Organic crystal engineering with 1,4-piperazine-2,5-diones. 6. Studies of the hydrogen-bond association of cyclo[(2-methylamino-4,7-dimethoxyindan-2- carboxylic acid)(2-amino-4,7-dimethoxyindan-2-carboxylic acid)]

Article abstract of DOI:10.1021/jo0509096

The title 1,4-piperazine-2,5-dione was synthesized in 23% yield over six steps from ethyl 2-amino-4,7-dimethoxyindan-2-carboxylate. Crystallization by slow diffusion of ether into a chloroform solution and by slow evaporation of an ethanol-chloroform-benz

Full text of DOI:10.1021/jo0509096

Organic Crystal Engineering with 1,4-Piperazine-2,5-diones. 6.
Studies of the Hydrogen-Bond Association of
Cyclo[(2-methylamino-4,7-dimethoxyindan-2-carboxylic
acid)(2-amino-4,7-dimethoxyindan-2-carboxylic acid)]
Robin A. Weatherhead-Kloster, Hugh D. Selby, Walter B. Miller III, and Eugene A. Mash*
Department of Chemistry, University of Arizona, Tucson, Arizona 85721-0041
emash@u.arizona.edu
Received May 7, 2005
The title 1,4-piperazine-2,5-dione was synthesized in 23% yield over six steps from ethyl 2-amino-
4,7-dimethoxyindan-2-carboxylate. Crystallization by slow diffusion of ether into a chloroform
solution and by slow evaporation of an ethanol-chloroform-benzene solution produced polymorphic
crystalline forms as determined by single-crystal X-ray analysis. The polymorphs exhibited different
hydrogen-bonding networks. The association of this piperazinedione in solution was studied using
mass spectrometric and nuclear magnetic resonance spectroscopic techniques. The MS and NMR
data were interpreted using the solid-state structures as models for solution aggregation. Association
constants extracted from the NMR data are in line with those of other cyclic cis amides in chloroform
solvent.
Introduction
for compounds 1-5 decreased as the length of the alkoxy
chains increased.6,7 The available crystallographic data
indicated that the geometries of the hydrogen bonds, and
therefore their strengths, were very similar in this
homologous series.6 Furthermore, hydrogen-bonding in-
teractions were expected to be the strongest and most
persistent of the intermolecular interactions in these
crystals.8 If for compounds 1-5 hydrogen bonds of
comparable strength are the last intermolecular interac-
tions broken during the melting processes (and thus the
first intermolecular interactions formed during the crys-
tallization processes), we reasoned that the contribution
of alkyl chain motion to the entropic component of the
Noncovalent interactions govern intermolecular con-
tacts that are of universal importance in biology, chem-
istry, and materials science. Understanding and har-
nessing these interactions is one goal of crystal engi-
neering.1 We have employed reciprocal amide hydrogen-
bonding,2 arene-arene,3 and van der Waals4 interactions
resident on a piperazinedione scaffold in an effort to
produce organic crystals that possess liquid crystallinity
(Figure 1).5 We observed that the clearing temperature
(1) (a) Desiraju, G. R. Crystal Engineering. The Design of Organic
Solids; Elsevier: New York, 1989. (b) Desiraju, G. R. The Crystal As
a Supramolecular Entity; Wiley: New York, 1996. (c) Seddon, K. R.;
Zaworotko, M. Crystal Engineering: The Design and Application of
Functional Solids; Kluwer Academic: Dordrecht, 1999.
(2) (a) Desiraju, G. R. The Weak Hydrogen Bond: In Structural
Chemistry and Biology; Oxford University Press: Oxford, 1999. (b)
Etter, M. Acc. Chem. Res. 1990, 23, 120-126. (c) MacDonald, J. C.;
Whitesides, G. M. Chem. Rev. 1994, 94, 2383-2420.
(3) (a) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem.
Soc., Perkin Trans. 2 2001, 651-669. (b) Waters, M. L. Curr. Opin.
Chem. Biol. 2002, 6, 736-741.
(4) Kitaigorodsky, A. I. Molecular Crystals and Molecules; Academic
Press: New York, 1973.
(5) (a) Saeva, F. D. Liquid Crystals; Dekker: New York, 1979. (b)
Kelker, H.; Hatz, R. Handbook of Liquid Crystals; Verlag Chemie:
Weinheim, 1980. (c) Dunmur, D. A. Liquid Crystals; World Scientific:
Singapore, 2002. (d) Collings, P. J. Liquid Crystals: Nature’s Delicate
Phase of Matter; Princeton University Press: Princeton, NJ, 2002.
(6) Wells, K. E. Ph.D. Dissertation, University of Arizona, 2001.
(7) A similar trend was reported for the clearing temperatures of
N-alkylammonium chlorides, see: Terreros, A.; Galera-Gomez, P. A.;
Lopez-Cabarcos, E. J. Therm. Anal. Calorimetry 2000, 61, 341-350.
(8) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry; Wiley:
Chichester, 2000.
10.1021/jo0509096 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/29/2005
J. Org. Chem. 2005, 70, 8693-8702
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Weatherhead-Kloster et al.
FIGURE 1. Self-assembly of a piperazinedione derived from 4,7-dialkoxy-2-aminoindane-2-carboxylic acid.
free energy could be responsible for the unusual trend
observed for the clearing temperatures.9
with Cbz anhydride. The success of the N-methylation
of 8 was dependent upon the order of reagent addition.11
When sodium hydride was added to a solution of iodo-
methane and 8 in 10:1 THF:DMF, an immediate and
vigorous exothermic reaction occurred, producing 9 in
80% yield. Saponification of 9 gave acid 10 in 81% yield.
Amine 7 and acid 10 were coupled using bromotri-
pyrrolidinophosphonium hexafluorophosphate (PyBroP)
to provide amide 11 in 97% yield.12 Removal of the Cbz
by catalytic transfer hydrogenation13 and thermolysis of
the resulting amino ester afforded 6 in 43% yield.
Crystals of 6 for X-ray analysis were obtained by slow
diffusion of ether into a chloroform solution (crystal 6A)
and by slow evaporation of an ethanol-chloroform-
benzene solution (crystal 6B).
Crystal StructuressMolecular. Structure data for
crystal polymorphs14 6A and 6B is given in the Support-
ing Information. Molecules (the asymmetric units) from
6A and 6B are depicted and data describing their
conformations is given in Table 1.15 Dihedral angles R
and â are measures of the degree of nonplanarity of the
piperazinedione ring (for planar rings R ) â ) 180°).16
The dihedral angle ø is a measure of the degree of
nonplanarity of the cyclopentene ring component of the
Indane moiety (for planar rings ø ) 180°).10 The C4-C7-
O3-C11 torsion angle, δ, measures the orientation of the
methoxy substituent relative to the plane of the benzene
ring.
Unfortunately, hydrogen-bond associations of com-
pounds 1-5 could not be studied due to their insolubility
in noninterfering solvents such as carbon tetrachloride,
carbon disulfide, and benzene. In addition, the monomer-
dimer equilibrium would undoubtedly be accompanied by
formation of higher oligomers. Compound 6 was designed
to address these issues. Mono-N-methylation of the
piperazinedione ring limits reciprocal amide hydrogen-
bond association (eq 1). The synthesis of 6, its crystal-
lization and structure in the solid state, and mass
spectrometric and nuclear magnetic resonance spectro-
scopic studies of its association in solution are presented
herein.
Piperazinedione 6A crystallized in space group P21/c.
The piperazinedione ring of 6A exists in a very shallow
boat conformation (R6A ) 174°, â6A ) 173°) with the
(10) Williams, L. J.; Jagadish, B.; Lyon, S. R.; Kloster, R. A.;
Carducci, M. D.; Mash, E. A. Tetrahedron 1999, 55, 14281-14300.
(11) The yield of N-methylation increased substantially upon re-
versal of the normal sequence of reagent addition, see: Coggins, J. R.;
Benoiton, N. L. Can. J. Chem. 1971, 49, 1968-1971.
(12) Coupling failed when the BOC-protected analogue of 8 was
employed, see: Coste, J.; Frerot, E.; Jouin, P. J. Org. Chem. 1994, 59,
2437-2446.
Results and Discussion
Synthesis and Crystallization of 6. Construction of
6 followed established protocols for the synthesis of
Indane diketopiperazines (Scheme 1). Amino ester 710
was converted to carbamate 8 in 84% yield by treatment
(13) Johnstone, A. J. R. Synthesis 1976, 685-687.
(14) Bernstein, J. Polymorphism in Molecular Crystals; Oxford
University Press: New York, 2002.
(15) IUPAC-IUB Commission on Biochemical Nomenclature. Bio-
chemistry 1970, 9, 3471-3479.
(9) The melting points of the normal alkanes from C3 to C18 increase
with chain length, see: Handbook of Chemistry and Physics, 53rd ed.;
CRC Press: Boca Raton, FL,1972.
(16) Palacin, S.; Chin, D. N.; Simanek, E. E.; MacDonald, J. C.;
Whitesides, G. M.; McBride, M. T.; Palmore, G. T. R. J. Am. Chem.
Soc. 1997, 119, 11807-11816.
8694 J. Org. Chem., Vol. 70, No. 22, 2005

Hydrogen-Bond Association of Piperazinediones
SCHEME 1. Synthesis of 6
TABLE 1. Conformational Data for Piperazinediones 6A and 6Ba
a Values are in degrees and given for each unique substructural element. b The dihedral angles φ, ψ, and ω are the torsion angles
defined for conformational analysis of amide bonds in peptides (ref 15). c The dihedral angles R and â were previously defined (ref 16) and
are measures of the degree of nonplanarity of the piperazinedione ring (for flat rings R ) â ) 180°). d The dihedral ø was previously
defined (ref 10) and is a measure of the degree of nonplanarity of the cyclopentene ring component of the Indane moiety (for flat rings ø
) 180°). e The C4-C7-O3-C11 torsion angle, δ, measures the twist of the methoxy substituent relative to the plane of the benzene ring.
cyclopentene rings folded, one bent slightly toward the
N-methylated nitrogen atom and the other bent some-
what more substantially toward the proximal carbonyl
(ø6A ) 170° and 160°, respectively). Piperazinedione 6B
crystallized in space group P21/n. The piperazinedione
ring of 6B exists in a very shallow pseudo-twist boat
conformation (R6B ) 177°, â6B ) 177°) with the cyclo-
pentene rings folded, one bent slightly toward the N-
methylated nitrogen atom and the other bent much more
substantially toward the unmethylated nitrogen atom
(ø6B ) 174° and 145°, respectively). For both crystal
structures 6A and 6B the torsion angles of the methoxy
groups are unique (δ6A ) 163°, -167°, 170°, and -174°,
δ6B ) -172°, -174°, 176°, and -179°) and the N-methyl
groups are rotationally disordered.
Crystal StructuressSupramolecular. The supra-
molecular assembly is very different in crystals 6A and
6B. In the former, molecules form one-dimensional
hydrogen-bonded tapes through establishment of a non-
reciprocal C(5) hydrogen-bond network17 involving NH
moieties and carbonyl oxygen atoms of N-methyl amide
moieties (Figure 2). Adjacent molecules in the tape are
rotated by 180°, producing a tape with a “Y”-shaped cross
section perpendicular to the long axis (Figure 2). Nearest-
neighbor tapes are rotated by 180° (Figure 3). This
permits intertape offset face-to-face interactions with
arene centroid-to-centroid distances of 3.60 and 3.73 Å.
(17) (a) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystal-
logr. B 1990, 46, 256-262. (b) Grell, J.; Bernstein, J.; Tinhofer, B. Acta
Crystallogr. B 1999, 55, 1030-1043.
J. Org. Chem, Vol. 70, No. 22, 2005 8695

Weatherhead-Kloster et al.
FIGURE 3. View of five neighboring tapes in 6A parallel to
the hydrogen-bonding axis. Hydrogen atoms have been re-
moved for clarity. Arene centroid-to-centroid distances are 3.60
and 3.73 Å.
FIGURE 2. Association via nonreciprocal hydrogen bonding
forms one-dimensional tapes in 6A. (Top) View perpendicular
to the hydrogen-bonding axis. The O‚‚‚H distance is 2.63 Å,
the N‚‚‚O distance is 3.05 Å, and the O-H-N angle is 104°.
(Bottom) View parallel to the hydrogen-bonding axis showing
the “Y”-shaped motif of the tape in cross section.
gentleness of desolvation favors the detection of com-
plexes in the gas phase that are not unlike those found
in solution. In tandem with X-ray crystal structure data,
ion populations from ESI-MS have been used to support
solution-phase structural models and equilibrium distri-
butions.19
Solutions of 6 (0.8, 9, 20, and 100 µM) in 1:1:1
acetonitrile:methanol:water were analyzed by ESI-MS.
Standard conditions were employed.20 The percent com-
position of monomer [M + H+], dimer [2M + H+] plus
[2M + Na+], trimer [3M + Na+], and tetramer [4M +
Na+] were determined for each concentration (Figure 7).
Dimer and trimer concentrations increased and the
monomer concentration decreased going from 0.8 to 100
µM. A small amount of tetramer (∼1%, not shown in
Figure 7) was evident at 9 µM and did not increase or
decrease at higher concentrations.
The detection of significant populations of dimeric and
trimeric ions, along with monomer ions, suggests that
these are stable aggregates in both the gas and solution
phases. At concentrations above 20 µM, dimers were the
principal constituents of the mixture, detected as both
protonated and sodiated ions. Interestingly, monomers
were observed only as protonated ions while trimers and
tetramers were observed only as sodiated ions. While
there are different ways in which molecules of 6 might
aggregate, the linearly hydrogen-bonded tapes and re-
ciprocally hydrogen-bonded pairs observed in the crystal
In the case of 6B pairs of molecules form zero-
dimensional hydrogen-bonded “dimers” through estab-
lishment of reciprocal R22(8) amide hydrogen bonds17
and arene edge-to-face interactions (Figure 4). The N‚‚‚
O distance is 2.82 Å, and the arene centroid-to-centroid
and hydrogen-to-centroid distances are 4.58 and 3.02 Å,
respectively. Neighboring dimers associate through
arene face-to-face contacts and form infinite one-
dimensional tapes (Figure 4). The face-to-face centroid-
to-centroid distance is 3.80 Å. Adjacent tapes, offset by
one-half a period, form sheets by interdigitation of
methoxy groups over hydrogen-bonded piperazinedione
rings (Figure 5). Adjacent sheets, rotated by 180° and
offset by one-half a period, engage in van der Waals
contacts (Figure 6).
Studies of Association in Solution by ESI-MS.
Electrospray ionization mass spectrometry (ESI-MS) has
been used to characterize supramolecular complexes
bound by ion-ion, dipole-dipole, hydrogen-bonding, and
van der Waals forces.18 For example, homochiral oc-
tameric serine clusters have been shown to be favored
over heterochiral octameric clusters or clusters of another
size.18e While the solute concentration increases during
the spray and subsequent desolvation processes, the
(18) (a) Cole, R. B. J. Mass. Spectrom. 2000, 35, 763-772. (b)
Brodbelt, J. S. Int. J. Mass. Spectrosc. 2000, 200, 57-69. (c) Przybyliski,
M.; Glocker, M. O. Angew. Chem., Int. Ed. Engl. 1996, 35, 806-826.
(d) Schalley, C. A. Int. J. Mass. Spectrosc. 2000, 194, 11-39. (e) Myung,
S.; Julian, R. R.; Nanita, S. C.; Cooks, R. G.; Clemmer, D. E. J. Phys.
Chem. B 2004, 108, 6105-6111 and references therein.
(19) (a) Szumna, A.; Jurczak, J. Eur. J. Org. Chem. 2001, 4031-
4039. (b) Cacace, F.; de Petris, G.; Giglio, E.; Punzo, F.; Troiani, A.
Chem. Eur. J. 2002, 8, 1925-1933. (c) Ventola, E.; Rissanen, K.;
Vainiotalo, P. Chem. Commun. 2002, 1110-1111.
(20) Flow rate 8 µL/min; spray voltage 4.57 kV.; sheath gas flow
rate 60; capillary voltage 26.05 V; capillary temperature 200.3 °C.
8696 J. Org. Chem., Vol. 70, No. 22, 2005

Hydrogen-Bond Association of Piperazinediones
FIGURE 4. Association via hydrogen bonding and arene interactions forms dimers and one-dimensional tapes in 6B. For each
dimer the O‚‚‚H distance is 1.94 Å, the N‚‚‚O distance is 2.82 Å, the O-H-N angle is 178°, the edge-to-face centroid-to-centroid
distance is 4.58 Å, and the hydrogen-to-centroid distance is 3.02 Å. Between dimers the face-to-face centroid-to-centroid distance
is 3.80 Å.
FIGURE 5. Complementary tape topography produces a sheet. This view of three tapes (top to bottom) is perpendicular to the
sheet and parallel to the plane of the piperazinedione rings. Molecules in each dimer are color matched.
polymorphs 6A and 6B provide useful physical models.
Dimers present in solution are likely part of a larger
concentration-dependent dynamic equilibrium. Associa-
tion of monomers through formation of one hydrogen
bond can involve either a tertiary or a secondary amide
carbonyl (Equation 2). In the former case formation of a
second hydrogen bond between the molecules is not
possible. Such dimers more closely resemble the linearly
hydrogen-bonded tape structure found in 6A. In the latter
case formation of a second hydrogen bond is both possible
and energetically favorable.21 This should lead to a
preponderance of dimers that resemble the reciprocally
hydrogen-bonded pair structure found in 6B. At suf-
ficiently high concentrations any of the dimeric species
shown in eq 2 could interact with additional molecules
of 6, leading first to a complex mixture of soluble
oligomers and ultimately to crystallization.
(21) Doig, A. J.; Williams, D. H. J. Am. Chem. Soc. 1992, 114, 338-
343.
J. Org. Chem, Vol. 70, No. 22, 2005 8697

Weatherhead-Kloster et al.
FIGURE 6. Complementary sheet topography produces a solid. This view of three sheets (top to bottom) is perpendicular to the
plane of the piperazinedione rings. Molecules in each dimer are color matched.
FIGURE 8. Selected HMBC correlations and chemical shifts
observed at 500 MHz for 105.6 mM 6 in CDCl3 at 283 K.
temperatures (253, 298, and 313 K). The use of chloro-
form as solvent was necessary due to the low solubility
of 6 in more inert solvents. HSQC and HMBC experi-
FIGURE 7. Percent composition of monomeric ([), dimeric
ments conducted at 500 MHz on the 105.6 mM sample
(b), and trimeric (2) species in the gas phase as a function of
1
of 6 at 283 K permitted the complete assignment of H
concentration of 6 in a 1:1:1 acetonitrile:methanol:water
and 13C signals. Selected HMBC correlations and chemi-
solution as determined by ESI-MS.
cal shifts are given in Figure 8.
While the 13C NMR spectrum and much of the 1H NMR
spectrum appeared largely unaffected, the chemical shifts
for the amide NH proton and the aryl protons Ha were
found to be both concentration and temperature depend-
ent (e.g., Figures 9 and 10). Tables of concentration- and
temperature-dependent chemical shift data are given in
the Supporting Information.
In an optimal linear hydrogen bond, as observed in
crystal 6B, the donated proton resides in the NMR
deshielding region of the acceptor carbonyl. Since an
increase in concentration or a decrease in temperature
favors hydrogen-bond formation,24 the observed downfield
shift from TMS for the NH proton with an increase in
the concentration of 6 or a decrease in the temperature
was expected.23
Studies of Association in Solution by NMR. Nuclear
magnetic resonance (NMR) spectroscopy has been used
to characterize molecular associations,22 including the
self-association of cyclic secondary cis-amides.23 In
these cases the chemical shifts of the NH protons
exhibit concentration and temperature dependence
owing to changes in intermolecular hydrogen bonding.
Chemical shift data has been used to extract equilibrium
association constants (Ka) as well as enthalpies and
entropies of association. For example, Ka for dimerization
of δ-valerolactam in CDCl3 at 306 K was determined to
be 5.35 ( 0.06 M-1 23c
.
Proton NMR spectra were obtained at 300 MHz for
solutions of 6 in CDCl3 at eight concentrations (10.6, 14.1,
25.1, 33.4, 44.6, 59.4, 79.2, and 105.6 mM) and at three
A more unusual result was the upfield movement of
one set of aryl protons, Ha, relative to the other nearly
stationary set of aryl protons, Hf, upon increasing the
(22) Connors, K. A. Binding Constants; Wiley-Interscience: New
York, 1987; Chapter 5.
(23) (a) Purcell, J. M.; Susi, H.; Cavanaugh, J. R. Can. J. Chem.
1969, 47, 3655-3660. (b) Blackwell, L. F.; Buckley, P. D.; Jolley, K.
W.; Watson, I. D. Aust. J. Chem. 1972, 25, 67-73. (c) Chen, J.-S.;
Rosenberger, F. Tetrahedron Lett. 1990, 31, 3975-3978. (d) Chen, J.-
S. J. Chem. Soc., Faraday Trans. 1994, 90, 717-720. (e) Chen, J.-S.;
Fang, C. Z. Phys. Chem. (Munich) 1997, 199, 49-60.
(24) By Le Chaˆtelier’s principle, perturbation of the monomer-dimer
equilibrium by an increase in monomer concentration favors dimer
formation. Assuming ∆S° for formation of dimers from 6 is negative
(ref 23d), a decrease in temperature will favor dimer formation.
8698 J. Org. Chem., Vol. 70, No. 22, 2005

Hydrogen-Bond Association of Piperazinediones
FIGURE 9. Concentration dependence of the chemical shifts of the NH proton and the aryl protons Ha and Hf of 6 at 300 MHz
in CDCl3 at 298 K.
FIGURE 10. Temperature dependence of the chemical shifts
of the NH proton and the aryl protons Ha and Hf of 6 at 105.6
mM in CDCl3 at 300 MHz.
FIGURE 12. Concentration dependence of the chemical shifts
of the aryl protons Hg of 12 at 300 MHz in CDCl3 at 298 K.
zene25 (12) in CDCl3 at three concentrations (11.1, 111,
and 222 mM) and at two temperatures (298 and 313 K).
Owing to symmetry, compound 12 exhibits only one aryl
proton signal, Hg. This signal displayed no temperature
dependence at any concentration but did move slightly
downfield with increased concentration at 298 or 313 K
(Figure 12). Deprived of preorganization by hydrogen-
bond association, compound 12 does not appear to
organize, at least in solution over the concentration range
studied, in an edge-to-face fashion.
Solvents with strong hydrogen-bond-donating and/or
-accepting properties can intercede and prevent formation
of reciprocal amide hydrogen bonds between piper-
azinedione molecules during crystallization.26 We ob-
served an unstable 2:1 cocrystal between trifluoroacetic
acid (TFA) and piperazinedione 13.27 The TFA molecules
were shown by X-ray crystallography to “cap” the amide
moieties of 13 (Figure 13). It was reasoned that addition
of sufficient TFA-d to the CDCl3 samples of 6 would
disrupt dimer formation and remove the concentration
and temperature dependence of the Ha chemical shift.28
FIGURE 11. Rationalization of the upfield shift observed for
Ha at increased dimer concentrations.
concentration of 6 or decreasing the temperature. This
can be rationalized if one assumes reversible formation
in solution of dimers with a reciprocally hydrogen-bonded
and arene-associated structure similar to that observed
in crystal 6B. In that case, protons Ha would lie in the
shielding cone of the edge-to-face associated arene ring
(Figure 11). The magnetic environment of protons Hf
would be largely unperturbed in this dimer.
Control experiments support this interpretation of the
concentration and temperature dependence of the chemi-
cal shift of Ha. Proton NMR spectra were obtained at 300
MHz for solutions of 1,4-dimethoxy-2,3-dimethylben-
(25) Kang, J.; Hilmersson, G.; Santamaria, J.; Rebek, J. J. Am.
Chem. Soc. 1998, 120, 3650-3656.
(26) (a) Jagadish, B.; Williams, L. J.; Carducci, M. D.; Bosshard,
C.; Mash, E. A. Tetrahedron Lett. 2000, 41, 9483-9487. (b) Jagadish,
B.; Carducci, M. D.; Bosshard, C.; Gu¨nter, P.; Margolis, J. I.; Williams,
L. J.; Mash, E. A. Cryst. Growth Des. 2003, 3, 811-821.
(27) Williams, L. J.; Bruck, M. A.; Mash, E. A. Unpublished results.
The crystal decomposed in air due to evaporative loss of TFA.
(28) The NH signal is lost due to proton-deuterium exchange
between 6 and TFA-d.
J. Org. Chem, Vol. 70, No. 22, 2005 8699

Weatherhead-Kloster et al.
NH
The magnitudes of the Ka values obtained (Ka 0.4-
0.7 M-1, Ka ≈ 0.1 M-1) are in line with reported values
Ha
for self-association of other cis lactams in chloroform.30
Self-association of cis lactams, including 6, is impeded
by complexation of chloroform with the amide moieties.
For this reason, the effort to obtain more and better NMR
data from compound 6 was abandoned in favor of
redesigning the probe to increase solubility in nonpar-
ticipatory NMR solvents.
The present study contributes to the substantial body
of work by others on crystal nucleation and growth.31
Others have shown that polymorphism can be controlled
by addition of small molecules that reversibly mask one
or more features of a molecule undergoing crystalliza-
tion.32 For example, aggregation of tetrolic acid in ethanol
and chloroform was studied by FTIR-ATR and correlated
with spectra of crystal polymorphs that exhibit C(4) and
R22(8) hydrogen-bonding patterns.33 Herein, a combina-
tion of X-ray crystallographic, mass spectrometric, and
nuclear magnetic resonance spectroscopic studies led to
descriptions of alternative aggregation modes and quali-
tative and quantitative analyses of the equilibria involv-
ing monomer and dimers of 6 in solution. In future work
replacement of the N-methyl by a more lipophilic group
will permit NMR studies of aggregation in noninterfering
solvents. This should make possible extraction and
comparison of values of ∆G, ∆H, and ∆S for self-
FIGURE 13. Sketch of piperazinedione 13 capped by trifluoro-
acetic acid molecules after unpublished work by Williams,
Bruck, and Mash.27 The preliminary crystal structure report
for 13‚2TFA appears in the Supporting Information.
associations of
a set of mono-N-alkyl piperazine-
diones related to compounds 1-5 and shed light on the
effect of alkyl chain length on self-association. This
information would inform future crystal design efforts
by providing a more complete understanding of the
thermodynamics and kinetics of relevant intermolecular
associations.34
FIGURE 14. Concentration dependence of the chemical shifts
of the aryl protons Ha and Hf of 6 at 300 MHz in CDCl3
containing 4% TFA at 298 K.
Experimental Section
TFA-d (4% v/v, 520 mM) was added to the CDCl3
solutions of 6 used in the concentration- and tempera-
ture-dependent NMR studies. This proved to be enough
TFA to disrupt hydrogen bonding without introducing an
overwhelming solvent effect. In the presence of TFA the
signals due to aryl protons Ha and Hf both shift slightly
upfield with increasing concentration (Figure 14). Little
or no temperature dependence was observed. These
observations support attribution of the more substantial
upfield shift of Ha, but not Hf, to arene edge-to-face
association in the hydrogen-bonded dimer.
Linear relationships exist between the observed NH
and Ha proton chemical shifts and concentration over the
concentration range studied, indicative of dynamic equi-
libria between monomer and dimers (see eq 2 and Figures
15 and 16). Since separate signals for the monomer and
dimers were not observed, equilibration was rapid on the
NMR time scale and the observed chemical shifts repre-
sented the weighted averages of the chemical shifts of
the contributing species.
Ethyl 2-Benzyloxycarbonylamino-4,7-dimethoxyindan-
2-carboxylate (8). Dibenzyl dicarbonate (1.68 g, 5.89 mmol)
was added to a solution of ethyl 2-amino-4,7-dimethoxyindan-
2-carboxylate10 (7, 520 mg, 1.96 mmol) in CH2Cl2 (15 mL) and
the solution heated to reflux. After 19 h the mixture was
cooled, diluted with CH2Cl2 (200 mL), and washed with water
(100 mL) and saturated NaCl (100 mL). The organic phase
was dried with MgSO4, concentrated under reduced pressure
to a crude yellow oil, and purified by gravity chromatography
(230-400 mesh silica pretreated with 1% NEt3, 30% EtOAc
in hexanes) to give 8 as an off-white solid (660 mg, 84% yield).
Rf ) 0.71 (50% EtOAc/hexanes). mp 113-114 °C. IR (KBr,
cm-1): 1741, 1701. 1H NMR (CDCl3, 300 MHz): δ 1.18 (s, 3H),
3.25 (d, J ) 16.8 Hz, 2 H), 3.54 (d, J ) 16.8 Hz, 2 H), 3.73 (s,
6H), 4.17 (s, 2H), 5.06 (s, 2H), 5.54 (s, 1H), 6.62 (s, 2H), 7.29
(s, 5H). 13C NMR (CDCl3, 75 MHz): δ 13.9, 41.4, 55.4, 61.5,
65.7, 66.5, 109.2, 127.9, 128.3, 129.1, 136.2, 149.9, 155.2, 173.2.
(30) (a) Chen, C.; Swenson, C. J. Phys. Chem. 1969, 73, 2999-3008.
(b) Krikorian, S. J. Phys. Chem. 1982, 86, 1875-1881.
(31) (a) Weissbuch, I.; Lahav, M.; Leiserowitz, L. Cryst. Growth Des.
2003, 3, 125-150. (b) Blagden, N.; Davey, R. J. Cryst. Growth Des.
2003, 3, 873-885.
(32) (a) Luo, T.-J. M.; MacDonald, J. C.; Palmore, G. T. R. Chem.
Mater. 2004, 16, 4916-4927. (b) Blagden, N.; Song, M.; Davey, R. J.;
Seton, L.; Seaton, C. C. Cryst. Growth Des. 2005, 5, 467-471. (c)
Weissbuch, I.; Torbeev, V. Y.; Leiserowitz, L.; Lahav, M. Angew. Chem.,
Int. Ed. 2005, 44, 3226-3229.
(33) Parveen, S.; Davey, R. J.; Dent, G.; Pritchard, R. G. J. Chem.
Soc., Chem. Commun. 2005, 1531-1533.
(34) Kloster, R. A.; Carducci, M. D.; Mash, E. A. Org. Lett. 2003, 5,
3683-3686.
The concentration- and temperature-dependent chemi-
cal shift data for 6 were treated quantitatively by
application of the method of Horman and Dreux29 and
the results confirmed by iterative best-fit least-squares
analysis. The details of this analysis appear in the
Supporting Information.
(29) Horman, I.; Dreux, B. Helv. Chim. Acta 1984, 67, 754-764.
8700 J. Org. Chem., Vol. 70, No. 22, 2005

Hydrogen-Bond Association of Piperazinediones
FIGURE 15. Chemical shift of the NH proton of 6 as a function of concentration.
FIGURE 16. Chemical shift of the Ha proton of 6 as a function of concentration.
HRMS (FAB+) calcd for C22H26NO6 399.1682 (M+), found
2-(Benzyloxycarbonylmethylamino)-4,7-dimethoxy-
399.1683 (+0.2 ppm).
indan-2-carboxylic Acid (10). A solution of 9 (480 mg, 1.2
mmol) and KOH (670 mg, 12 mmol) in an 80% aqueous ethanol
solution (25 mL) was heated to reflux. After 4 h the solution
was cooled to room temperature and volatiles were removed
under reduced pressure to give a white salt. The solid was
dissolved in water (50 mL), the solution was acidified with
concentrated HCl to a pH 2, and the solution was extracted
with EtOAc (3 × 50 mL). The organic phase was washed with
water (150 mL) and saturated NaCl (150 mL), dried with
MgSO4, and concentrated under reduced pressure to a sticky
oil. The oil was azeotroped with benzene and triturated with
hot hexanes to give 10 as an off-white solid (370 mg, 81%
yield). mp 171-172 °C. Rf ) 0.21 (50% EtOAc/hexanes). IR
(KBr, cm-1): 3421, 1709, 1685. 1H NMR (CDCl3, 300 MHz): δ
2.99 (s, 3H), 3.34 (d, J ) 16.9 Hz, 2 H), 3.65 (d, J ) 19.8 Hz,
2 H), 3.75 (s, 6H), 5.13 (s, 2H), 6.63 (s, 2H), 7.32 (s, 5H), 10.44
(s, 1H). 13C NMR (CDCl3, 75 MHz): δ 32.6, 40.1, 55.5, 62.0,
67.6, 71.1, 109.3, 127.9, 128.4, 129.2, 136.2, 149.6, 156.7, 179.2.
HRMS (FAB+) calcd for C21H23NO6 (M+) 385.1525, found
385.1526 (+0.1 ppm).
Ethyl 2-(Benzyloxycarbonylmethylamino)-4,7-dimeth-
oxyindan-2-carboxylate (9). Iodomethane (740 µL, 11.9
mmol) was added to a solution of 8 (590 mg, 1.5 mmol) in 10:1
THF:DMF (20 mL) under argon, and the solution was brought
to reflux. After 45 min the heat source was removed and
sodium hydride (180 mg, 7.4 mmol) was slowly added to the
hot solution (caution! exothermic). The reaction mixture was
heated at reflux for an additional 20 min, then cooled to room
temperature, and slowly quenched by the addition of water
(1.5 mL). The solution was diluted with water (200 mL) and
extracted with EtOAc (3 × 200 mL). The organic phase was
then washed with saturated Na2SO3 (150 mL) and saturated
NaCl (150 mL) and dried with MgSO4. The volatiles were
removed under reduced pressure to give 9 as a light yellow
oil (490 mg, 80% yield). Rf ) 0.41 (30% EtOAc/hexanes). IR
1
(NaCl plate, cm-1): 1741, 1693. H NMR (CDCl3, 300 MHz):
δ 1.12 (s, 3 H), 2.98 (s, 3 H), 3.36 (d, J ) 17.1 Hz, 2 H), 3.61
(d, J ) 17.1 Hz, 2 H), 3.74 (s, 6H), 4.12 (s, 2H), 5.14 (s, 2H),
6.63 (s, 2H), 7.34 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 13.9,
32.2, 39.9, 55.5, 61.1, 67.2, 71.2, 109.2, 127.7, 127.9, 128.3,
129.3, 136.3, 149.6, 156.3, 173.4. HRMS (FAB+) calcd for
C23H28NO6 (M+ + H) 414.1917, found 414.1924 (+1.8 ppm).
Ethyl 2-[2-(Benzyloxycarbonylmethylamino)-4,7-di-
methoxyindane-2-carbonyl]amino-4,7-dimethoxyindan-2-
carboxylate (11). N,N-Diisopropylethylamine (100 µL, 630
J. Org. Chem, Vol. 70, No. 22, 2005 8701

Weatherhead-Kloster et al.
1
µmol) was added to a solution of 7 (56 mg, 210 µmol), 10 (123
mg, 320 µmol), and PyBroP (150 mg, 320 µmol) in dry CH2Cl2
(4 mL) at 0 °C under argon. The mixture was allowed to warm
to room temperature. After 36 h the reaction mixture was
fractionated by silica gel flash chromatography (230-400
mesh, pretreated with 1% NEt3, 50% EtOAc in hexanes) to
provide 11 as a sticky solid. Upon trituration with hot hexanes
11 was obtained as a white solid (130 mg, 97% yield). mp 145-
146 °C. Rf ) 0.42 (50% EtOAc/hexanes). IR (KBr, cm-1): 1741,
1701. 1H NMR (CDCl3, 300 MHz): δ 1.13 (t, J ) 7.0 Hz, 3 H),
2.95 (s, 3 H), 3.09 (d, J ) 17.3 Hz, 2 H), 3.19 (d, J ) 16.8 Hz,
2 H), 3.49 (d, J ) 16.8 Hz, 2 H), 3.71 (s, 12 H), 3.79 (d, J )
17.3 Hz, 2 H), 4.09 (q, J ) 6.8 Hz, 2 H), 5.03 (s, 2H), 6.59 (s,
4H), 6.95 (s, 1H), 7.28 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ
13.9, 33.1, 39.7, 41.3, 55.5, 55.5, 61.3, 64.9, 67.4, 72.1, 109.1,
109.3, 127.8, 128.4, 129.3, 129.4, 136.2, 149.6, 149.9, 157.0,
172.7, 173.1. HRMS (FAB+) calcd for C35H41N2O9 633.2812 (M+
+ H), found 633.2805 (-1.2 ppm).
Cyclo[(2-methylamino-4,7-dimethoxyindan-2-carbox-
ylic acid)(2-amino-4,7-dimethoxyindan-2-carboxylic acid)]
(6). A solution of 11 (209 mg, 330 µmol) in absolute EtOH (15
mL) was prepared by heating until homogeneous. The solution
was then cooled to ambient temperature, and cyclohexene (700
µL, 6.6 mmol) and 10% Pd/C (210 mg) were added. The mixture
was heated at reflux for 40 min and then filtered and
concentrated under reduced pressure. The resulting oil was
triturated in a 1:1 mixture of hot Et2O and hexanes to give a
white solid. After the hot solution had cooled to room temper-
ature it was further cooled to -22 °C and filtered while cold
to give an off-white solid (147 mg). Part of this white solid
(100 mg) was thermolyzed in a sealed, evacuated tube for 50
min at 260-265 °C. The residue was taken up in CH2Cl2,
treated with charcoal, filtered, and volatiles were removed to
leave a yellow residue. The residue was purified by trituration
with 10% Et2O in hexanes (2 × 5 mL) to give 6 as an off-white
solid (65 mg, 43% for two steps). mp 278 °C (dec). IR (KBr,
cm-1) 3188, 3051, 1669, 1660. H NMR (105.6 mM in CDCl3,
298 K, 300 MHz,): δ 2.82 (s, 3H), 3.08 (d, J ) 16.1 Hz, 2 H),
3.23 (d, J ) 17.6 Hz, 2 H), 3.71 (m, 16 H), 6.60 (s, 2H), 6.64 (s,
2H), 6.76 (s, 1H). 13C NMR (105.6 mM in CDCl3, 298 K, 75
MHz): δ 29.9, 43.3, 44.9, 55.5, 55.6, 66.2, 69.2, 109.3, 128.0,
129.5, 149.4, 150.3, 167.7, 170.8. HRMS (FAB+) calcd for
C25H28O6N2 (M+) 452.1947, found 452.1935 (-2.8 ppm).
Acknowledgment. This work was supported in part
by the Office of Naval Research through the Center for
Advanced Multifunctional Nonlinear Optical Polymers
and Molecular Assemblies, by the National Science
Foundation (CHE9610374), by Research Corporation,
and by the University of Arizona through the Materials
Characterization Program and the Office of the Vice
President for Research. We thank Tammy Timmons for
assistance with the chemical synthesis, Michael D.
Carducci for assistance in obtaining the crystal struc-
tures of 6A and 6B, Arpad Somogyi for assistance in
obtaining MS data, Neil Jacobsen for assistance in
obtaining NMR data, and Michael Bruck and Lawrence
Williams for the preliminary crystal structure of 13‚
2TFA.
Supporting Information Available: General experimen-
tal procedures, ESI mass spectra of 6 at various concentra-
tions, proton and carbon NMR spectra for compounds 6 and
8-11, 2D NMR spectra for compound 6, X-ray crystallographic
information files (CIF) for crystals of 6A and 6B, a preliminary
crystal structure report for 13‚2TFA, and concentration- and
temperature-dependent chemical shift data and analysis. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0509096
8702 J. Org. Chem., Vol. 70, No. 22, 2005