Reaction of an introverted carboxylic acid with carbodiimide

Article abstract of DOI:10.1016/j.tet.2007.03.075

The reaction of carboxylic acids with carbodiimides is reviewed, and an 'introverted' carboxylic acid is proposed as a means of trapping reactive intermediates along the reaction pathway. The introverted acid is a cavitand with the carboxylic function directed toward the floor of the cavity. Its reaction with diisopropyl carbodiimide gives a covalent adduct that is either the elusive O-acylisourea or the commonly encountered N-acylurea.

Full text of DOI:10.1016/j.tet.2007.03.075

Tetrahedron 63 (2007) 6506–6511
Reaction of an introverted carboxylic acid with carbodiimide
*
Tetsuo Iwasawa, Paul Wash, Christoph Gibson and 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, USA
Received 31 January 2007; revised 9 March 2007; accepted 12 March 2007
Available online 16 March 2007
Abstract—The reaction of carboxylic acids with carbodiimides is reviewed, and an ‘introverted’ carboxylic acid is proposed as a means of
trapping reactive intermediates along the reaction pathway. The introverted acid is a cavitand with the carboxylic function directed toward the
floor of the cavity. Its reaction with diisopropyl carbodiimide gives a covalent adduct that is either the elusive O-acylisourea or the commonly
encountered N-acylurea.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
present and the symmetrical anhydride is formed. De Tar and
Silverstein4 showed that the N-acylurea is readily formed
at higher temperatures and established that it does not
arise from the acylation of the urea with the symmetrical
anhydride.
Typical carboxylic acids react with dicyclohexylcarbo-
diimide (DCC) and amines to give amides (Scheme 1) in a
process so broadly used in peptide synthesis, particularly
on the solid phase, that its importance would be hard to over-
state. The terminal acylating agent (that which reacts with
the amine) likely varies with the concentrations and the com-
ponents in the specific system,1–3 but the initial acylating
agent is undoubtedly the O-acylisourea.4,5 Support for this
intermediate comes from kinetic methods and stereochem-
ical probes,6 rather than direct observation. A report involv-
ing direct NMR observation7 was subsequently shown to be
a misassignment,8 but an old claim of TLC separation of an
O-acylisourea persists,9 and a more recent publication
describes the crystallization of a series of O-acylisoureas
from coumarin-3-carboxylic acid derivatives and DCC.10
In other studies Benoiton11 obtained high yields of N-acyl-
ureas from the reaction of symmetrical anhydrides of
BOC-protected amino acids with carbodiimides (Scheme 2).
We have been intrigued with the behavior of the reactive in-
termediates along this pathway for sometime and report here
our efforts to trap them with the aid of an unconventional
carboxylic acid. Carboxylic acids are especially difficult to
place in a sterically demanding environment; their oxygens
are exposed and convoluted molecular architectures must be
created to bring intramolecular elements near them in space.
Cleft-like structures with convergent functional groups
are used in molecular recognition studies and offer models
for naturally occurring receptors such as enzyme active
sites.12–17 The introverted acid 18–20 1 (Fig. 1) is a promising
example, and its structure hints at its unique properties. The
oxygens are in a well-defined cavity surrounded by four
aromatic walls, held in place by intramolecular hydrogen
bonds. The carboxyl O–H bond is directed toward the floor
of the cavity, and is trained on small molecules held inside.
The inversion/rotation rates of amines inside the cavity are
profoundly slowed, and the isolation of the acids and bases
in a hydrophobic environment results in interactions that
resemble those in protein interiors. The cavity as a molecular
A number of factors make the O-acylisourea elusive: its
formation may be reversible, limiting its steady state con-
centration to a vanishingly small one; its rearrangement to
the N-acylurea4—a pesky side product frequently encoun-
tered in peptide synthesis—provides another pathway for
its disappearance. This stable product arises from conven-
tional carboxylic acids and DCC by what appears to be an
intramolecular O-to-N acyl rearrangement. But even if the
rearrangement to the N-acylurea is suppressed, the in-
discriminate acylation of any available nucleophiles by the
O-acylisourea insures its rapid disappearance. In the absence
of added nucleophiles, the carboxylic acid itself is, of course,
3
˚
host has a volume ofw180 A in which a single guest enjoys
a uniquely high (w6 M) concentration. Considerable ener-
getic barriers including the rupture of hydrogen bonds
must be overcome to allow passage to and fro from the
cavity. Its isolation has been used to control the steric
Keywords: Introverted acid; Carbodiimide; N-Acylurea; O-Acylisourea;
Reaction mechanism.
* Corresponding author. Tel.: +1 858 784 2250; fax: +1 858 784 2876;
e-mail: jrebek@scripps.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.075

T. Iwasawa et al. / Tetrahedron 63 (2007) 6506–6511
6507
Scheme 1. Typical reactions of carboxylic acids and amines with dicyclohexylcarbodiimide.
Scheme 2. N-Acylureas from the reaction of symmetrical anhydrides of BOC-protected amino acids with carbodiimides.
Figure 1. The introverted acid 1.
environment around the carboxylic acid—a derivative of
Kemp’s triacid.21 This positioning slows some of its
reactions,22 or precludes them altogether: a symmetrical
anhydride of the acid, for example, is hard even to imagine.
These properties—probably not found elsewhere in the
world of carboxylic acids—tempted us to examine the
acid’s reaction with a carbodiimide; to trap the O-acyl-
isourea intermediate.
2. Results and discussion
In the experiment, the reaction of acid 1 with diisopropyl-
carbodiimide at millimolar concentrations was very slow
at room temperature (Scheme 3). The overnight reaction at
80 ꢀC in C6D6 or C9D12 (deuterated mesitylene) barely pro-
ceeded to give the addition product. The stable product
was isolated by evaporation of volatiles and washing with

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T. Iwasawa et al. / Tetrahedron 63 (2007) 6506–6511
Scheme 3. Trapping the reactive intermediate in the reaction of 1 with diisopropylcarbodiimide.
hexane. The electrospray ionization (ESI) mass spectrum
provided clear evidence for the covalent adduct O-(or N)
acylurea (m/z 2188, MH+; m/z 1095, [MH2]2+) and four
improbable cyclization trajectory (Fig. 3b) and a highly
contorted intermediate for an already sterically challenged
Kemp’s triacid derivative.
1
methyl groups were seen in the upfield region of the H
NMR spectrum (Fig. 2). The two doublet methyls were
situated at d ꢁ2.35 (d, J¼6.0 Hz, 3H) and ꢁ2.87 (d, J¼
6.0 Hz, 3H), the other two broad-singlet methyls were situ-
ated at d ꢁ2.29 (br, 3H) and –2.63 (br, 3H). Since 1 is chiral,
the two methyls of each isopropyl group are diastereotopic,
and the aromatic walls that line the cavity create an aniso-
tropy that causes NMR signals of the guest species to shift
upfield (note that they appear upfield of tetramethylsilane).
The IR spectrum showed no trace of the N]C]N stretch
but was otherwise uninformative; many carbonyl stretching
absorptions were evident in the 1800–1500 cmꢁ1 range but
this part of the spectrum of the adduct was indistinguishable
from that of the starting acid. Treatment of the product with
excess isobutyl amine, aq HCl (15% w/w) or methanol for
2 days showed no evidence of reaction.
For reasons mentioned above, the intermediacy of the sym-
metrical anhydride is out of the question. In addition to the
N
Nu
N
O
O
H
N
O
N
O-
N
O
O
?
N
N
H
N
2
Urea
Is the adduct the O-acyl or N-acylurea? The unreactivity is
inconsistent with the former but a pathway to the latter is
hard to defend. Assuming an intramolecular hydrogen
bond and extended delocalization, the lowest energy con-
formation of the O-acylisourea has coplanar heteroatoms
(Fig. 3). Any external nucleophilic attack on the carbonyl
carbon along the preferred angles23 is roughly perpendicular
to this plane. One face of the function is already shielded by
the benzimidazole wall, so the nucleophile must approach
from the other face. Such an approach forces the oxygens
into the p system of the cavitand’s odd wall as indicated
in Figure 3a. The intramolecular O-to-N acyl shift requires
the nitrogen nucleophile to assume a stereoelectronically
plane
+
N
N
N
N
O
O
N
O -
N
O
HN
HN
O
?
O
Ester
plane
Figure 3. (a) External nucleophiles and the O-acylisourea 2 and (b) intra-
molecular rearrangement to a tetrahedral intermediate.
?
N
N
2
N
O
N
N
O +
NH
O
O
H
N
- O
N
O
3
Figure 2. Upfield region of 1H NMR spectrum (600 MHz, 300 K, benzene-
d6) in the reaction of 1 with diisopropylcarbodiimide.
Figure 4. Possible rearrangement to the N-acylurea via an acylium ion.

T. Iwasawa et al. / Tetrahedron 63 (2007) 6506–6511
6509
Scheme 4. An improved procedure for synthesis of the introverted acid 1.
conformation shown for 1, a ‘kite-shaped’ conformation
with the four walls flipped outward, has been characterized
for related molecule.24 It is likely that this conformation is
an intermediate that appears during guest uptake and is
release by 1.25 Recent work also establishes a conformation
with only two walls flipped outward.26 An alternate, disso-
ciative mechanism leading to the N-acylurea 3 via an
acylium ion has little appeal under the mild conditions
here. Even so, the N-acylurea structure for the adduct cannot
be excluded (Fig. 4).
modified.41–43 Accordingly, encapsulation is already un-
locking secrets of reaction pathways and provides realistic
models for reactions confined to enzyme interiors.
4. Experimental
4.1. General
All chemicals were purchased from Aldrich Chemical Com-
pany and were used without purification unless otherwise
specified. The cavitand 1 was prepared from corresponding
resorcinarene 4 as follows (Scheme 4) in an improvement on
the published procedure (18). Proton (1H) and carbon (13C)
NMR spectra were recorded on a Bruker DRX-600
(600 MHz) spectrometer. Proton (1H) chemical shifts, re-
ported in parts per million (ppm), were indirectly referenced
to an external tetramethylsilane employing resonances due
to trace protiated solvent as an internal references. Abbre-
viations are as follows: s, singlet; d, doublet; t, triplet; m,
multiplet; br s, broad singlet. Deuterated NMR solvents
were obtained from Cambridge Isotope Laboratories, Inc.,
and used without further purification. Electrospray ioniza-
tion time-of-flight reflection experiments were performed
on an Agilent Electrospray ionization time-of-flight mass
spectrometer.
3. Conclusion
Related molecule-within-molecule assemblies are providing
physical organic chemistry with a new tool for the study of
reactive intermediates, either as the covalently-bonded
structures, carcerands27–29 and cryptophanes,30 or reversibly
formed capsules held together with hydrogen bonds,31–33
and with metal–ligand interactions.34–36 The Kemp’s triacid
derivative of the present case is, admittedly, unique; extra-
polation of these results to other acids is not without peril.
If, indeed, the adduct is the elusive O-acylisourea, its isola-
tion is due to the cavitand’s ability shut down some reaction
pathways to reveal intermediates along others. Only crystal-
lography can resolve the structure of the adduct as neither
NMR nor IR is up to the task. Further progress in this admit-
tedly narrow investigation must now await the growth of
suitable crystals for X-ray analysis. In the meantime, we
note that confinement of reactants in synthetic capsules
and other limited spaces has already given rise to exclusive
regioselectivities37 and even unthinkable regioselectivities38
in some cycloaddition reactions. The stabilization of unseen
reaction intermediates39 and ground states unknown in free
solution40 has also been observed. Even carbodiimides
have been encapsulated, where their reactivities are much
4.1.1. Synthesis of hexa-amide cavitand (6). Under a nitro-
gen atmosphere, to the mixture of resorcinarene 4 (26.4 g,
24 mmol) and 1,2-difluoro-4,5-dinitrobenzene (14.6 g,
72 mmol) in DMF (700 mL) at 50 ꢀC was added Et3N
(20.0 mL, 144 mmol) dropwise over 10 min. After overnight
stirring, the reaction mixture was allowed to cool to ambient
temperature, and the mixture was poured into 1 N HCl aq
(960 mL). The solid materials were filtered off, washed
with water, and then completely dissolved in CH2Cl2

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T. Iwasawa et al. / Tetrahedron 63 (2007) 6506–6511
(1500 mL). The solution was transferred into a separatory
funnel, and the separated organic layer was dried over
Na2SO4 and filtered, and concentrated in vacuo to give the
crude as dark brown solid material. The crude was purified
by column chromatography (CH2Cl2/EtOAc¼100/0w100/
1w100/2) to afford the hexa-nitro cavitand 5 as yellow solid
material in 26% yield (10.0 g). To the cavitand 5 (7.2 g,
4.5 mmol) and SnCl2$H2O (27 g. 120 mmol) was added
a mixture of EtOH (320 mL)/concd HCl aq (80 mL). After
overnight stirring at 70 ꢀC, the volatiles were evaporated.
To the residue was added EtOAc (1000 mL), followed by
the slow addition of aq K2CO3 (85 g, 500 mL). Then pro-
pionyl chloride (25 mL) was added dropwise over 20 min.
After vigorous stirring for 30 min, the mixture was trans-
ferred into a separatory funnel, and the aqueous phase was
extracted with EtOAc (200 mLꢂ4). The combined organic
phases were dried over Na2SO4, filtered, and concentrated
in vacuo. To the resultant material was added toluene
(100 mL)/ethanol (100 mL), followed by hydrazine (1 M
THF solution, 60 mL). The mixture was stirred at 70 ꢀC
for 1 h, and allowed to cool to ambient temperature, and
all the volatiles were removed in vacuo. The residue was
purified by silica gel column chromatography (EtOAc/
CH2Cl2¼70/30) to give yellow materials, which were
recrystallized from EtOAc (13 mL gꢁ1) to afford snow-
white crystals of 6 (5.6 g, 72%). HRMS (ESI, MH+) Calcd
for C108H149N6O14: 1754.1126. Found: 1754.1198 (error
in vacuo to give 8 as pale brown solid (178 mg, 92%).
ESIMS m/z: 1858 (MH+), 1880 (MNa+). 1H NMR
(600 MHz, CDCl3) d 9.49 (s, 2H), 9.34 (s, 2H), 8.73 (s,
2H), 7.55 (s, 2H), 7.50 (s, 2H), 7.42 (s, 2H), 7.25–7.23 (m,
4H), 7.21–7.20 (m, 4H), 6.97 (s, 2H), 5.76 (t, J¼7.8 Hz,
1H), 5.71 (t, J¼8.4 Hz, 2H), 5.66(t, J¼7.8 Hz, 1H), 5.47
(br s, 2H), 5.37 (br s, 2H), 2.49–2.16 (m, 20H), 1.43–1.15
(m, 80H), 0.89–0.87 (m, 12H).
4.1.4. Synthesis of the introverted acid (1). To the sealed
tube charged with 8 (449 mg, 0.24 mmol) and Kemp’s tri-
acid chloride anhydride (62 mg, 0.24 mmol) was added a mix-
ture of p-xylene (6 mL) and Et3N (0.10 mL, 0.72 mmol),
then flushed with argon and sealed. The mixture was stirred
for 30 min at room temperature, then the tube was immersed
in an oil bath pre-heated at 135 ꢀC (the dark gray cloudy
mixture becomes a yellow solution). After overnight stirring,
the tube was allowed to cool to ambient temperature, and the
reaction mixture was filtered through a pad of cotton, and
concentrated in vacuo to give brown solid material. The resi-
due was dissolved in CH2Cl2 (40 mL) and to this solution
was added 1 N HCl aq (10 mL). The mixture was transferred
into a separatory funnel, and the organic phase was washed
with 1 N HCl aq (10 mL), and dried over Na2SO4, filtered,
and concentrated in vacuo to give brown crude solid
(466 mg). Purification by column chromatography (47 g sil-
ica gel, CHCl3/EtOAc¼1/0w4/1w1/1) afforded 1 230 mg
(46%) as a white powder. HRMS (ESI, MH+) Calcd for
C126H165N8O17: 2062.2287. Found: 2062.2242 (error
1
<1 ppm). H NMR (600 MHz, acetone-d6) d 9.53 (s, 2H),
9.41 (s, 2H), 9.12 (s, 2H), 8.95 (s, 2H), 7.89 (s, 2H), 7.74–
7.67 (m, 8H), 7.50 (s, 2H), 6.75 (s, 2H), 5.87 (t, J¼7.8 Hz,
1H), 5.75 (t, J¼7.8 Hz, 2H), 4.37 (t, J¼7.8 Hz, 1H), 2.56–
2.27 (m, 20H), 1.44–1.21 (m, 80H), 0.89–0.87 (m, 12H).
1
<2.2 ppm). H NMR (600 MHz, CDCl3) d 9.92 (s, 1H),
9.47 (s, 1H), 9.06 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.10
(s, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.66 (s,
1H), 7.48 (s, 1H), 7.29–7.27 (m, 3H), 7.25–7.23 (m, 6H),
7.21–7.20 (m, 2H), 5.84 (t, J¼8.4 Hz, 1H), 5.79 (t, J¼
8.4 Hz, 1H), 5.73 (t, J¼8.4 Hz, 1H), 5.66 (t, J¼8.4 Hz,
1H), 2.75–2.14 (m, 24H), 1.59–1.16 (m, 98H), 0.92–0.88
(m, 15H).
4.1.2. Synthesis of hexa-amide di-nitro cavitand (7). To
the mixture of hexa-amide cavitand 6 (1.80 g, 1.03 mmol)
and 1,2-difluoro-4,5-dinitrobenzene (230 mg, 1.13 mmol)
in DMF (30 mL) at 60 ꢀC was added Et3N (0.22 mL,
1.55 mmol) dropwise over 2 min. After overnight stirring,
the reaction mixture was allowed to cool to ambient temper-
ature, and the volatiles were removed in vacuo. The residue
was purified by silica gel column chromatography (CH2Cl2/
EtOAc¼4/1), followed by recrystallization from ethanol
(15 mL) to afford the target compound 7 as a pale orange
powder (1.61 g, 81%). HRMS (ESI, MH+) Calcd for
C114H149N8O18: 1918.0984. Found: 1918.0990 (error
13C NMR (150 MHz, CDCl3): d 175.9, 175.3, 174.8, 173.9,
173.5, 173.4 (two coincident resonances), 172.7, 159.5,
156.2, 155.5, 155.4, 155.2, 155.0, 154.9, 154.8, 154.6,
151.8, 151.6, 151.3, 150.9, 150.8, 150.1, 150.0, 149.6,
141.0, 136.3, 136.2, 136.0, 135.9, 135.8, 135.7, 135.6,
135.4, 130.5, 128.8, 128.5, 128.4, 128.3, 127.9, 126.5,
124.2, 124.1, 124.0, 123.7, 123.0, 122.6, 122.5, 121.8,
121.2, 119.5, 116.8, 116.5, 116.4, 116.1, 115.6, 111.8, 47.5,
46.9, 44.6, 42.5, 41.9, 35.4, 34.0, 33.9, 33.8, 33.7, 33.6,
33.3, 32.4, 33.0, 32.2, 31.8, 31.6, 30.9, 30.5, 30.3(1),
30.2(8), 30.2(6), 30.2(5), 30.1, 30.0(9), 30.0(3), 29.8, 29.3,
28.6, 28.5, 28.4(8), 28.4(2), 23.1, 14.6, 11.1, 10.9, 10.6,
10.5, 9.5; numbers in parentheses indicate resonances that
differ by hundredths of a ppm (i.e., 30.09 and 30.03).
1
<0.3 ppm). H NMR (600 MHz, CDCl3) d 9.45 (s, 2H),
9.30 (s, 2H), 8.21–8.19 (br s, 4H), 7.68 (br s, 2H), 7.55 (s,
4H), 7.36–7.35 (m, 2H), 7.31–7.30 (m, 6H), 5.83 (t, J¼
8.4 Hz, 2H), 5.80 (t, J¼8.4 Hz, 1H), 5.61 (t, J¼8.4 Hz,
1H), 2.52–2.21 (m, 20H), 1.49–1.25 (m, 80H), 0.94–0.91
(m, 12H).
4.1.3. Synthesis of hexa-amide di-amino cavitand (8). The
di-nitro starting compound 7 (200 mg, 0.104 mmol) was dis-
solved in a mixture of EtOAc (6 mL) and toluene (2 mL). To
this solution was added a catalytic amount of Raney nickel
(pre-washed with methanol, 2 mLꢂ5) suspended in MeOH
(6 mL), followed by the addition of anhydrous hydrazine
(0.3 mL), and the flask was filled with N2. The flask was fit-
ted with a N2 balloon then immersed in a pre-heated oil bath
(100 ꢀC). After vigorous stirring for 1 h, the (mostly color-
less) reaction mixture was allowed to cool to ambient tem-
perature, filtered through a pad of Celite, and concentrated
4.1.5. The adduct of the acid 1 with diisopropylcarbo-
diimide. To a flask charged with acid 1 (16 mg, 7.76ꢂ
10ꢁ3 mmol) in 1.5 mL of mesitylene-d12 (or 1.5 mL of benz-
ene-d6) was added a 1.5 mL mesitylene-d12 (or 1.5 mL of
benzene-d6) solution of diisopropylcarbodiimide (3.9 mg,
31.0ꢂ10ꢁ3 mmol). The tube was dipped into a pre-heated
oil bath at 80 ꢀC. After overnight heating, the volatiles
were evaporated under vacuum. The resultant residue was
thoroughly washed with hexane (10 mL), and dried over-
night in vacuo to give white solid materials (10 mg, 60%).

T. Iwasawa et al. / Tetrahedron 63 (2007) 6506–6511
6511
1H NMR (600 MHz, 300 K, mesitylene-d12) d 9.88–9.78 (m,
2H), 9.23–9.11 (m, 2H), 8.64–8.56 (m, 2H), 8.48 (s, 1H),
8.15–8.06 (m, 2H), 7.91 (s, 1H), 7.75–7.72 (m, 1H), 7.64–
7.54 (m, 6H), 7.32–6.96 (m, 6H), 6.24–6.04 (m, 4H), 2.71–
2.29 (m, 17H), 1.60–0.47 (m, 128H), ꢁ2.48 (d, J¼6.0 Hz,
3H), ꢁ2.80 (d, J¼6.0 Hz, 2H), ꢁ3.01 (d, J¼6.0 Hz, 1H).
HRMS (ESI, MH+) Calcd for C133H179N10O17: 2188.3443.
Found: 2188.3391. ESIMS (m/z): 2210 (MNa+), 2188
(MH+), 1095 ([MH2]2+).
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Acknowledgements
We are grateful for financial support from the Skaggs Insti-
tute for Research and the National Institutes of Health (GM
50714). We are pleased to thank Dr. John Thomas for assis-
tance with mass spectrometry. Dr. T.I. is a Skaggs Postdoc-
toral Fellow.
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