamically than
-
1
CB[6] or CB[7] (>2.8 kcal mol ). When iCB[6] or iCB[7] is heated under aqueous acidic conditions,
a preference for ring contraction is noted in the formation of CB[5] and CB[6], respectively. Interestingly,
under anhydrous acidic conditions ring size is preserved with iCB[6] delivering CB[6] cleanly. To establish
the intramolecular nature of the iCB[6] to CB[6] conversion under anhydrous, but not aqueous, acidic
1
3
conditions we performed crossover experiments involving mixtures of iCB[6] and its CdO labeled
13
isotopomer C12-iCB[6]. An unusual diastereomeric CB[6] with a M o¨ bius geometry (13) is proposed as
a mechanistic intermediate in the conversion of iCB[6] to CB[6] under anhydrous acidic conditions. The
improved mechanistic understanding provided by this study suggests improved routes to CB[n]-type
compounds.
5
Introduction
which contains two symmetry equivalent cavities. The cavity
3
volumes of these CB[n]-type compounds (82-870 Å ) span and
The synthetic and supramolecular chemistry of the cucurbit-
exceed those available with R-, â-, and γ-cyclodextrins and
1
[n]uril family (CB[n]) of macrocycles has undergone rapid
therefore a wide range of applications has been demonstrated
expansion in recent years with the development of a homologous
series of macrocycles (CB[n], n ) 5, 6, 7, 8, 10), diastere-
omeric inverted CB[n] (iCB[n]),4 and bis-nor-seco-CB[10],
6
including molecular shuttles and machines, supramolecular dye
lasers, supramolecular dendrimers, novel drug carriers, peptide
2,3
7
8
9
*
To whom correspondence should be addressed.
University of Maryland.
Pohang University of Science and Technology.
(5) Huang, W.-H.; Liu, S.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc.
2006, 128, 14744-14745.
†
‡
(6) Jeon, W. S.; Ziganshina, A. Y.; Lee, J. W.; Ko, Y. H.; Kang, J.-K.;
Lee, C.; Kim, K. Angew. Chem., Int. Ed. 2003, 42, 4097-4100. Ko, Y. H.;
Kim, K.; Kang, J.-K.; Chun, H.; Lee, J. W.; Sakamoto, S.; Yamaguchi, K.;
Fettinger, J. C.; Kim, K. J. Am. Chem. Soc. 2004, 126, 1932-1933. Jeon,
W. S.; Kim, E.; Ko, Y. H.; Hwang, I.; Lee, J. W.; Kim, S.-Y.; Kim, H.-J.;
Kim, K. Angew. Chem., Int. Ed. 2005, 44, 87-91. Ooya, T.; Inoue, D.;
Choi, H. S.; Kobayashi, Y.; Loethen, S.; Thompson, D. H.; Ko, Y. H.;
Kim, K.; Yui, N. Org. Lett. 2006, 8, 3159-3162. Sobransingh, D.; Kaifer,
A. E. Org. Lett. 2006, 8, 3247-3250. Sindelar, V.; Silvi, S.; Kaifer, A. E.
Chem. Commun. 2006, 2185-2187. Liu, Y.; Li, X.-Y.; Zhang, H.-Y.; Li,
C.-J.; Ding, F. J. Org. Chem. 2007, 72, 3640-3645. Tuncel, D.; O¨ zsar, O¨ .;
Tiftik, H. B.; Salih, B. Chem. Commun. 2007, 1369-1371. Ko, Y. H.; Kim,
E.; Hwang, I.; Kim, K. Chem. Commun. 2007, 1305-1315.
(1) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew.
Chem., Int. Ed. 2005, 44, 4844-4870. Lee, J. W.; Samal, S.; Selvapalam,
N.; Kim, H.-J.; Kim, K. Acc. Chem. Res. 2003, 36, 621-630.
(2) Freeman, W. A.; Mock, W. L.; Shih, N.-Y. J. Am. Chem. Soc. 1981,
1
03, 7367-7368. Kim, J.; Jung, I.-S.; Kim, S.-Y.; Lee, E.; Kang, J.-K.;
Sakamoto, S.; Yamaguchi, K.; Kim, K. J. Am. Chem. Soc. 2000, 122, 540-
41. Day, A. I.; Blanch, R. J.; Arnold, A. P.; Lorenzo, S.; Lewis, G. R.;
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Dance, I. Angew. Chem., Int. Ed. 2002, 41, 275-277. Liu, S.; Zavalij, P.
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001, 66, 8094-8100.
(4) Isaacs, L.; Park, S.-K.; Liu, S.; Ko, Y. H.; Selvapalam, N.; Kim, Y.;
Kim, H.; Zavalij, P. Y.; Kim, G.-H.; Lee, H.-S.; Kim, K. J. Am. Chem.
Soc. 2005, 127, 18000-18001.
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ChemPhysChem. 2007, 8, 54-56.
10.1021/jo071034t CCC: $37.00 © 2007 American Chemical Society
6
840
J. Org. Chem. 2007, 72, 6840-6847
Published on Web 08/04/2007

iCB[6] to CB[6] Mechanism
recognition,10 DNA delivery and cleavage, mediation of
11
CHART 1. Chemical Structures of CB[n] and iCB[n]
1
2
13
organic reactions, chemical sensors, and self-sorting sys-
1
4
tems. Despite the fact that the recognition properties of
CB[n] molecular containers surpass those of the cyclodextrins,
their use in industrial applications has been limited by several
factors. These include the following: (1) cyclodextrinssbut not
CB[n]scan be accessed in a size-selective manner by the
inclusion of appropriate complexation agents in the cyclodextrin
forming reaction mixture, (2) R-, â-, and γ-cyclodextrin have
very good aqueous solubility whereas CB[n] (n ) 6, 8, 10)
compounds have low solubility in unbuffered water, and (3)
strategies for the chemical derivatization of the cyclodextrins
are better developed. We, and others, have been pursuing a
synthetic and mechanistic approach toward the tailor-made
synthesis of CB[n], CB[n] derivatives, and CB[n] analogues as
science applications.20 In this manner, significant progress has
been made toward alleviating the limitations of the second and
third factors. In this paper, we continue to tackle the first
limitation by enhancing our knowledge of the mechanism of
formation of the CB[n] family of macrocycles. Specifically, we
show that iCB[6] and iCB[7] are kinetically controlled inter-
mediates in the formation of CB[n] and investigate the mech-
anism of the conversion of iCB[6] to CB[6] under acidic
conditions.
part of our efforts to remove these impediments toward their
industrial application.1
5-18
For example, Kim’s group has
developed the direct functionalization of preformed CB[n] that
yields (HO)2nCB[n] compounds that undergo further covalent
derivatization reactions.19 These CB[n] derivatives have en-
hanced water and organic solubility, enable attachment to solid
phases for separations and immobilization applications, and
serve as multivalent building blocks in biology and materials
Results and Discussion
This section begins with a brief presentation of the state-of-
the-art regarding the mechanism of CB[n] formation, which
serves as a basis for the subsequent discussion of the mechanism
of conversion of iCB[6] to CB[6].
Previous Mechanistic Studies. Scheme 1 shows the funda-
mental steps of the mechanism of CB[n] formation that were
presented by the groups of Isaacs and Day previously and
modified here to include the presence of iCB[n] as kinetically
(
8) Lee, J. W.; Ko, Y. H.; Park, S.-H.; Yamaguchi, K.; Kim, K. Angew.
Chem., Int. Ed. 2001, 40, 746-749. Wang, W.; Kaifer, A. E. Angew. Chem.,
Int. Ed. 2006, 45, 7042-7046. Sobransingh, D.; Kaifer, A. E. Langmuir
2
006, 22, 10540-10544. Kim, S.-Y.; Ko, Y. H.; Lee, J. W.; Sakamoto, S.;
Yamaguchi, K.; Kim, K. Chem. Asian J. 2007, 2, 747-754.
3
,21
(9) Wheate, N. J.; Day, A. I.; Blanch, R. J.; Arnold, A. P.; Cullinane,
controlled intermediates in the process. In brief, glycoluril 1
undergoes dimerization in the presence of a source of formal-
dehyde under acidic conditions to yield a mixture of two
diastereomers (2C and 2S). These dimers are hypothesized to
undergo further oligomerization to yield Behrend’s polymer (3),
which has a large number of possible diastereomers dependent
on the relative orientation of the H-atoms on the convex face
of the glycoluril oligomer. Behrend’s polymer 3 then intercon-
verts most or all of its S-shaped to C-shaped subunitssperhaps
C.; Collins, J. G. Chem. Commun. 2004, 1424-1425. Bali, M. S.; Buck,
D. P.; Coe, A. J.; Day, A. I.; Collins, J. G. Dalton Trans. 2006, 5337-
5
2
344. Wheate, N. J.; Buck, D. P.; Day, A. I.; Collins, J. G. Dalton Trans.
006, 451-458; Jeon, Y. J.; Kim, S.-Y.; Ko, Y. H.; Sakamoto, S.;
Yamaguchi, K.; Kim, K. Org. Biomol. Chem. 2005, 3, 2122-2125.
(10) Bush, M. E.; Bouley, N. D.; Urbach, A. R. J. Am. Chem. Soc. 2005,
1
27, 14511-14517. Heitmann, L. M.; Taylor, A. B.; Hart, P. J.; Urbach,
A. R. J. Am. Chem. Soc. 2006, 128, 12574-12581. Rekharsky, M. V.;
Yamamura, H.; Ko, Y. H.; Kim, K.; Inoue, Y. Peptide Sci. 2006, 43, 393-
3
94.
(11) Lim, Y.-B.; Kim, T.; Lee, J. W.; Kim, S.-M.; Kim, H.-J.; Kim, K.;
22
under the influence of templating groups sto create an
Park, J.-S. Bioconj. Chem. 2002, 13, 1181-1185. Isobe, H.; Sato, S.; Lee,
oligomer (e.g., 4 or 5) that is poised to undergo macrocyclization
to enter the CB[n] family manifold.
J. W.; Kim, H.-J.; Kim, K.; Nakamura, E. Chem. Commun. 2005, 1549-
1
9
551. Huo, F.-J.; Yin, C.-X.; Yang, P. Bioorg. Med. Chem. Lett. 2007, 17,
32-936.
The majority of the previously reported mechanistic studies
of CB[n] formation have been reported by the groups of Day
(12) Mock, W. L.; Irra, T. A.; Wepsiec, J. P.; Adhya, M. J. Org. Chem.
1
989, 54, 5302-5308. Jon, S. Y.; Ko, Y. H.; Park, S. H.; Kim, H.-J.; Kim,
3
,18,21,22
K. Chem. Commun. 2001, 1938-1939. Choi, S.; Park, S. H.; Ziganshina,
A. Y.; Ko, Y. H.; Lee, J. W.; Kim, K. Chem. Commun. 2003, 2176-2177.
Pattabiraman, M.; Natarajan, A.; Kaliappan, R.; Mague, J. T.; Ramamurthy,
V. Chem. Commun. 2005, 4542-4544. Wang, R.; Yuan, L.; Macartney,
D. H. J. Org. Chem. 2006, 71, 1237-1239.
and Isaacs.
For example, the Day group focused on the
latter stages of the mechanism of CB[n] formation compounds
by examining the influence of a variety of potential templates
(e.g., ammonium ions and alkali metal cations) on the distribu-
tion of CB[n] compounds obtained. Day’s group also reported
the influence of acid type, acid concentration, and concentration
of glycoluril on the outcome of the CB[n]-forming reaction.
Although these variables do influence the outcome of the
CB[n]-forming reaction, the impact of these variables on the
(13) Sindelar, V.; Cejas, M. A.; Raymo, F. M.; Chen, W.; Parker, S. E.;
Kaifer, A. E. Chem. Eur. J. 2005, 11, 7054-7059. Lagona, J.; Wagner, B.
D.; Isaacs, L. J. Org. Chem. 2006, 71, 1181-1190. Ling, Y.; Wang, W.;
Kaifer, A. E. Chem. Commun. 2007, 610-612.
(14) Mukhopadhyay, P.; Wu, A.; Isaacs, L. J. Org. Chem. 2004, 69,
6
157-6164. Liu, S.; Ruspic, C.; Mukhopadhyay, P.; Chakrabarti, S.; Zavalij,
P. Y.; Isaacs, L. J. Am. Chem. Soc. 2005, 127, 15959-15967. Mukho-
padhyay, P.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2006, 128, 14093-
1
4102.
(20) Lee, H.-K.; Park, K. M.; Jeon, Y. J.; Kim, D.; Oh, D. H.; Kim, H.
S.; Park, C. K.; Kim, K. J. Am. Chem. Soc. 2005, 127, 5006-5007.
Nagarajan, E. R.; Oh, D. H.; Selvapalam, N.; Ko, Y. H.; Park, K. M.; Kim,
K. Tetrahedron Lett. 2006, 47, 2073-2075. Hwang, I.; Baek, K.; Jung,
M.; Kim, Y.; Park, K. M.; Lee, D.-W.; Selvapalam, N.; Kim, K. J. Am.
Chem. Soc. 2007, 129, 4170-4171. Kim, D.; Kim, E.; Kim, J.; Park, K.
M.; Baek, K.; Jung, M.; Ko, Y. H.; Sung, W.; Kim, H. S.; Park, C. G.; Na,
O. S.; Lee, D.-K.; Lee, K. E.; Han, H. S.; Kim, K. Angew. Chem., Int. Ed.
2007, 46, 3471-3474.
(21) Chakraborty, A.; Wu, A.; Witt, D.; Lagona, J.; Fettinger, J. C.;
Isaacs, L. J. Am. Chem. Soc. 2002, 124, 8297-8306.
(22) Day, A. I.; Blanch, R. J.; Coe, A.; Arnold, A. P. J. Inclusion Phenom.
Macrocycl. Chem. 2002, 43, 247-250.
(15) Day, A. I.; Arnold, A. P.; Blanch, R. J. Molecules 2003, 8, 74-84.
Zhao, Y.; Xue, S.; Zhu, Q.; Tao, Z.; Zhang, J.; Wei, Z.; Long, L.; Hu, M.;
Xiao, H.; Day, A. I. Chin. Sci. Bull. 2004, 49, 1111-1116.
(
16) Lagona, J.; Fettinger, J. C.; Isaacs, L. Org. Lett. 2003, 5, 3745-
3
747.
17) Jon, S. Y.; Selvapalam, N.; Oh, D. H.; Kang, J.-K.; Kim, S.-Y.;
(
Jeon, Y. J.; Lee, J. W.; Kim, K. J. Am. Chem. Soc. 2003, 125, 10186-
1
0187.
(18) Lagona, J.; Fettinger, J. C.; Isaacs, L. J. Org. Chem. 2005, 70,
1
0381-10392.
(19) Kim, K.; Selvapalam, N.; Ko, Y. H.; Park, K. M.; Kim, D.; Kim,
J. Chem. Soc. ReV. 2007, 36, 267-279.
J. Org. Chem, Vol. 72, No. 18, 2007 6841

Liu et al.
SCHEME 1. Proposed Mechanism of CB[n] Formation
SCHEME 2. Equilibrium between S- and C-Shaped
Methylene-Bridged Glycoluril Dimers
nature of the isomerization process and lead us to formulate
the isomerization mechanism shown in Scheme 3. In brief, the
(()-7S to (()-7C interconversion proceeds by protonation and
fragmentation of (()-7S to yield iminium ion (()-8. Iminium
ion (()-8 undergoes intramolecular capture (under anhydrous
acidic conditions) to yield spirocyclic intermediate (()-9 that
can fragment in the opposite sense to yield iminium ion
(()-10, which then closes to yield (()-7C.
The mechanistic insights gained from the studies of Day and
Isaacs lead both groups to independently suggest that building
block approaches would deliver tailor-made CB[n]-type com-
pounds. These predictions were subsequently demonstrated
experimentally by the directed synthesis of Me6CB[6], Me4-
individual steps of the mechanism of CB[n] formation has not
yet been clarified. In an elegant product resubmission experiment
Day also showed that CB[8] is converted into the smaller
CB[n] homologues (n ) 5, 6, 7) under the reaction conditions.
In contrast, the Isaacs group has focused on the formation
and interconversion of C-shaped and S-shaped methylene-
bridged glycoluril dimers (e.g., 2S and 2C) in the earliest stages
of the mechanism of CB[n] formation. For this purpose, we
previously prepared S- and C-shaped methylene-bridged gly-
coluril dimers bearing o-xylylene end-groups and CO2Et solu-
bilizing groups (6S and 6C) by dimerization under anhydrous
1
5,16,18
CB[6], and CB[n] analogues.
Despite the successful
synthesis of CB[n] analogues based on our mechanistic reason-
ing derived from studies of solubilized methylene bridged
glycoluril dimers in anhydrous organic solVents we wanted to
assess whether those mechanistic insights carried over to true
CB[n] systems based on unsubstituted glycoluril (1) where
synthesis and study are typically performed under aqueous acidic
conditions.
Isolation of iCB[n] (n ) 6 and 7) Enables Further
Mechanistic Studies. In 2005, the groups of Isaacs and Kim
reported the isolation of two new members of the CB[n]
familysiCB[6] and iCB[7]sthat contain a single inverted
acidic conditions (ClCH2CH2Cl, p-toluenesulfonic acid (PTSA),
reflux).21,23
By product resubmission experiments, we estab-
lished that the C-shaped compounds are thermodynamically
more stable than their S-shaped diastereomers by factors of ca.
4
glycoluril unit (Scheme 4). Similar to 6S and 7S described
9
5:5 (Scheme 2). At the time, this high preference for the
2
4
above, the H-atoms on the convex face of the inverted glycoluril
ring of iCB[6] and iCB[7] point in the opposite direction to
those of the neighboring glycoluril rings. Hence, the iCB[6]
and iCB[7] can be recognized as being the macrocyclic relatives
of the S-shaped methylene bridged glycoluril dimers studied
earlier. Since iCB[6] and iCB[7] are macrocyclic they can be
viewed as containing two S-shaped methylene-bridged glycoluril
dimer subunits. This realization immediately raised several
questions in our mind and presented us with the opportunity to
test the mechanistic conclusions of our model system studies
within the real system. Are iCB[6] and iCB[7] kinetically
controlled intermediates in the synthesis of CB[n]? What are
the stabilities of iCB[6] and iCB[7] relative to CB[6] and
CB[7]? Does the mechanism presented above for the transfor-
mation of (()-7S to (()-7C also apply to the conversion of
iCB[6] to CB[6]?
C-shaped form allowed us to rationalize the high yield (82%)
obtained in the synthesis of CB[6], which contains six inde-
6
pendent C-shaped subunits (e.g., 0.95 ) 74%). It also alerted
us to the possibility of diastereomeric CB[n] where one or more
glycoluril subunits adopt the S-shaped configuration with respect
to the neighboring glycolurils (e.g., iCB[n]).
In the course of these studies we made several observations
that led us to suspect that the S- to C-shaped equilibrium might
be an intramolecular process. To test this hypothesis, we devised
a crossover experiment based on doubly methoxy-labeled
(()-7S. When (()-7S was heated under the anhydrous reaction
conditions we observed the clean transposition of the OMe labels
under the formation of (()-7C. This observation and control
experiments described previously establish the intramolecular
(23) Witt, D.; Lagona, J.; Damkaci, F.; Fettinger, J. C.; Isaacs, L. Org.
Lett. 2000, 2, 755-758. Wu, A.; Chakraborty, A.; Witt, D.; Lagona, J.;
Damkaci, F.; Ofori, M. A.; Chiles, J. K.; Fettinger, J. C.; Isaacs, L. J. Org.
Chem. 2002, 67, 5817-5830.
Inverted CB[n] (n ) 6, 7) Are Kinetic Intermediates in
the Formation of CB[n]. To test whether iCB[n] (n ) 6, 7),
which contain S-shaped fragments similar to 6S above, are
kinetic intermediates in CB[n] synthesis, we performed product
(
24) Buschmann, H.-J.; Fink, H.; Schollmeyer, E. Ger. Offen. DE
1
9603377, 1997 [Chem. Abstr. 1997, 127, 205599].
6842 J. Org. Chem., Vol. 72, No. 18, 2007

iCB[6] to CB[6] Mechanism
2
SCHEME 3. Proposed Mechanism for the Diastereoselective Conversion of S-Shaped (()-7S to C-Shaped (()-7C (R ) CO Et)
C-shaped conversion of our model studies21 under anhydrous
SCHEME 4. Synthesis of iCB[n]
acidic conditions was not valid under the aqueous acidic
CB[n]-forming reaction conditions. To determine whether this
discrepancy was due to the change from anhydrous to aqueous
acidic conditions or the presence of the CO2Et solubilizing or
o-xylylene capping groups of our model compounds (6S and
6
C) we performed the transformation of iCB[6] to CB[n] in
anhydrous MeSO3H and also in mixtures of concd HCl and
2
6
MeSO3H (Figure 1). Interestingly, when anhydrous MeSO3H
was used as the solvent CB[6] was the only product. No CB[5]
or CB[7]sthat would be the products of ring contraction or
ring expansionswas observed under anhydrous acidic condi-
tions. When mixtures of concd HCl and MeSO3H were used as
solvent a smooth transition between these two extreme situationss
ring contraction versus retention of ring sizeswas observed
SCHEME 5. Conversion of iCB[6] to CB[n] under Acidic
Conditions
(Figure 1). This result strongly suggestedsbut did not proves
that the conversion of iCB[6] to CB[6] under anhydrous acidic
conditions was an intramolecular process analogous to that
observed for model system 7S and 7C (Scheme 3).
resubmission experiments (Scheme 5). When iCB[6] and
iCB[7] were separately heated in concentrated HCl complete
consumption of iCB[n] starting material was observed with the
formation of CB[n]. Inverted CB[6] yields a 24:13:1 mixture
of CB[5], CB[6], and CB[7] whereas iCB[7] yields a 4:1 mixture
of CB[6] and CB[7]. This result establishes that iCB[6] and
iCB[7] are kinetic intermediates in the formation of CB[n] and
that iCB[6] and iCB[7] are significantly less stable than CB[n]
Mechanistic Extremes in the Transformation of iCB[6]
to CB[6]. On the basis of the previously published mechanistic
3
,21,22
studies in the CB[n] area
we can postulate the presence of two mechanistic extremes
aqueous versus anhydrous) in the conversion of iCB[6] into
and the results described above
(
CB[n] (Scheme 6; blue: aqueous pathway; light blue: some
H2O present; green: anhydrous pathway). In both extremes, the
initial steps in the proposed mechanism are similar, namely
protonation of iCB[6] followed by bond cleavage to yield
iminium ion 11. Under anhydrous acidic conditions, iminium
ion 11 is forced to react with an internal (e.g., intramolecular)
nucleophilesnamely the ureidyl N-atomsto yield spirocyclic
N-acyl ammonium ion 12. Spiro-intermediate 12 may then
undergo cleavage in the opposite direction followed by ring
(
n ) 5-7). Although our model system studies suggest that
-1
-1
iCB[6] and iCB[7] should be ca. 4 kcal mol (2 × 2 kcal mol /
S-shaped fragment) less stable than the corresponding CB[n],
1
the sensitivity of our H NMR only allows us to provide a lower
estimate on the difference in stability between CB[n] and
-
1
iCB[n] (g98:2, ∆G g 2.8 kcal mol ). An interesting aspect
of this set of experiments under aqueous acidic conditions was
the propensity for ring contraction concomitant with the
transformation of iCB[n] to CB[n], that is, iCB[6] yields mainly
CB[5] whereas iCB[7] yields mainly CB[6]. This observation
requires the extrusion of one glycoluril unitsmost likely the
inverted glycoluril unitsand dictates the cleavage of four
adjacent N-CH2 bonds.25
The Presence of H2O Influences the Size Distribution
Obtained in the Conversion of iCB[6] to CB[n]. The
observation described abovesthe preference for ring contraction
of iCB[6] and iCB[7] to CB[5] and CB[6], respectivelys
suggested that the intramolecular nature of the S-shaped to
(
25) To conclusively establish that the inverted glycoluril unit is extruded
3
FIGURE 1. Influence of the composition of the concd HCl/MeSO H
solvent system on the distribution of CB[n] obtained from iCB[6].
Key: CB[6], 9; CB[7], [; CB[5], B.
would require the availability of iCB[6] specifically isotopically labeled
on the inverted glycoluril unit. Unfortunately, the statistical synthesis process
makes such a compound inaccessible.
J. Org. Chem, Vol. 72, No. 18, 2007 6843

Liu et al.
SCHEME 6. Mechanistic Possibilities for the Transformation of iCB[6] to CB[6] under Acidic Conditionsa
a
Color code: green equilibria, anhydrous conditions; light blue equilibria, some water present; blue equilibria, high concentrations of water.
5
) is also able to insert a glycoluril unit to undergo ring
27
expansion. When the concentration of H2O is low, intermediate
4 can be transformed into 16 by a repetition of steps 1-3.
1
Interestingly, intermediate 16 can be redrawn in a manner that
makes it clear that it is now poised to undergo a series of
intramolecular ring closures (via 17) to yield CB[6].28
The data presented in Figure 1 suggest that the [H2O] controls
which of the three pathways dominates under a given set of
conditions. It is tempting to suggest that the pathway via
M o¨ bius-intermediate 13 must operate to the exclusion of the
water-mediated pathways in MeSO3H. Unfortunately, all
CB[n] compounds are quite hygroscopic and removal of residual
H2O from samples of iCB[6]sand similarly from MeSO3Hsis
impractical. Hence, it is possible that small amounts of H2O
are present even under anhydrous conditions. To address
whether small quantities of adventious waterseither from
solvent or iCB[6]smight influence the mechanistic pathway
followed during the reaction, we followed the conversion of
FIGURE 2. Cross-eyed stereoview of the PM3 minimized geometry
of M o¨ bius CB[6] (13).
closure to yield 13. Intermediate 13 is quite unusual in that it
has the connectivity of a M o¨ bius strip. Although 13 may appear
to be a prohibitively high energy intermediate, PM3 calculations
-1
suggest that 13 (Figure 2) is only 7.1 kcal mol higher in energy
than iCB[6]. Repetition of the protonation, cleavage, intramo-
lecular N-atom capture, cleavage, and ring closure processes
(analogous to Scheme 3) is then capable of producing CB[6]
1
iCB[6] to CB[6] by H NMR as a function of [iCB[6]] both
by a completely intramolecular process with no possibility for
either ring contraction or ring expansion. Under aqueous acidic
conditions, iminium ion 11 can undergo intramolecular N-atom
capture to yield 12 followed by addition of H2O to yield 14.
When the concentration of H2O is high (e.g., concd HCl) we
believe the dominant pathway leads to intermediate 15 by a
process of multiple N-CH2 bond cleavage events mediated by
water. Intermediate 15 (n ) 4 or 5) may then undergo ring
closure to yield CB[5] or CB[6]. The small but reproducible
amount of CB[7] observed suggests that intermediate 15 (n )
without and with (2% v:v) added water (Figure 3). As can be
readily seen, changing the concentration of iCB[6] by 50-fold
has only a small effect on the relative rate of conversion to
CB[6], which strongly suggests that the transformation of
iCB[6] to CB[6] is a first-order process. Similarly, the presence
of small amounts of water (2% v:v) does not significantly
(27) We have attempted to insert functionalized glycolurils or glycoluril
cyclic ethers via a ring expansion process but were not able to isolate a
single pure compound from these reactions. We believe that differential
reactivity between 1 and functionalized glycolurils as well as stoichiometric
imbalance between glycoluril and formaldehyde is responsible.
(28) Intermediate 16 is C2 symmetric and chiral. A related intermediate
with Cs symmetry is also possible (Supporting Information) that leads to
CB[6] in an analogous manner.
(26) These experiments were performed with iCB[6] rather than iCB[7]
because of its much greater abundance in the crude CB[n] forming reaction
mixture and also its far greater ease of purification.
6844 J. Org. Chem., Vol. 72, No. 18, 2007

iCB[6] to CB[6] Mechanism
2
FIGURE 3. Influence of the concentration of iCB[6] and H O on the
rate of transformation of iCB[6] to CB[6] in MeSO
3
H at 85 °C. Key:
iCB[6]] ) 20 mM, B; [iCB[6]] ) 2 mM, 9; [iCB[6]] ) 0.4 mM, [;
iCB[6]] ) 2 mM, 2% H O, 0; [iCB[6]] ) 0.4 mM, 2% H O, ].
[
[
2
2
FIGURE 5. ES-MS spectra collected for(a) iCB[6]‚18, (b) 13C12-iCB-
1
3
[
(
6]‚18, (c) an equimolar mixture of iCB[6]‚18 and
C
12-iCB[6]‚18,
12-CB[6] obtained from the reaction of
12-iCB[6] in MeSO H as their complexes with 18, and
12-CB[6], and partially labeled
13
d) a mixture of CB[6] and C
13
iCB[6] and
C
3
e) a mixture of CB[6], 13
C
13
C
<12-CB-
(
[
13
6] obtained from the reaction of iCB[6] and
C12-iCB[6] in concd
HCl as their complexes with 18.
to obtain 13C2-glycoluril ( C2-1). Compound 13C2-1 was then
13
reacted with formaldehyde in HCl to yield a mixture of fully
1
1
3
3
C-labeled CB[n] and iCB[n] from which we isolated
13
1
C12-CB[6] and C12-iCB[6]. Figure 4 shows the H NMR
1
3
spectra recorded for iCB[6] and C12-iCB[6]. As expected the
resonances for the methine protons on the equator of
1
3
C12-iCB[6] are split (Ha, triplet; Hb and Hc, doublet of triplets)
3
due to two equivalent JC-H couplings. The magnitude of these
3
FIGURE 4. (a) Cross-eyed stereoview of the X-ray crystal structure
coupling constants ( JC-H ) 2.1-2.4 Hz) is consistent with the
1
13
of iCB[6] and H NMR spectra (400 MHz, 20% DCl/D
2
O, rt) for (b)
H-C-N- C dihedral angles (112-127°) observed in the
1
3
iCB[6] and (c)
C12-iCB[6].
X-ray structure of iCB[6]. Similarly, the doublet of triplets
3
observed for Hi and Hk ( JC-H ) 4.7-5.0 Hz) is consistent with
change the relative rate of the iCB[6] to CB[6] conversion,
which suggests that the interconversion of iCB[6] to CB[6]
proceeds via M o¨ bius intermediate 13 under anhydrous
conditions.
13
the range of H-C-N- C dihedral angles (125-142°) to the
13
CdO group on the two flanking glycoluril rings. More
interesting is the doublet of doublets observed for the methylene
proton Hg connected to the inverted glycoluril ring. In this case,
1
3
13
C12-iCB[6] and iCB[6] Do Not Undergo Crossover
there are two H-C-N- C dihedral angle ranges (145-159°
During the Transformation to 13C12-CB[6] and CB[6] in
MeSO3H. Although the experiments described above clearly
suggest the mechanism of the transformation of iCB[6] to
CB[6] is an intramolecular process under anhydrous acidic
conditions and involves intermolecular (e.g., ring contraction
or expansion) under aqueous acidic conditions we did not regard
that as sufficient proof. Accordingly, we set out to prepare a
labeled version of iCB[6] with the goal of transforming a
mixture of labeled iCB[6] and iCB[6] into labeled CB[6] and
CB[6] to observe whether any scrambling of the label occurs.
For this purpose we chose to react 13C-labeled urea with glyoxal
and 84-96°) resulting in one modest ( JC-H ) 6.5 Hz) and
3
3
2
one very small value of JC-H which in addition to the JHCH )
14.0 Hz for the diastereotopic CH2-group results in the observed
doublet of doublets.
Once we had prepared and characterized 13C12-iCB[6] we set
out to perform crossover experiments by transforming a mixture
of iCB[6] and C12-iCB[6] into labeled CB[n] under either
anhydrous or aqueous acidic conditions. Spectra a and b of
Figure 5 show the electrospray mass spectra obtained for
1
3
1
3
iCB[6]‚18 (hexanediammonium ion, 18) and C12-iCB[6]‚18
which show parent ions at m/z 557.24 and 563.27, respectively,
J. Org. Chem, Vol. 72, No. 18, 2007 6845

Liu et al.
for their doubly charged cations. We measure the electrospray
mass spectra in the presence of 18 to avoid the possibility of
stability relative to CB[n] (n > 8) due to reduced ring strain.
(3) The larger iCB[n] and iCB[n] containing multiple (func-
+
+
interaction with adventitious alkali metal cations (Li , Na , or
tionalized) inverted glycoluril units may be best accessed by
+
15,16,18
K ) which would distort the results of the crossover experi-
using a building block approach
oligomers
that employs preformed
ment.29 As a control experiment we measured the electrospray
mass spectrum of a physical mixture (equimolar) of iCB[6]‚18
and 13C12-iCB[6]‚18 (Figure 5c). We next heated an equimolar
16,18
containing S-shaped subunits. The use of low
temperatures and acidic solvents containing no or only small
amounts of H2Oswhich preserve ring size during the reactions
is predicted to be particularly suitable. The enhanced under-
standing of the mechanism of CB[n] formation described herein
suggests routes toward tailor-made CB[n] compounds, which
promises to broaden the range of applications to which the
CB[n] family may be applied.
1
3
mixture of iCB[6] and C12-iCB[6] in either anhydrous
MeSO3H or concd HCl and obtained the electrospray mass
spectra shown in Figure 5, spectra d and e. In anhydrous
MeSO3H, no crossover products (e.g., 13C<12-CB[6]‚18) were
observed, which conclusively established the intramolecular
nature of the transformation in this solvent. In contrast when
the solvent was concd HCl, a substantial amount of crossover
product ( C<12-CB[6]) was observed. This observation estab-
lishes that iCB[6] ejects glycoluril units into solution and
reincorporates those glycoluril units during the transformation
into CB[6]. Under aqueous acidic conditions, the pathway that
proceeds via intermediate 14 is operative whereas under
anhydrous acidic conditions the pathway that proceeds via
M o¨ bius intermediate 13 is dominant.
Experimental Section
13
Preparation of 13C
-glycoluril ( C
13
-1). To a solution of
2
2
13
H
4
(
2
N CONH
0% aq solution of glyoxal (4.6 g, 31.7 mmol) and concd HCl
0.6 mL). The resulting solution was heated at ca. 85-90 °C until
2
(5.0 g, 81.9 mmol) in water (10 mL) was added a
a heavy precipitate had formed. The reaction mixture was allowed
to cool to room temperature and filtered. The filter cake was washed
with water (10 mL) and then acetone. The resulting white solid
1
3
was dried under high vacuum to yield
(
C
2
-1 as a white solid
6
1
3.50 g, 78%). H NMR (400 MHz, DMSO-d ) δ 7.14 (d, J ) 2.4,
Conclusions
4
6
H), 5.20 (t, J ) 2.9, 2H). 13C (100 MHz, DMSO-d
6
) δ 162.1,
+
5.4. MS (FAB, glycerol) m/z 145 ([M + H] ).
In summary, we have shown that diastereomeric iCB[6] and
iCB[7] form as kinetic intermediates during CB[n] formation.
Product resubmission experiments establish that iCB[n] are less
Preparation of 13
C12-CB[6] and
13
C
12-iCB[6]. 13C
-1 (3.44 g,
2
23.9 mmol) and powdered paraformaldehyde (1.50 g, 47.8 mmol)
were thoroughly mixed. To this mixture was added concd HCl
4.0 mL) while the mixture was stirred rapidly. Gelation was
-
1
stable than CB[n] by more than 2.8 kcal mol . Interestingly,
the transformation of iCB[6] and iCB[7] into CB[n] under
aqueous acidic conditions occurs with substantial amounts of
ring contraction. In contrast, under anhydrous acidic conditions
(
observed in 2 min. The mixture was then heated to 100 °C for 6 h.
After cooling to rt, the reaction mixture was poured into MeOH
(80 mL) under stirring. The precipitate was collected by centrifuga-
tion and dried under high vacuum. 13
C
10-CB[5] and
13
C14-CB[7]
iCB[6] is cleanly transformed into CB[6]. No crossover products
were observed when mixtures of iCB[6] and 13C12-iCB[6] were
were removed from the mixture by washing with water three times
1
3
(
3 × 50 mL).
C16-CB[8] was removed as an insoluble solid by
used, which establishes that this conversion is an intramolecular
process. An unusual diastereomeric CB[6] with a M o¨ bius
geometry (13) is proposed as a critical intermediate in the
mechanism of intramolecular conversion of iCB[6] to CB[6]
under anhydrous acidic conditions. These studies shed light on
the fate of one of the final kinetically controlled intermediates
in the formation of CB[n].
partially dissolving the mixture with 3 M HCl (60 mL). After the
filtrate was concentrated (20 mL) it was poured into MeOH
(
120 mL) and the solid was isolated by filtration. 13
C
12-CB[6] was
obtained by recrystallization from concentrated HCl (1.50 g, 35%).
13
13
Fractions containing mixtures of
C12-CB[6] and C12-iCB[6] were
collected and then purified by ion exchange chromatography
(Dowex 50WX2). A mixture of 13C -CB[6] and 13C -iCB[6]
1
2
12
Although we previously reached conclusions about the
mechanism of the earliest steps in the formation of CB[n] (e.g.,
thermodynamics and mechanism of the 2S to 2C conversion)
based on o-xylylene capped methylene-bridged glycoluril dimers
bearing solubilizing CO2Et groups, the applicability of those
conclusions to systems based on unsubstituted glycoluril 1 was
questionable. The elucidation of the mechanism of one of the
final steps in CB[n] formation, namely, the iCB[6] to CB[n]
conversion described heresbased on and in complete accord
with the predictions from the model studiessfurther reinforces
the value and relevance of model studies in the CB[n] area.
That enhanced confidence allows us to make a series of
predictions: (1) Despite the thermodynamic instability of
iCB[n] relative to CB[n], the iCB[n] have good kinetic stability.
This kinetic stability suggests that inverted CB[n] compounds
containing two or more inverted glycoluril rings will be
accessible. (2) Although iCB[6] and iCB[7] are less stable than
the diastereomeric CB[6] and CB[7] we believe that larger
iCB[n] (e.g., n > 8) may exhibit enhanced thermodynamic
2
(0.80 g) was dissolved in H O/88% formic acid (1:1, 15 mL). The
column was eluted with 0.4 M HCl/88% formic acid (1:1). After
1
monitoring the collected fractions by H NMR, fractions were
1
3
combined and dried under high vacuum overnight to give
12
C -
iCB[6] (32 mg, 1%) as a white solid. 13
C
12-CB[6]: H NMR
1
(
1
400 MHz, 20% DCl/D
2
O) δ 5.38 (s, 12H), 5.34 (d, J ) 15.6 Hz,
13
2H), 4.15 (dt, J ) 15.6, 3 Hz, 12H). C (400 MHz, 20% DCl/
2+
D
2
O) δ 155.1, 68.9 (m), 50.3 (m). ES-MS 505 (M + 2H) .
13
12-iCB[6]: 1H NMR (400 MHz, 20% DCl/D
2
O) δ 5.59 (dt, J )
C
8.6, 2.3 Hz, 2H), 5.48 (dt, J ) 8.6, 2.3 Hz, 2H), 5.45-5.35 (m,
14H), 5.18 (d, J ) 13.9 Hz, 4H), 4.75 (t, J ) 2.1 Hz, 2H), 4.35
(dd, J ) 14.0, 6.5 Hz, 4H), 4.28 (dt, J ) 15.7, 5.0 Hz, 4H), 4.17
(
1
5
dt, J ) 15.6, 4.7 Hz, 4H). 13C (400 MHz, 20% DCl/D
2
O) δ 155.2,
55.1, 154.7, 154.6, 70-67 (m), 62-60 (m), 52-49 (m). ES-MS
05 (M + 2H)2
Transformation of iCB[6] to CB[6] in a Mixture of MeSO
and Concentrated HCl. A solution of iCB[6] (20 mg) in the
indicated v:v mixture of MeSO H and 37% HCl (0.6 mL) was
heated at 85 °C for 4 h. The solution was pipetted into methanol
10 mL). The precipitate was collected by centrifugation and dried
+
.
3
H
3
(
under high vacuum overnight to give a mixture of the various
CB[n] compounds (17.4-18.4 mg, 87-92%). The distribution of
the various CB[n] compounds was obtained by careful integration
29) The isotope pattern for 13C12-iCB[6] is somewhat irregular, but
(
1
of the H NMR spectrum of the mixture obtained with 20% DCl/
reproducibly so, in that the peak intensities oscillate. We do not understand
the cause of this effect.
2
D O as the solvent.
6846 J. Org. Chem., Vol. 72, No. 18, 2007

iCB[6] to CB[6] Mechanism
Concentration Effect on the Transformation of iCB[6] to
13C12-iCB[6] (10 mg) in 37% HCl (0.6 mL) was heated at 85 °C
for 4 h. The solution was pipetted into methanol (10 mL). The
precipitate was collected by centrifugation and dried under high
CB[6]. A solution of iCB[6] in MeSO
3 3
H (0.6 mL) or MeSO H/
H
2
O (98:2 v:v, 0.6 mL) was heated at 85 °C. After the indicated
time, the reaction was pipetted into MeOH to yield a precipitate,
the precipitate was isolated by centrifugation, and the crude solid
was dried under high vacuum. The content of iCB[6] and CB[6]
vacuum overnight to give a mixture of partially labeled
13Ce12-CB[6] (17.2 mg, 86%) as established by analysis of the
electrospray mass spectrum.
1
was monitored by careful integration of the H NMR spectrum
(
H
a
singlet versus the 4.5-4.1 ppm region) obtained with 20%
DCl/D O as the solvent.
Transformation of a Mixture of iCB[6] and 13C12-iCB[6]
Acknowledgment. L.I. thanks the National Science Founda-
tion (CHE-0615049), Maryland TEDCO, and ACS-PRF (PRF-
45228-AC4) for financial support. K.K. thanks the Creative
Research Initiatives and BK21 programs for financial support.
We all thank Dr. Young Ho Ko and Dr. N. Selvapalam for
helpful suggestions.
2
13
into CB[6] and
(
C12-CB[6] in MeSO
3
H. A solution of iCB[6]
H (0.6 mL) was
10 mg) and 13C12-iCB[6] (10 mg) in MeSO
3
heated at 85 °C for 4 h. The solution was pipetted into me-
thanol (10 mL). The precipitate was collected by centrifuga-
tion and dried under high vacuum overnight to give CB[6]
and 13
ficant crossover (e.g.,
C12-CB[6] (18.2 mg, 91%) as a pale brown solid. No signi-
Supporting Information Available: Synthetic procedures and
characterization data for new compounds and crystallographic
information file (CIF) for iCB[6]. This material is available free
of charge via the Internet at http://pubs.acs.org.
13
C
<12-CB[6]) products were observed by
electrospray mass spectrometric analysis of the reaction
mixture.
Intermolecular Isomerization of a Mixture of iCB[6] and
13C
12-iCB[6] in 37% HCl. A solution of iCB[6] (10 mg) and
JO071034T
J. Org. Chem, Vol. 72, No. 18, 2007 6847