Reasons why aldehydes do not generally participate in cucurbit[ n ]uril forming reactions

Article abstract of DOI:10.1021/jo100186q

The reaction of substituted glycolurils or a glycoluril dimer with a dialdehyde (o-phthalaldehyde) delivers S-shaped dimers and an S-shaped tetramer selectively. A combination of X-ray crystallography, PM3 calculations, and product resubmission experiments establish that the S-shaped isomers are thermodynamically more stable than the C-shaped diastereomers which we attribute to the conformational preferences of the newly formed benzo bicyclo[3.3.2]decane ring system. The preferential formation of S-shaped subunits is one reason why o-phthalaldehyde and possibly other aldehydes do not usually participate in CB[n] forming reactions. We also present evidence that points toward an equilibrium between glycoluril monomer + phthalaldehyde and S-shaped dimer + water that responds to concentration over the 1-50 mM range. This result suggests a second reason, insufficient reactivity (e.g., low equilibrium constant), why o-phthalaldehyde and possibly other aldehydes do not participate in CB[n] forming reactions. Delineation of the reasons why some aldehydes fail in these reactions is the first step toward devising methods to overcome these limitations.

Full text of DOI:10.1021/jo100186q

pubs.acs.org/joc
Reasons Why Aldehydes Do Not Generally Participate in Cucurbit[n]uril
Forming Reactions
†
Da Ma, Zuzana Gargulakova, Peter Y. Zavalij, Vladimir Sindelar,* and Lyle Isaacs*
‡
†
,‡
,†
†
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, and
Department of Chemistry, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic
‡
lisaacs@umd.edu; sindelar@chemi.muni.cz
Received February 3, 2010
The reaction of substituted glycolurils or a glycoluril dimer with a dialdehyde (o-phthalaldehyde)
delivers S-shaped dimers and an S-shaped tetramer selectively. A combination of X-ray crystal-
lography, PM3 calculations, and product resubmission experiments establish that the S-shaped
isomers are thermodynamically more stable than the C-shaped diastereomers which we attribute to
the conformational preferences of the newly formed benzo bicyclo[3.3.2]decane ring system. The
preferential formation of S-shaped subunits is one reason why o-phthalaldehyde and possibly other
aldehydes do not usually participate in CB[n] forming reactions. We also present evidence that points
toward an equilibrium between glycoluril monomer þ phthalaldehyde and S-shaped dimer þ water
that responds to concentration over the 1-50 mM range. This result suggests a second reason,
insufficient reactivity (e.g., low equilibrium constant), why o-phthalaldehyde and possibly other
aldehydes do not participate in CB[n] forming reactions. Delineation of the reasons why some
aldehydes fail in these reactions is the first step toward devising methods to overcome these
limitations.
4
Introduction
between certain acetylenes and azides. Around the turn of the
millenium, the groups of Kim and Day reported that the
condensation of glycoluril (1 equiv, generally >1 M) with
formaldehyde (2 equiv) under milder conditions (e.g., conc
HCl, 100 °C) results in the formation of a homologous series of
In 1981 Mock and co-workers disclosed that the condensa-
tion reaction of glycoluril (1 ) with formaldehyde under
strongly acidic conditions delivers cucurbit[6]uril (CB[6]) in
H
1
high yield (Scheme 1). In a series of elegant papers throughout
5,6
cucurbit[n]uril (CB[n]; n = 5, 6, 7, 8, 10) hosts. In the inter-
vening years, the supramolecular chemistry of the larger CB[n]
homologues (CB[7] and CB[8]) have been shown to be parti-
cularly exciting with applications ranging from molecular
machines, chemical sensors, solid phases for sequestration
the 1980s, Mock established that CB[6] is a truly remarkable
host with the ability to bind to alkaneammonium ions with
2
high affinity and selectivity, to act as a bead in a pH-switchable
3
molecular shuttle, and even to accelerate the click reaction
7-9
and chromatography, and drug delivery vehicles.
(
1) Freeman, W. A.; Mock, W. L.; Shih, N.-Y. J. Am. Chem. Soc. 1981,
03, 7367–7368.
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1
(
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511.
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1
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934 J. Org. Chem. 2010, 75, 2934–2941
Published on Web 03/26/2010
DOI: 10.1021/jo100186q
r 2010 American Chemical Society

Ma et al.
JOCArticle
14
SCHEME 1. Synthesis of CB[n]
1H and 1Ph resulted in the formation of Ph CB[6]. Other
2
16,17
research groups have developed building block strategies
based on condensation between glycoluril monomers and
13
glycoluril oligomers. For example, the group of Tao demon-
strated that the condensation between glycoluril dimer 2C and
13
bis(cyclic ether) 1MeBCE yields Me CB[6] (Scheme 2c). Per-
4
haps the most useful method for the synthesis of CB[n]
derivatives involves the direct functionalization of preformed
CB[n] (n = 5, 6). For example, Kim’s group has described the
perhydroxylation of CB[n] (n= 5, 6) to yield (HO) CB[n] (n=
2
n
1
8
As a result of these exciting recognition properties, a
number of groups have been interested in the synthesis of
CB[n] derivatives with new structures and tailor-made prop-
erties (e.g., enhanced solubility). For this purpose, a number
of synthetic strategies have been investigated (Scheme 2).
For example, the condensation reaction between a few sub-
5, 6) that is amenable to further functionalization reactions
(Scheme 2d), which allows the properties of CB[6] derivatives
8
to be tailored toward specific applications.
All of the methods described above involve the use of
glycoluril derivatives or the functionalization of the convex
face of the glycoluril ring system. Is it possible to expand the
scope of the CB[n] forming reaction beyond formaldehyde?
Although this question has been posed and attempted ex-
perimentally by several researchers, the reasons behind the
failure of such synthetic routes have remained unclear to
date. Here we address this question and delineate two of the
reasons why aldehydes do not generally participate in CB[n]
forming reactions.
stituted glycolurils (1 ) and formaldehyde was shown to
R
1
0,11
give R CB[5] and R CB[6] compounds (Scheme 2a).
1
0
12
Cy CB[5] and Cy CB[6] have enhanced solubility in organic
5
6
solvents and can be used in the formation of ion-selective
1
1
8
electrodes. Unfortunately, the self-condensation of a single
glycoluril derivative (e.g., 1Me) does not yield any substituted
CB[7] or CB[8], presumably due to steric interactions bet-
ween substituents that increase as the size of the ring
1
2
increases. To address this concern a number of researchers
have performed the condensation between two different
glycolurils and have been able to isolate partially substituted
Results and Discussion
This section is organized as follows. First, we present a
summary of a portion of the mechanism of CB[n] formation
proceeding via oligomers 2-6 that is relevant to the use of
aldehydes in CB[n] forming reactions. Next, we present the
unsuccessful attempts to react glycolurils with monoaldehydes
followed by the successful synthesis of several S-shaped glyco-
luril dimers from glycolurils and o-phthalaldehyde. We use the
results of these experiments along with product resubmission
experiments to explain why aldehydes do not generally parti-
cipate in CB[n] forming reactions.
1
2-15
CB[n] (Scheme 2b).
For example, the condensation of
(
7) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew.
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Chakrabarti, S.; Mukhopadhyay, P.; Lin, S.; Isaacs, L. Org. Lett. 2007, 9,
Mechanism of CB[n] Formation. The Isaacs group has been
heavily involved in the elucidation of the mechanism of
1
6,19-21
CB[n] formation.
This section presents an overview
of portions of the mechanism of CB[n] formation (Scheme 3)
that are relevant to our discussion of the use of aldehydes in
CB[n] forming reactions. Initially, glycoluril 1H undergoes
condensation with formaldehyde to yield a mixture of C-shaped
and S-shaped glycoluril dimers (2C and 2S). Diastereomers
2C and 2S differ in the relative orientation of the pairs of
methine H-atoms on the convex face of each equivalent of
glycoluril. Previously, we studied the equilibrium between
the C-shaped and S-shaped forms using end-capped deriva-
tives of 1COOEt and established a large (>95:5) thermo-
2
6
349–2352. Hennig, A.; Bakirci, H.; Nau, W. M. Nat. Methods 2007, 4, 629–
32. Lee, J. W.; Hwang, I.; Jeon, W. S.; Ko, Y. H.; Sakamoto, S.; Yamaguchi,
K.; Kim, K. Chem.;Asian J. 2008, 3, 1277–1283. Montes-Navajas, P.;
Baumes, L. A.; Corma, A.; Garcia, H. Tetrahedron Lett. 2009, 50, 2301–
2
304. Nagarajan, E. R.; Oh, D. H.; Selvapalam, N.; Ko, Y. H.; Park, K. M.;
Kim, K. Tetrahedron Lett. 2006, 47, 2073–2075. Praetorius, A.; Bailey,
D. M.; Schwarzlose, T.; Nau, W. M. Org. Lett. 2008, 10, 4089–4092.
Sindelar, V.; Silvi, S.; Kaifer, A. E. Chem. Commun. 2006, 2185–2187.
Sindelar, V.; Silvi, S.; Parker, S. E.; Sobransingh, D.; Kaifer, A. E. Adv.
Funct. Mater. 2007, 17, 694–701. Sun, S.; Zhang, R.; Andersson, S.; Pan, J.;
Zou, D.; Akermark, B.; Sun, L. J. Phys. Chem. B 2007, 111, 13357–13363.
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1
9
1
989–1991. Hwang, I.; Ziganshina, A. Y.; Ko, Y.-H.; Yun, G.; Kim, K.
dynamic preference for the C-shaped form. Subsequently,
the 2C may grow to yield trimer (3), tetramer (4), pentamer (5),
hexamer (6), and higher oligomers by the stepwise addition
Chem. Commun. 2009, 416–418. Park, K. M.; Suh, K.; Jung, H.; Lee, D.-W.;
Ahn, Y.; Kim, J.; Baek, K.; Kim, K. Chem. Commun. 2009, 71–73. Tuncel,
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2
2
(8) Kim, K.; Selvapalam, N.; Ko, Y. H.; Park, K. M.; Kim, D.; Kim, J.
of 1H. When the oligomer is long enough (e.g., 5 or 6),
addition of 1 equiv of formaldehyde yields nor-seco-CB[n],
Chem. Soc. Rev. 2007, 36, 267–279.
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10392.
(
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8446–8454.
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(
009, 113, 11054–11057.
2
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SCHEME 2. Synthesis of Substituted CB[6] Compounds
SCHEME 3. Portion of the Mechanism of CB[n] Formation
SCHEME 4. Possible Products from Condensation of 7 and an Aldehyde
which then goes on to yield CB[n] by addition of a final
equivalent of formaldehyde. The Isaacs group has pre-
viously isolated ns-CB[6] and demonstrated its conversion
Day has demonstrated by product resubmission experi-
ments that the final conversion to CB[6] is an irreversible
5
step and is indicted as such in Scheme 3. Another fact worth
2
3
to CB[6] by product resubmission experiments. It is also
possible for oligomers (e.g., 3 or 5) to condense by a step-
growth process (not shown) to yield nor-seco-CB[n] with
double cavity (bis-ns-CB[10]) or even chiral ((()-ns-CB[6])
noting is that CB[n] formation is a condensation reaction
and that one molecule of H O is produced (highlighted in
2
aqua) for each molecule of CH O that is consumed. Two
2
factors that are critical in the successful formation of CB[6]
from 1 and CH O are (1) that the equilibrium between 1 þ
2
4
structures. Please note that in the depicted mechanism
H
2
H
2
5
(Scheme 3) oligomers 2-6 are connected by equilibrium
CH O and 2S/ 2C þ H O favors the dimers and (2) that the
2
2
arrows that reflect the reversibility of these steps. At this
time no quantitative information is available regarding the
equilibrium constants for any of these steps. In contrast,
equilibrium between S-shaped (e.g., 2S) and C-shaped (e.g.,
2
C) diastereomers greatly favors the C-shaped forms.
Reactions between Capped Glycoluril 7 and Some Alde-
hydes Do Not Yield Dimeric Products. As described above it
is critical that the equilibrium between 1H þ formaldehyde
(
formed, but as demonstrated for 2C and 2S the equilibrium favors the all
C-shaped form, which is conducive to macrocyclization.
22) At each step along the way (e.g., 3-6) S-shaped diastereomers can be
and 2C/2S þ H O favors products for a successful CB[n]
2
(23) Huang, W.-H.; Zavalij, P. Y.; Isaacs, L. Org. Lett. 2008, 10, 2577–
580.
forming reaction. We wondered whether this fundamental
2
(24) Huang, W.-H.; Liu, S.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc.
006, 128, 14744–14745. Huang, W.-H.; Zavalij, P. Y.; Isaacs, L. Angew.
2
Chem., Int. Ed. 2007, 46, 7425–7427.
(25) By analogy it is important that the equilibrium also favors the
formation of oligomers 3- 6 from shorter oligomers.
2
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Ma et al.
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SCHEME 5. Reactions between 7 and (a) Benzaldehyde and
SCHEME 6. Synthesis of 10
(
b) Butanal
would favor the formation of dimer as a consequence of Le
Chatelier’s principle. Unfortunately, similar to the reactions
in HCl as solvent we did not observe the formation of any
dimeric products. In many of the reactions between 7 and 8Ph
we observed the formation of hydantoin side product SP1 in
low yield (Scheme 5a). This result is consistent with the
known tendency of glycolurils to undergo transformation
step of the mechanism of CB[n] formation would still favor
products when aldehydes are used instead of formaldehyde.
To address this question we decided to use capped glycoluril
derivative 7 in place of 1H to limit the complexity of the
2
6,29
into hydantoins
followed by condensation with 8Ph.
2
6-28
Similar attempted dimerization reactions were conducted
between 7 and acetaldehyde (8Me), pivaldehyde (8t-Bu), and
acrolein (8CHdCH2) (Supporting Information, Figures
reaction to the formation of dimers.
Scheme 4 shows the
theoretical reaction between 7 and an aldehyde to yield
dimers comprising 2 equiv of 7 and 2 equiv of aldehyde.
Similar to the condensation of 1H and formaldehyde
described above (Scheme 3), there are two sets of diastereo-
mers (C-shaped, 9a-9c and S-shaped, 9d- 9e) that differ in
the orientation of the H-atoms on the convex face of the
glycoluril ring system. In addition, the use of an aldehyde
generates two new stereogenic centers each of which could
conceivably adopt two possible configurations. In total, five
possible diastereomers could be formed (Scheme 4).
1
S20-S22). In these cases H NMR showed the loss of the
resonances due to the starting aldehyde, but no resonances
that could be attributed to dimer 9 were observed.
We also conducted the reaction between 7 (1 M) and 8Pr
(
1 M) in TFA at 50 °C (Scheme 5b). Once again, we did not
observe the formation of dimer, but in this case we were able
to isolate (()-SP2 in 67% yield (Supporting Information,
Figure S23). Compound (()-SP2 is an N-acyl enamine
that forms from 1 equiv of 7 and 2 equiv of 8 . We believe
3
0
First, we investigated the reaction between 7 (100 mM)
and benzaldehyde (8 , 100 mM) in conc DCl at 70 °C.
Pr
that (()-SP2 probably forms results from intramolecular
enamine-iminium ion condensation of intermediate I. The
isolation of (()-SP2 provides strong evidence that aldehydes
do react with glycoluril NH groups under acidic conditions
but that other factors may divert the reaction away from the
formation of methylene bridged glycoluril dimers that are
required for CB[n] formation.
Ph
1
Analysis of the H NMR spectrum of the crude reaction
mixture showed consumption of starting materials 7 and 8Ph,
but resonances corresponding to the formation of 9 were not
observed (Supporting Information, Figure S14). On the
basis of this result we surmised that benzaldehyde and 7
are not sufficiently reactive (e.g., starting materials are favored
under normal concentrations) and that eventually 7 and 8Ph
undergo decomposition reactions instead. To be certain that
this observation was not due to the particular experimental
conditions, we conducted several additional sets of experi-
ments. In one set of experiments we varied the concentra-
tions of 7 and 8Ph (1 mM to 1 M) and still did not observe any
Reaction between ns-CB[6] and Phthaldehyde. Our lack of
success in the reactions described in the previous section was
somewhat surprising to us given that we previously reported
that the reaction between ns-CB[6] and o-phthaldehyde (11)
2
3
delivers CB[6] derivative 10 (Scheme 6). Compound 10 is
somewhat unusual in that it contains an N-C-O-C-N
bridge rather than the standard N-C-N connection typical
of CB[n] reactions. Despite this idiosyncrasy it was clear that
1
dimer formation by H NMR (Supporting Information,
Figures S13-S16). In a second set of experiments we varied
the temperature (70 °C, 50 °C, and room temperature) and
followed the reaction by H NMR (Supporting Information,
1
1, probably facilitated by the entropic advantage provided
1
by using a dialdehyde, was sufficiently reactive to participate
in a CB[n] forming reaction. Accordingly, we wondered
whether phthaldehyde 11 would be reactive toward glyco-
lurils and glycoluril oligomers and provide a new route
toward the formation of CB[n] derivatives.
Figures S13, S17, and S18). Once again we could not detect
the formation of dimers. Given that the reaction between 7
and an aldehyde is a condensation reaction that leads to
the formation of H O as byproduct we decided to conduct
2
Reaction between Glycolurils and Phthaldehyde 11. Given
our interest in the development of building block strate-
gies for the construction of CB[n] derivatives and analo-
gues, we wondered whether 11 would participate in such
the reaction under anhydrous (CF CO H) rather than
3
2
aqueous (conc HCl) conditions (Supporting Information,
Figure S19). We hoped that the use of CF CO H as solvent
1
6,31
3
2
(
(
26) Nematollah, J.; Ketcham, R. J. Org. Chem. 1963, 28, 2378–2380.
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SCHEME 7. Synthesis of Dimers and Tetramers from Glycolurils and Phthaldehyde 11
FIGURE 1. Stereoviews of the X-ray crystal structures of (a) 12S,
(b) 16S, and (c) 17S rendered with CrystalMaker. Color code: C,
gray; H, white; N, blue; O, red; H-bonds, red-yellow striped.
reactions. First, we decided to conduct the reaction between
glycoluril dimer 2C (3 equiv) and 11 (3 equiv) in the hopes of
creating a CB[6] derivative. This experiment was conducted
in CF CO H rather than HCl because 2C is nicely soluble in
3
2
CF CO H. Contrary to expectation, we observed the for-
3
FIGURE 2. Stereoscopic representations of the X-ray crystal struc-
ture of (a) 2C and the MMFF94s minimized geometries of (b) 16S,
2
mation of tetramer 12S (Scheme 7a) whose structure was
established by spectroscopic methods and also by X-ray cry-
stallography (Figure 1a). Minor resonances were observed in
(
c) 16Cb, and (d) 16Ca. Color code: C, gray; H, white; N, blue; O,
-1
red. The quoted relative heats of formation (kcal mol ) were
obtained from PM3 calculations.
1
the crude H NMR that may correspond to diastereomers
3
2Ca and 12Cb. The formation of 12S was very interesting
2
1
to us for a number of reasons. First, phthaldehyde 11
displayed a more normal reactivity in which the o-xylylene
ring acts as bridge between the 1,5-positions of the newly
formed eight-membered ring. Second, even though the con-
densation of two molecules of 2C and one molecule of 11
could, in theory, yield three diastereomers (12S, 12Ca, and
(
32) The poor solubility of many glycoluril oligomers and their erratic
chromatographic behavior prevented the isolation and structural elucidation
of these minor products.
2
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Ma et al.
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2
FIGURE 3. Plots of mole fraction of 16S versus time for the (a) formation and (b) fragmentation of 16S. Conditions: 5% DCl in D O, room
temperature. The solid lines are intended merely as guides for the eye.
1
2Cb), we observe the dominant formation of 12S. Next, we
SCHEME 8. Formation of C-Shaped Glycoluril Dimer 19C
examined the reaction between phthaldehyde 11 and glyco-
luril 1H or capped glycolurils 7, 13, and 14. In all cases, we
observed the dominant formation of a single product (15S-
1
8S) with an S-shaped geometry (Scheme 7b-e). We were
fortunate to obtain single crystals of 12S, 16S, and 17S and
solve their structures (Figure 1). Figure 1a shows the X-ray
crystal structure of 12S, which illustrates the overall S-shape
of the oligomer due to the relative orientation of the methine
C-H groups on the convex face of 2 equiv of building block
case of 16S one of the two 7-MR adopts the chair conforma-
tion whereas the other adopts the boat form. For 16Cb both
of these new 7-MR adopt the chair conformation, whereas
for 16Ca both adopt the boat conformation. This analysis
predicts that 16Cb should be the most stable diastereomer
followed by 16S and finally 16Ca, which is contrary to the
observed dominant formation of 16S. Accordingly, we cal-
culated the relative heats of formation of 16S, 16Cb, and
16Ca of the MMFF94s minimized conformers using the
PM3 method and found that theory predicts that 16S is
2
C within 12S. Figure 1b shows the X-ray crystal structure of
6S which adopts a very similar geometry. In this case
solvating MeOH molecules within the crystal form O-
OdC H-bonds to the ureidyl carbonyls of 16S. Com-
1
H
3
3 3
pound 17S also displays a similar overall geometry in the
crystal (Figure 1c), but in this case the bridging o-xyly-
lene rings of two adjacent molecules of 17S in the crystal
undergo π-π stacking interactions.
The formation of the S-shaped diastereomers 12S and
-
1
1
5S-18S is of high relevance toward the use of 11 or
2.21 kcal mol more stable than 16Cb (chair-chair) and
-1
aldehydes in CB[n] forming reactions. The formation of
S-shaped subunits prevents the reactive NH tips of the
oligomers from being close enough in space to undergo
macrocyclization reactions. For this reason the use of 11 in
CB[n] forming reactions is unlikely to be successful. We
surmise that the reaction between ns-CB[6] and 11 is success-
ful because ns-CB[6] is preorganized into the C-shape needed
for macrocyclization before reaction with 11.
11.29 kcal mol more stable than 16Ca (boat-boat). We
believe that unfavorable H H nonbonded interactions
3
3 3
3
4
˚
(2.01 A) between H-atoms on adjacent glycoluril rings
(Figure 2c) destabilize 16Cb. On the basis of this analysis,
it becomes clear that the conformational preferences of the
newly forming 8-MR and 7-MR control the diastereomer
(e.g., S-shaped or C-shaped) that is formed. For a CB[n]
derivative forming reaction to proceed smoothly, it is critical
that the equilibrium between S-shaped and C-shaped forms
greatly favors the C-shaped form.
Why Do the S-Shaped Diastereomers Predominate? The
results described above and supported further below by pro-
duct resubmission experiments establish that the S-shaped
diastereomers 12S and 15S-18S are more stable than the
corresponding C-shaped diastereomers. More importantly,
why do the S-shaped forms predominate in this case? An
Product Resubmission Experiments. In combination, the
synthetic and theoretical studies described above strongly
suggested that the S-shaped diastereomers 12S and 15S-18S
were thermodynamically more stable than the C-shaped
diastereomers. In previous model system studies of the
equilibrium between S-shaped and C-shaped methylene
bridged glycoluril dimers we used product resubmission
experiments to transform the S-shaped diastereomers into
2
0
examination of the X-ray crystal structure of 2C and the
MMFF94s energy minimized structures of 16S, 16Ca, and
1
membered ring of 2C exists in the crown-conformation
6Cb (Figure 2) gives some insights. The central eight-
3
3
Figure 2a). Introduction of the bridging o-xylylene ring
19
(
the C-shaped forms. We decided to attempt similar experi-
in 12 and 15- 18 results in the formation of two new seven-
membered rings (7-MR). It is well-known that 7-MR prefer
the chair conformation over the boat conformation. In the
ments with 16S. Accordingly, we monitored the composition
of a solution of 16S (12.5 mM) in 5% DCl at room
temperature and observed a decrease in the concentration
of 16S over several days and somewhat surprisingly an
increase in the concentration of glycoluril monomer 7
(33) Isaacs, L; Anet, F. A. L.; Basus, V. J. J. Am. Chem. Soc. 1973, 95, 4424–
426. Dorofeeva, O. V.; Mastryukov, V. S.; Allinger, N. L.; Almenningen, A.
35
1
(Figure 3a). No H NMR resonances were detected that
4
J. Phys. Chem. 1985, 89, 252–257. Pakes, P. W.; Rounds, T. C.; Strauss, H. L.
J. Phys. Chem. 1981, 85, 2469–2475. Calucci, L.; Zimmermann, H.; Poupko, R.;
Luz, Z. J. Phys. Chem. 1995, 99, 14942–14948.
(34) Rowland, R. S.; Taylor, R. J. Phys. Chem. 1996, 100, 7384–7391.
J. Org. Chem. Vol. 75, No. 9, 2010 2939

Ma et al.
JOCArticle
FIGURE 4. Plots of mole fraction of 19C versus time for the (a) formation and (b) fragmentation of 19C (5% DCl in D
2
O, 70 °C) and (c)
formation and (d) fragmentation of 19C (5% DCl in D
2
O, 50 °C). The solid lines are intended merely as guides for the eye.
would indicate the formation of C-shaped diastereomers
1
described above. The observation of the mixture of S-shaped
dimer 16S and glycoluril monomer 7 suggested to us that the
equilibrium constant for the conversion of 7 and 11 into 16S
large changes over the 1-100 mM range. As further evidence
of the relevance of this behavior to CB[n] forming reactions
similar experiments were performed on the transformation
of 7 and formaldehyde into 19C (Scheme 8) previously
6Ca or 16Cb, which is in accord with the PM3 calculation
2
8
reported by the Sindelar group. Given the higher reactivity
of formaldehyde compared with that of aldehydes, we
anticipated that we would need to resort to higher tempera-
tures to entropically favor monomer 7. Figure 4a shows a
plot of mole fraction of 19C versus time obtained during the
formation of 19C (5% DCl, 70 °C) at three different con-
centrations. In all three cases we observe an initial increase in
the mole fraction of 19C followed by a maximum and finally
a decrease. At higher concentrations the mole fraction
reaches a higher maximal value and decreases more slowly
after this maximum is reached. As a complementary experi-
ment we dissolved 19C in 5% DCl at 70 °C and followed the
and H O might be small due to the decreased reactivity of 11
2
relative to formaldehyde. To further verify this hypothesis,
we dissolved 16S in 5% DCl at room temperature at different
concentrations (50, 12.5, 3.8, and 1 mM) and followed the
1
decrease in the mole fraction of 16S by H NMR spectro-
scopy (Figure 3b). We also followed the formation of 16S
from equimolar mixtures of glycoluril monomer 7 and
phthaldehyde 11 under identical conditions (Figure 3a).
Figure 3 shows two important trends. First, both the forma-
tion and fragmentation of 16S plateau at comparable mole
3
6
fractions of 16S. Second, as the concentration increases
from 1 to 50 mM we observe an increase in the mole fraction
of 16S at the plateau level. Both of these observations suggest
1
fragmentation of 19C by H NMR as a function of time
(Figure 4b). At higher concentrations of 19C the mole
fraction of 19C decreases more slowly. We interpret this
behavior as being indicative of two competing processes: (1)
equilibrium between 7 and dimer 19C, and (2) chemical
that the conversion of 7 and 11 into 16S and H O is an
2
equilibrium process with a modest equilibrium constant.
In sharp contrast to the reaction between glycolurils and
formaldehyde which greatly favors products over starting
3
7
decomposition of glycoluril monomer 7. We performed
identical experiments at 50 °C in 5% DCl (Figure 4c and d)
and observe clearer plateau regions, which indicates lower
levels of side reactions (e.g., decomposition) relative to
monomer-dimer equilibrium at this temperature.
5
materials over a range of conditions, the use of less reactive
phthalaldehyde 11 results in only partial dimerization in the
1
-50 mM concentration regime. We infer that the lack of
observed reactivity between 7 and benzaldehyde probably
reflects an even lower equilibrium constant that cannot be
accessed over the concentration range employed (up to 1 M).
Equilibrium and Reversibility of Formaldehyde Based Di-
mers. The previous section demonstrated that the formation
of glycoluril dimer 16S from 7 and phthaldehyde 11 is a
reversible process with the mole fraction of 16S experiencing
Conclusions
We have shown that glycolurils react with a dialdehyde (o-
phthaldehyde) to deliver S-shaped glycoluril dimers 15S-18S
and tetramer 12S. We established that S-shaped compounds
12S and 15S-18S are thermodynamically preferred over the C-
shaped diastereomers and trace this preference to the confor-
mational biases of the newly formed benzo bicyclo[3.3.2]octane
1
35) We did not observe H NMR resonances for free phthaldehyde 11
(
under these conditions. We suspect that 11 undergoes oxidative decomposi-
tion.
(
decomposition of 7. This prevents us from measuring a value of Keq for this
reaction.
36) At higher temperatures or longer reaction times we observe the
(37) We have confirmed that 7 undergoes decomposition when heated at
70 °C in 5% DCl.
2
940 J. Org. Chem. Vol. 75, No. 9, 2010

Ma et al.
JOCArticle
ring system. The presence of S-shaped segments in glycoluril
oligomers hinders macrocyclization to CB[n]-type compounds
by holding the reactive NH groups far apart in space. Accord-
ingly, the observation of the dominant formation of S-shaped
dimers in the reaction between glycolurils and 11 provides one
reason for the inability of o-phthalaldehyde and possibly other
aldehydes to participate in CB[n] forming reactions. The side
o-phthaldiadehyde (108 mg, 0.81 mmol) was added. The mixture
was heated at 70 °C for 3 h. The solution was then poured into
MeOH (150 mL). The precipitate was filtered to yield the crude
product (580 mg). The crude solid was stirred in a mixture of
formic acid and water (1:2, v:v, 120 mL) 30 min. The filtrate
was concentrated under reduced pressure and then poured into
MeOH (200 mL). After filtration and drying, the precipitate was
further purified by recrystallization from TFA and water (4:1, v/v,
20 mL) to yield 12S as a white solid (216 mg, 0.30 mmol, 37%).
products observed in the reaction between 7 and aldehydes 8Ph
-
1
and 8Pr illustrate two alternative reaction pathways (hydantoin
formation and enamine-iminium ion cyclization) that become
viable when less reactive aldehydes are used.
We used product resubmission experiments to provide
evidence for an equilibrium between dimer 16S and mono-
mer 7 that responds to changes in concentration over the
Mp 350 °C (dec). IR (ATR, cm ): 3450w, 1715s, 1445s, 1318 m,
1
1228s, 1185s. H NMR (400 MHz, DMSO-d ): 7.71 (s, 2H), 7.61
6
(s, 2H), 7.60-7.55 (m, 2H), 7.45-7.40 (m, 2H), 6.46 (s, 2H), 5.56
(d, J = 14.6 Hz, 2H), 5.54 (d, J = 6.8 Hz, 1H), 5.42 (d, J = 14.6 Hz,
2
H), 5.41 (d, J = 8.6 Hz, 1H), 5.30 (d, J = 8.6 Hz, 1H), 5.23 (d,
J = 8.6 Hz, 1H), 5.13 (d, J = 8.6 Hz, 1H), 5.10 (d, J = 8.6 Hz,
H). 4.79 (d, J = 8.6 Hz, 1H), 4.16 (d, J = 14.6 Hz, 2H), 4.06 (d,
1
1
-50 mM range. This indicates that the equilibrium constant
1
3
J = 14.6 Hz, 2H). C NMR (100 MHz, TFA, external DMSO
reference): δ 158.6, 158.5, 154.5, 153.8, 130.1, 129.6, 127.8, 72.5,
for dimer formation with o-phthalaldehyde is modest and
that high concentrations of starting materials are needed to
drive the reaction toward completion. In contrast to the
results obtained with o-phthalaldehyde, we did not observe
any reaction between benzaldehyde and glycoluril 7 under
the range of concentrations (1 mM to 1 M) employed. We
interpret this result as meaning that the reactivity of alde-
hydes toward glycolurils is even lower (lower equilibrium
constant) than that of o-phthalaldehyde 11. Given that
concentrations of 50 mM are needed to drive the reaction
with o-phthalaldehyde 11 to completion, perhaps it is not
surprising that monoaldehydes do not react with glycolurils
at concentrations up to 1 M. Accordingly, these results point
toward poor reactivity (low equilibrium constant) as a
second reason for the inability of aldehydes to participate
in CB[n] forming reactions.
7
2.3, 69.0, 68.5, 63.7, 61.7, 61.5, 61.3, 49.5, 49.1 (only 17 of the 18
expected resonances were observed). MS (ESI): m/z 715 ([M þ
þ
þ
27 16 8
H] ). HR-MS (ESI ): m/z 715.2220, calcd for C28H N O
715.2198. X-ray crystal structure.
Compound 16S. Compound 7 (300 mg, 1.76 mmol) was
dissolved in TFA (7 mL), and o-phthaldialdehyde 11 (120 mg,
0
6
.89 mmol) was added. The mixture was stirred and heated at
0 °C for 3 h. The solvent was removed under reduced pressure.
The crude mixture was recrystallized from MeOH to yield 16S as
a white crystalline solid (300 mg, 0.68 mmol, 77%). Mp 322 °C
-1
(
3 f
dec). TLC (CHCl /MeOH 6:1) R 0.28. IR (ATR, cm ):
3
493w, 3003w, 2933w, 1692s, 1482s, 1405s, 1380s, 1203s, 1036s.
1
H NMR (400 MHz, CDCl
H), 6.59 (s, 2H), 5.34 (d, J = 7.9 Hz, 1H), 4.93 (d, J = 8.4 Hz,
1H), 4.85 (d, J = 7.9 Hz, 1H), 4.84 (d, J = 8.4 Hz, 1H), 3.01 (s,
3
): 7.50-7.45 (m, 2H), 7.40-7.35 (m,
2
1
3
6H), 2.84 (s, 6H). C NMR (100 MHz, CDCl ): δ 155.2, 155.2,
3
The delineation of two of the reasons why aldehydes do
not generally participate in CB[n] forming reactions, i.e. the
critical importance of the S- to C-shaped equilibrium and the
magnitude of the equilibrium constant for chain growth, is
important because it suggests methods to overcome these
limitations in the future. When it is possible to introduce
134.2, 130.0, 129.2, 71.2, 71.1, 64.9, 64.3, 62.3, 30.2, 29.8. MS
ESI): m/z 439 ([M þ H] ). HR-MS (ESI ): m/z 439.1818, calcd
þ
þ
(
for C H N O 439.1842. X-ray crystal structure.
20 23
8
4
Acknowledgment. L.I. thanks the National Science Found-
ation (CHE-0615049 and CHE-0914745) for financial support.
V.S. acknowledges the Grant Agency of the Czech Republic
for grant 203/07/P382. V.S. thanks M. Necas (Masaryk
University) for the X-ray structure of 17S and M. Stancl
(Masaryk University) for his assistance in the preparation
and characterization of 17S and 18S.
functionality onto the bridging CH groups of CB[n], we
2
expect that the range of applications (e.g., targeted drug
delivery, affinity chromatography, and sensing arrays) to
8
which CB[n] derivatives can be applied will expand.
Experimental Section
9,28
General experimental details have been reported previously.
Supporting Information Available: Experimental proce-
dures and characterization data for SP1, (()-SP2, 15S, 17S,
and 18S; H and C NMR spectra for all new compounds and
Starting materials were obtained from commercial suppliers and
used without further purification. Compounds 2C, 7, 13, and 14
Compound SP1
1
13
20,28
were prepared by the literature procedures.
1
selected H NMR spectra for crude reaction mixtures; crystallo-
3
0
has been reported in the literature previously.
Compound 12S. Compound 2C (498 mg, 1.62 mmol) was
dissolved in a mixture of TFA and water (19:1, v/v, 6 mL), and
graphic information files for 12S, 16S, and 17S in CIF format.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 9, 2010 2941