Organic crystal engineering with 1,4-piperazine-2,5-diones. 8. Synthesis, crystal packing, and thermochemistry of piperazinediones derived from 2-amino-4,7-dialkoxyindan-2-carboxylic acids

Article abstract of DOI:10.1021/cg301003p

1,4-Piperazine-2,5-diones possessing C_2hmolecular symmetry and bearing four methoxy, ethoxy, butoxy, hexyloxy, octyloxy, nonyloxy, dodecyloxy, or octadecyloxy groups weresynthesized from 2-amino-4,7-dialkoxyindan-2- carboxylic acids. Where poss

Full text of DOI:10.1021/cg301003p

Article
pubs.acs.org/crystal
Organic Crystal Engineering with 1,4-Piperazine-2,5-diones. 8.
Synthesis, Crystal Packing, and Thermochemistry of Piperazinediones
Derived from 2‑Amino-4,7-dialkoxyindan-2-carboxylic Acids
Kirk E. Wells, Robin A. Weatherhead, Francis N. Murigi, Gary S. Nichol, Michael D. Carducci,
Hugh D. Selby, and Eugene A. Mash*
Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States
S
* Supporting Information
ABSTRACT: 1,4-Piperazine-2,5-diones possessing C2h molec-
ular symmetry and bearing four methoxy, ethoxy, butoxy, hexyl-
oxy, octyloxy, nonyloxy, dodecyloxy, or octadecyloxy groups were
synthesized from 2-amino-4,7-dialkoxyindan-2-carboxylic acids.
Where possible, the piperazinediones were crystallized from
appropriate solvents and the supramolecular organizations were
determined by X-ray crystallography. In each case so studied,
crystal assembly via three mutually orthogonal interactions,
namely, R22(8) hydrogen bonding, arene perpendicular edge-
to-center interactions, and alkyl chain interdigitation, was ob-
served. The thermochemical properties of these compounds were
studied by modulated differential scanning calorimetry. In most
cases, one or more reversible thermal events were observed between room temperature and melting to an isotropic liquid. In the
cooling cycle, freezing point temperatures were observed to decrease with increasing hydrocarbon chain length. This may be due to
greater entropic penalties for hydrogen-bond association of molecules with longer hydrocarbon chains.
INTRODUCTION
■
The field of crystal engineering1−6 seeks an understanding of
weak intermolecular associative forces and strives for rational
development of materials useful for a wide range of applications,
for example, liquid crystal materials7−9 for use in optical displays.
We consider the molecular framework of pentacyclic molecules 1
suitable for use in an exploration of structural effects on weak
stabilization of protein tertiary structures.25,26 Parallel center-
intermolecular associative forces and an appropriate scaffold for
to-center association27 is favored for arene rings that possess very
the design of compounds that could possess useful bulk
properties.10−17 The conformational freedom of such molecules
different electron densities, as in cocrystals of arenes and
is restricted,18 limiting the number of possible packing options.
At the same time, attachment of functional groups to the scaffold
can provide structural variability. For example, incorporation of
alkoxy groups as in 2 endows the molecule with three chemically
and spatially independent recognition elements (see Figure 1).
The central 1,4-piperazine-2,5-dione ring of 2 is known to
favor formation of supramolecular “one-dimensional” tapes
through reciprocal amide-to-amide R22(8) hydrogen bonding
(z-axis, Figure 1).19 Control of order in the second and third
dimensions for hydrogen-bonded one-dimensional (1D) tapes of
2 depends on harnessing arene−arene interactions (x-axis) and
van der Waals interactions (y-axis). van der Waals attractive
interactions almost always contribute significantly to stabilization
of the crystal structure as evidenced by the tendency of organic
compounds to achieve closest packing in the solid state.20−24
Various arene interaction types have been recognized as
important, from the packing of small molecules to the
perfluoroarenes.28−31 Parallel edge-to-center association27 also is
responsive to changes in π electron density due to substituent
effects.31,32 Perpendicular edge-to-center associations27 are often
observed for unsubstituted arenes, as in the crystal structures of
benzene,33 naphthalene,34 and anthracene,35 among others. Both
the nature and magnitude of perpendicular edge-to-center
interactions have been questioned, but there is agreement that
such interactions are stabilizing.36−43
We previously observed that the crystal packing of compound
3a (Figure 2, top) followed the assembly paradigm given in
Figure 1.44 Piperazinediones with topology similar to 3a packed
similarly.45 Given these observations and the fact that alkyl chains
longer than butyl generally adopt an extended zig−zag
Received: July 18, 2012
Revised: August 23, 2012
Published: August 24, 2012
© 2012 American Chemical Society
5056
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
Figure 1. Directionality of propagation of chemically and spatially independent intermolecular recognition elements on piperazinedione scaffold 2.
properties of the set of tetraalkoxy-substituted piperazinediones
3b−3h, and on the crystal structures of 3b, 3c, and 3g.
EXPERIMENTAL SECTION49
■
Syntheses of 3b and 3d provide representative examples of the synthetic
methods employed. Details of the syntheses and characterizations of 3c and
3e−h appear in the Supporting Information that accompanies this article.
1,4-Diethoxy-2,3-dimethylbenzene (5b). Sodium metal (4.69 g,
204 mmol) was cut into slivers and washed with hexanes prior to
suspension piecewise in absolute ethanol (150 mL). After complete
reaction, 2,3-dimethylhydroquinone (4, 11.5 g, 83.2 mmol) was added
to the sodium ethoxide solution. After 30 min, bromoethane (15.0 mL,
21.9 g, 201 mmol) was added dropwise via an addition funnel and the
funnel was washed with absolute ethanol (50 mL). The resultant
solution was heated to reflux under argon for 18 h. Ethanol was removed
in vacuo and diethyl ether (300 mL) was added to the residue. The white
precipitate was removed by filtration and washed with diethyl ether (2 ×
50 mL). The organic phases were combined and washed with sat aq
sodium bicarbonate (400 mL) and brine (400 mL). The organic layer
was dried over magnesium sulfate and filtered, and volatiles were
removed in vacuo. The residue was crystallized from absolute ethanol
at −20 °C, yielding 10.5 g (53.8 mmol, 65%) of 5b as tan plates, Rf 0.44
(5% EtOAc/hexanes). 1H NMR (CDCl3) δ 1.24 (6H, t, J = 7.0 Hz), 2.02
Figure 2. Top: Cartoon representations of the observed hydrogen-
(6H, s), 3.79 (4H, q, J = 7.0 Hz), 6.47 (2H, s); 13C NMR (CDCl3) δ
bonded tape cross-section (left) and crystal packing (right) viewed
down the long axis of the tape for compound 3a. Bottom: Cartoon
representations of a hypothetical hydrogen-bonded tape cross-section
(left) and crystal packing (right) viewed parallel to the long axis of the
12.2, 15.1, 64.5, 109.4, 127.0, 151.1.
1,4-Bis-hexyloxy-2,3-dimethylbenzene (5d).50 A solution of 4
(2.48 g, 18.0 mmol) in dry THF (35 mL) was slowly added via cannula
to a suspension of sodium hydride (950 mg, 40 mmol) in THF (35 mL)
tape for 3g, the dodecyloxy homologue of 3a.
under argon. The cannula was rinsed with THF (2 × 10 mL). Upon
injection, an exothermic reaction was observed, and the resulting green
conformation and pack in either a parallel or an antiparallel fashion
in the crystalline state,46,47 we postulated that tapes formed from
compounds related to 3a, but with elongated cross sections due to
extension of the alkyl chains (e.g., 3b−3h), would pack via
reciprocal amide hydrogen bonding, arene perpendicular edge-to-
center interactions, and van der Waals-driven interdigitation of the
alkyl chains in extended conformations (Figure 2, bottom).48
Molecules 3 possessing alkyl chains of sufficient length might
exhibit liquid crystal properties. As a step toward examining this
possibility, we report here on the synthesis and thermochemical
colored solution was allowed to stir at room temperature. After 20 min,
1-iodohexane (5.3 mL, 7.6 g, 36 mmol) was added via syringe and the
reaction mixture was heated to reflux for 72 h. The solution was cooled
to room temperature, slowly quenched by addition of water (15 mL),
and concentrated under a vacuum to a brown residue. The material was
purified by flash chromatography (230−400 mesh silica) using hexanes
as eluent to give 3.90 g (12.7 mmol, 71%) of 5d as a yellow oil, Rf 0.73
(40% EtOAc/hexanes). IR (NaCl) cm−1 1468, 1252; 1H NMR
(300 MHz, CDCl3) δ 0.91 (6H, t, J = 6.8 Hz), 1.35 (8H, m), 1.48 (4H,
pentet, J = 7.2 Hz), 1.77 (4H, pentet, J = 6.8 Hz), 2.17 (6H, s), 3.88 (4H, t,
J = 6.4 Hz), 6.63 (2H, s); 13C NMR (75 MHz, CDCl3) δ 12.1, 14.0, 22.6,
5057
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
25.8, 29.5, 31.6, 68.9, 109.1, 126.9, 151.2; HRMS (FAB+) calculated for
C20H34O2 (M+) 306.2559, found 306.2563 (+1.2 ppm).
using CH2Cl2, the plug was eluted with 10% methanol in CH2Cl2 (1 L),
and the eluent was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (300 mL), and the solution was washed with sat. aq. sodium
bicarbonate solution (200 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The residue was subjected to flash chromatog-
raphy on silica 60 (400 mL) using a gradient of 2.5−5% methanol in 1/1
EtOAc/hexanes, yielding 4.06 g (13.8 mmol, 40%) of 9b as a viscous
brown oil. 1H NMR (CDCl3) δ 1.28 (3H, t, J = 7.5 Hz), 1.37 (6H, t, J =
6.9 Hz), 1.78 (2H, bs), 2.92 (2H, d, J = 16.2 Hz), 3.46 (2H, d, J =
16.2 Hz), 3.98 (2H, q, J = 7.2 Hz), 4.21 (4H, q, J = 7.2 Hz), 6.62 (2H, s);
13C NMR (CDCl3) δ 14.2, 15.0, 43.8, 61.2, 63.9, 64.6, 110.5, 130.1,
1-Bromo-2,5-bis-hexyloxy-3,4-dimethylbenzene (6d). A sol-
ution of bromine (1.6 mL, 5.0 g, 31 mmol) in CHCl3 (75 mL) was added
dropwise over a 30 min period to a solution of 5d (8.92 g, 29.1 mmol) in
CHCl3 (75 mL) at room temperature under argon. After 45 min, the
reaction mixture was diluted with CH2Cl2 (100 mL) and washed
successively with sat aq NaHCO3 (100 mL), sat aq Na2SO3 (100 mL),
and brine (100 mL). The organic phase was dried (MgSO4), filtered, and
concentrated under a vacuum to give 10.1 g (26.2 mmol, 90%) of 6d as a
light yellow oil. IR (NaCl) cm−1 1462, 1375, 1227, 1103; 1H NMR (300
MHz, CDCl3) δ 0.92 (6H, m), 1.35 (8H, m), 1.49 (4H, septet, J = 7.4
Hz), 1.79 (4H, septet, J = 7.1 Hz), 2.09 (3H, s), 2.22 (3H, s), 3.78 (2H, t,
J = 6.6 Hz), 3.86 (2H, t, J = 6.5 Hz), 6.85 (1H, s); 13C NMR (75 MHz,
CDCl3) δ 12.1, 13.4, 14.0, 14.1, 22.6, 22.6, 25.7, 25.8, 29.2, 30.1,
31.5, 31.7, 68.6, 73.2, 113.1, 113.5, 126.0, 132.3, 147.9, 153.4; HRMS
(FAB+) calculated for C20H3379BrO2 (M+) 384.1664, found 384.1672
(+2.1 ppm).
1-Bromo-3,4-bis-bromomethyl-2,5-bis-ethoxybenzene (7b).
Compound 5b (7.79 g, 40.1 mmol) was dissolved in dry CCl4 (200 mL).
NBS (14.3 g, 80.3 mmol) and benzoyl peroxide (BPO, 100 mg, 0.72
mmol, ∼2 mol %) were added. The slurry was heated to reflux and
stirred vigorously under argon. Additional BPO (100 mg) was added
each hr. After 4.5 h 1H NMR showed ring bromination in addition to
side chain bromination. Additional NBS (7.14 g, 40.1 mmol) and BPO
(100 mg) were added and the slurry was heated at reflux for 24 h. The
slurry was cooled to room temperature and succinimide was removed by
filtration. The organic phase was washed with aq sodium thiosulfate
solution (100 mL), dried over magnesium sulfate, filtered, and
concentrated in vacuo. The brown solid residue was crystallized from
hexanes at −20 °C, yielding 11.8 g (27.4 mmol, 68%) of 7b as a tan solid.
1H NMR (CDCl3) δ 1.43 (6H, m, J = 6.6 Hz), 3.91 (2H, q, J = 6.6 Hz),
149.6, 176.7; HRMS (FAB) calculated for C16H23O4N 294.1705, found
294.1712.
Ethyl 2-Amino-4,7-bis-hexyloxyindan-2-carboxylate (9d).
Dry acetonitrile (850 mL) was added in one portion to a flask
containing 7d (14.2 g, 26.1 mmol), tetrabutylammonium iodide (1.9 g,
5.1 mmol), and finely ground potassium carbonate (43 g, 311 mmol)
under argon. The slurry was stirred and heated to reflux in an oil bath at
85−90 °C. Ethyl isocyanoacetate (3.1 mL, 3.2 g, 28 mmol) was injected.
Vigorous stirring was essential for an efficient and complete reaction.
After 15 h, the solution was cooled to room temperature and filtered,
and the salts were washed thoroughly with CH2Cl2. The organic phase
was concentrated under a vacuum to a brown residue. Flash
chromatography (230−400 mesh silica) using 10% EtOAc/hexanes as
eluent produced 9.0 g of crude 10d as a yellow oil, Rf 0.38 (10% EtOAc/
hexanes). The crude isocyanate was dissolved in a mixture of absolute
EtOH (80 mL) and conc. HCl (5 mL) and the solution was stirred
overnight at room temperature. The volatiles were removed under a
vacuum to leave a white solid. The solid was taken up in water (250 mL),
the solution was basified with conc. NH4OH, and extracted with Et2O
(3 × 200 mL). The organic extracts were combined, dried (MgSO4),
filtered, and concentrated under a vacuum to produce a yellow residue.
The material was subjected to flash column chromatography (230−400
mesh silica, pretreated with 1% NEt3) using 10% EtOAc/hexanes as
eluent until all yellow nonpolar impurities were removed. The eluent
was then changed to 30% EtOAc/hexanes, affording 5.0 g of crude 11d
as a brown oil, Rf 0.29 (30% EtOAc/hexanes). The crude amine 11d was
dissolved in absolute EtOH (50 mL), 10% Pd/C (2.4 g) was added, and
the compound was hydrogenolyzed using a Parr apparatus (H2 gas at
55 psi). Additional 10% Pd/C (100 mg) was added to the reaction each day.
After 4 days, the reaction mixture was filtered, the catalyst was washed
with CH2Cl2, and the filtrate was concentrated under a vacuum to leave
an orange residue. Gravity column chromatography (silica gel 60 eluted
with 40% EtOAc/hexanes, column pretreated with 1% NEt3) gave 1.97 g
(4.9 mmol, 19% for 3 steps) of 9d as a yellow oily solid, Rf 0.48 (50%
EtOAc/hexanes), mp 35−36 °C. IR (KBr) cm−1 1727; 1H NMR (200
MHz, CDCl3) δ 0.87 (6H, t, J = 6.6 Hz), 1.13 (15H, m), 1.71 (6H, m),
2.88 (2H, d, J = 16.4 Hz), 3.42 (2H, d, J = 16.4 Hz), 3.86 (4H, dt, J = 2.2,
6.4 Hz), 4.18 (2H, q, J = 7.2 Hz), 6.58 (2H, s); 13C NMR (50 MHz,
CDCl3) δ 13.9, 14.1, 22.5, 25.6, 29.7, 31.5, 43.8, 61.1, 64.6, 68.3, 110.4,
130.1, 149.8, 176.7; HRMS (FAB+) calculated for C24H40NO4 (M +
H)+ 406.2957, found 406.2952 (−1.3 ppm).
Ethyl 2-tert-Butoxycarbonylamino-4,7-diethoxyindan-2-car-
boxylate (12b). Amino ester 9b (3.00 g, 10.2 mmol) and di-tert-butyl
dicarbonate (2.45 g, 11.2 mmol) were dissolved in 50 mL of CH2Cl2.
Triethylamine (2.0 mL, 1.4 g, 14 mmol) was added and the solution was
allowed to stir at room temperature under argon for 18 h. Volatiles were
removed in vacuo and the residue was crystallized from absolute ethanol,
yielding 2.06 g (5.24 mmol, 51%) of 12b as pale yellow crystals, Rf 0.45
(35% EtOAc/hexanes); 1H NMR (CDCl3) δ 1.24 (3H, t, J = 5.5 Hz),
1.36 (6H, t, J = 7.2 Hz), 1.42 (9H, s), 3.20 (2H, d, J = 17.0 Hz), 3.54 (2H,
d, J = 17.0 Hz), 3.96 (4H, q, J = 6.6 Hz), 4.21 (2H, q, J = 6.9 Hz), 5.16
(1H, s), 6.61 (2H, s); 13C NMR (CDCl3) δ 14.1, 14.9, 28.2, 41.6, 61.4,
63.9, 65.6, 79.7, 110.7, 129.6, 149.35, 154.9, 173.5.
Anal. Calculated for C21H31NO6: C, 64.10; H, 7.94, N, 3.56. Found:
C, 64.15; H, 7.95, N, 3.74.
Ethyl 2-tert-Butoxycarbonylamino-4,7-bis-hexyloxyindan-2-
carboxylate (12d). Di-tert-butyl dicarbonate (1.47 g, 6.74 mmol) was
added to a solution of amino ester 9d (1.81 g, 4.5 mmol) in a mixture of
CH2Cl2 (25 mL) and brine (5 mL) and the reaction mixture was heated
4.05 (2H, q, J = 6.6 Hz), 4.60 (4H, s), 6.93 (1H, s).
1-Bromo-3,4-bis-bromomethyl-2,5-bis-hexyloxybenzene
(7d). NBS (9.8 g, 55 mmol) was added in one portion to a solution of 6d
(10.1 g, 26.2 mmol) in CCl4 (150 mL) under argon. A 250 W (115−125
V) IR heat lamp was positioned near the reaction flask to ensure a gentle
reflux. After 24 h, the solution was cooled to room temperature,
succinimide was removed by filtration, and the solid was washed with
CCl4 (20 mL). The solution was diluted with CH2Cl2 (100 mL) and
washed successively with sat aq NaHCO3 (100 mL), sat aq Na2SO3 (100
mL), and brine (100 mL). The organic phase was dried (MgSO4),
filtered, and concentrated under vacuum to give 14.0 g (25.8 mmol,
98%) of 7d as a yellow oil. IR (NaCl) cm−1 1455, 1245, 1011; 1H NMR
(300 MHz, CDCl3) δ 0.91 (6H, m), 1.34 (8H, m), 1.48 (4H, m), 1.83
(4H, septet, J = 7.2 Hz), 3.95 (2H, t, J = 6.4 Hz), 4.02 (2H, t, J = 6.6 Hz),
4.69 (2H, s), 4.70 (2H, s), 7.02 (1H, s); 13C NMR (75 MHz, CDCl3) δ
14.0, 14.0, 22.6, 22.6, 23.5, 23.7, 25.5, 25.7, 29.0, 30.0, 31.4, 31.6, 69.0,
74.2, 117.1, 118.4, 125.8, 132.7, 148.6, 153.7; HRMS (FAB+) calculated
for C20H3179Br281BrO2 (M+) 541.9855, found 541.9850 (−0.7 ppm).
Ethyl 2-Amino-4,7-diethoxyindan-2-carboxylate (9b). Ethyl 2-
(benzylideneamino)acetate (8.32 g, 43.5 mmol) was dissolved in dry
THF (1.8 L) and the solution was cooled to −78 °C under argon.
Sodium hexamethyldisilazane (87 mL, 1 M in THF, 87 mmol) was
added dropwise. After 30 min 7b (15.0 g, 34.8 mmol) in THF (200 mL)
was added dropwise. The reaction mixture was allowed to warm to room
temperature and was stirred for 18 h. The reaction mixture was poured
into brine (1 L) and the phases were separated. The aqueous phase was
extracted with ethyl acetate (300 mL), the organic layers were
combined, dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The resultant brown, viscous oil was dissolved in CH2Cl2 (200
mL) and passed through a plug of silica 60 (100 g) eluted with CH2Cl2,
yielding 9.5 g of crude 8b as a brown paste that was directly
hydrogenated. The paste was dissolved in absolute ethanol (100 mL),
10% palladium on carbon (400 mg) was added, and the mixture was
shaken for 48 h under H2 (55 psi) on a Parr apparatus. Additional 10%
palladium on carbon (1 g) was then added and the reaction was
continued for 18 h. The mixture was passed through a plug of silica 60
(75 g) eluted with CH2Cl2 (500 mL) and volatiles were removed
in vacuo. The brown residue was loaded onto a plug of silica 60 (100 g)
5058
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
Scheme 1. Synthesis of Tribromides 7b−h
at a gentle reflux overnight. Additional di-tert-butyl dicarbonate (0.5 g,
2.3 mmol) was added to the solution after 24 h, and the reaction was
heated at reflux an additional 6 h. The reaction mixture was diluted with
CH2Cl2 (150 mL) and washed with brine (100 mL). The organic phase
was dried (MgSO4), filtered, and concentrated under a vacuum to give a
yellow solid which was purified by flash chromatography (230−400
mesh silica, pretreated with 1% NEt3) using 20% EtOAc/hexanes as
eluent to obtain 1.99 g (3.93 mmol, 95%) of 12d as an off-white solid, Rf
0.67 (30% EtOAc/hexanes), mp 63−64 °C. IR (KBr) cm−1 3363 (b),
25.7, 28.2, 29.3, 31.6, 41.4, 65.4, 68.5, 80.3, 110.6, 129.5, 149.5, 155.4,
178.8; HRMS (FAB+) calcd for C27H43NO6 (M+) 477.3090, found
477.3089 (−0.3 ppm).
Ethyl 2-[(2-tert-Butoxycarbonylamino-4,7-diethoxyindane-
2-carbonyl)amino]-4,7-diethoxyindan-2-carboxylate (14b).
Acid 13b (150 mg, 0.410 mmol) and amine 9b (120 mg, 0.410
mmol) were dissolved in DMF (5 mL). Triethylamine (150 μL, 109 mg,
1.07 mmol) was added via syringe. BOP reagent (181 mg, 0.410 mmol)
was added and the mixture was stirred under argon for 72 h. The mixture
was then diluted with EtOAc (150 mL) and washed with brine (2 × 200
mL). The organic phase was dried over MgSO4, filtered, and volatiles
were removed in vacuo. The residue was dissolved in CH2Cl2 (25 mL)
and decolorizing charcoal (2 g) was added. After stirring at room
temperature for 48 h the charcoal was removed by filtration and volatiles
were removed, yielding 244 mg (0.381 mmol, 93%) of 14b as a tan solid,
Rf 0.81 (30% EtOAc/hexanes), 0.58 (20% EtOAc/hexanes). 1H NMR δ
1.21 (12H, t, J = 6.3 Hz), 1.32 (9H, s), 1.34 (3H, t, J = 6.5 Hz), 2.92 (1H,
s), 3.27 (4H, bd, J = 13.2 Hz), 3.57 (4H, d, J = 16.8 Hz), 3.94 (8H, m),
4.17 (2H, q, J = 6.6 Hz), 6.60 (4H, s), 7.19 (1H, s); 13C NMR (CDCl3) δ
14.0, 14.9, 28.0, 40.4, 41.3, 61.4, 63.9, 110.6, 129.7, 149.3, 149.5, 154.7,
172.9.
1
1733, 1709; H NMR (300 MHz, CDCl3) δ 0.87 (6H, t, J = 6.4 Hz),
1.20−1.40 (15H, m), 1.39 (9H, s), 1.50 (s, Boc2O contaminant), 1.70
(4H, pentet, J = 6.8 Hz), 3.17 (2H, broad d, J = 17.1 Hz), 3.51 (2H, d, J =
16.8 Hz), 3.86 (4H, t, J = 6.4 Hz), 4.20 (2H, q, J = 7.1 Hz), 5.09 (1H,
broad s), 6.58 (2H, s); 13C (75 MHz, CDCl3) δ 14.0, 14.1, 22.6, 25.7,
27.3 (Boc2O contaminant), 28.1, 29.3, 31.5, 41.5, 61.4, 65.7, 68.4, 79.8,
85.1 (Boc2O contaminant), 110.5, 129.6, 146.7 (Boc2O contaminant),
149.5, 154.8, 173.5; HRMS (FAB+) calculated for C29H47NO6 (M+)
505.3403, found 505.3403 (−0.1 ppm).
Anal. Calculated for C29H47NO6: C, 68.88; H, 9.37, N, 2.77 Found: C,
68.82; H, 9.48, N, 3.06.
2-tert-Butoxycarbonylamino-4,7-diethoxyindan-2-carbox-
ylic Acid (13b). Ester 12b (1.00 g, 2.54 mmol) was dissolved in ethanol
(25 mL). Distilled water (10 mL) and potassium hydroxide (1.00 g, 17.8
mmol) were added. The mixture was stirred under argon for 18 h and
then diluted to 150 mL with distilled H2O and acidified with 2 N HCl.
The mixture was extracted with ether (2 × 150 mL), the organic layers
were combined, dried over anhydrous Na2SO4, filtered, and volatiles
were removed in vacuo to give 859 mg (2.35 mmol, 92%) of 13b as a tan
foam, Rf 0.10 (20% EtOAc/hexanes). 1H NMR (CDCl3) δ 1.36 (6H, t,
J = 6.9 Hz), 1.41 (9H, s), 3.24 (2H, d, J = 15.3 Hz), 3.60 (2H, d, J =
17.1 Hz), 3.97 (4H, q, J = 6.9 Hz), 5.22 (1H, s), 6.61 (2H, s), 10.5
(1H, s); 13C NMR (CDCl3) δ 15.0, 28.2, 41.4, 64.0, 65.4, 80.4, 110.7,
129.5, 149.3, 155.5, 178.4.
Anal. Calculated for C35H48N2O9: C, 65.61; H, 7.55, N, 4.37 Found:
C, 65.74; H, 7.51, N, 4.46.
Ethyl 2-[(2-tert-Butoxycarbonylamino-4,7-bis-hexyloxyin-
dane-2-carbonyl)amino]-4,7-bis-hexyloxyindan-2-carboxylate
(14d). A procedure similar to that used in the synthesis of 14b
employing acid 13d (537 mg, 1.12 mmol), amine 9d (434 mg, 1.07
mmol), triethylamine (300 μL, 218 mg, 2.14 mmol), and BOP reagent
(473 mg, 1.07 mmol) in DMF (5 mL) gave a residue which was
chromatographed on silica 60 (250 mL) using 10% EtOAc/hexanes as
eluent. The product so obtained was crystallized from absolute ethanol,
yielding 347 mg of 14d as an off-white solid. The mother liquor was
concentrated in vacuo and the residue was chromatographed on silica 60
(150 mL) using ether as the eluent. The product so obtained was
crystallized from absolute ethanol, yielding an additional 134 mg of 14d
for a total yield of 481 mg (0.556 mmol, 52%), Rf 0.60 (30% EtOAc/
Anal. Calculated for C19H27NO6: C, 62.45; H, 7.45, N, 3.83 Found: C,
62.54; H, 7.68, N, 3.97.
1
2-tert-Butoxycarbonylamino-4,7-bis-hexyloxyindan-2-car-
boxylic Acid (13d). Potassium hydroxide (2.0 g, 30 mmol) was added
to a solution of ester 12d (1.83 g, 3.62 mmol) in absolute EtOH (60 mL)
followed by addition of water (15 mL). The solution gradually went
from opaque to a clear yellow solution upon heating to a gentle reflux.
After 1 h, the reaction mixture was cooled to room temperature and the
solvent was removed under a vacuum to leave a white solid. The solid
was dissolved in water (100 mL) and the solution was acidified with
conc. HCl to a pH of 2. The aqueous solution was extracted with EtOAc
(3 × 100 mL), and the organic phases were combined, washed with
brine (100 mL), dried (MgSO4), filtered, and concentrated under a
vacuum to give 1.57 g (3.29 mmol, 91%) of 13d as an off-white solid, Rf
0.56 (20% EtOAc/hexanes), mp 116 °C. IR (KBr) cm−1 3351, 3086,
hexanes). H NMR (CDCl3) δ 0.90 (12H, m), 1.23−1.42 (36H, m),
1.71 (8H, m), 3.00 (1H, s), 3.23 (4H, d, J = 16.5 Hz), 3.58 (4H, d, J =
17.1 Hz), 3.85 (8H, t, J = 6.5 Hz), 4.18 (2H, q, J = 7.2 Hz), 5.20 (1H, s),
6.56 (2H, s), 6.59 (2H, s); 13C NMR (CDCl3) δ 14.1, 22.6, 25.6, 25.7,
25.8, 28.0, 29.3, 29.4, 31.5, 31.6, 41.4, 61.4, 68.5, 110.7, 129.7, 149.5,
149.7, 154.7, 172.9.
Anal. Calculated for C51H80N2O9: C, 70.80; H, 9.32, N, 3.24 Found:
C, 70.72; H, 9.51, N, 3.33.
cyclo-Bis-(2-amino-4,7-diethoxyindan-2-carboxylic Acid)
(3b). A glass tube containing 14b (152 mg, 0.237 mmol) was evacuated
to ∼1 mmHg and sealed using an O2/methane torch. The tube was
heated to 250 °C in an oil bath for 15 min where melting, outgassing, and
recrystallization were observed. The resulting residue was insoluble in
CH2Cl2, butanol, or THF, but dissolved in hot DMSO (100 mL).
Decolorizing charcoal (2 g) was added, and the slurry was heated for 1 h
with stirring. The charcoal was removed by filtration and the hot
solution was diluted with 500 mL of brine. The brine/DMSO mixture
1
1746, 1672; H NMR (300 MHz, CDCl3) δ 0.88 (6H, t, J = 6.5 Hz),
1.20−1.50 (21H, m), 1.72 (4H, pentet, J = 6.8 Hz), 3.22 (2H, broad d,
J = 15.4 Hz), 3.58 (2H, d, J = 16.9 Hz), 3.87 (4H, t, J = 6.5 Hz), 5.18 (1H,
s), 6.58 (2H, s), 11.87 (1H, s); 13C NMR (75 MHz, CDCl3) δ 14.0, 22.6,
5059
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
Scheme 2. Synthesis of Amino Esters 9b−h
Scheme 3. Synthesis of Compounds 3b−3h
was extracted with THF (2 × 250 mL). The organic layers were
combined, dried over anhydrous MgSO4, and concentrated in vacuo.
The decolorizing procedure was repeated, and the residue washed with
methanol (2 × 10 mL). Slow recrystallization of the residue from hot
DMSO then yielded 72 mg (0.15 mmol, 61%) of 3b as white blocks.
1H NMR (TFA-d) 1.37 (12H, t, J = 6.75 Hz), 3.43 (4H, d, J = 17 Hz),
3.86 (4H, d, J = 17 Hz), 4.19 (8H, q, J = 6.7 Hz), 6.92 (4H, s); 13C NMR
(TFA-d) 15.4, 46.4, 68.8, 70.2, 119.0, 131.7, 151.6, 174.6.
Table 1. Crystallographic Data for Piperazinediones 3b, 3c,
and 3g
3b
3c
3g
formula
C28H34N2O6
494.57
C36H50N2O6
606.78
C68H114N2O6
1055.61
100(2)
synchrotron
monoclinic
P21/c
weight (g mol−1
temp (K)
radiation
cryst syst
space group
a (Å)
)
170(2)
Mo Kα
monoclinic
P21/n
170(2)
Mo Kα
monoclinic
P21/n
Anal. Calculated for C28H34N2O6: C, 68.00; H, 6.93, N, 5.66 Found:
C, 68.07; H, 7.04, N, 5.78.
cyclo-Bis-(2-amino-4,7-bis-hexyloxyindan-2-carboxylic Acid)
(3d). A glass tube containing 14d (251 mg, 0.290 mmol) was evacuated
to ∼1 mmHg and sealed using an O2/methane torch. The tube was
heated to 250 °C in an oil bath for 40 min where melting and outgass-
ing were observed. The oily residue solidified upon cooling to room
temperature. Recrystallization of the residue from absolute ethanol
9.8429(13)
6.1190(8)
21.635(3)
90
14.6172(19)
6.0380(8)
19.251(3)
90
21.981(4)
18.298(4)
24.801(5)
90
b (Å)
c (Å)
α (deg)
β (deg)
91.328(2)
90
92.895(3)
90
108.72(3)
90
1
yielded 163 mg (0.227 mmol, 78%) of 3d as white needles. H NMR
γ (deg)
V (Å3)
(CDCl3) δ 0.91 (12H, t, J = 6.3 Hz), 1.35−1.45 (24H, m), 1.76 (8H, m),
3.17 (4H, d, J = 16.5 Hz), 3.71 (4H, d, J = 16.2 Hz), 3.91 (8H, t, J = 6.3
Hz), 6.37 (2H, s), 6.65 (4H, s); 13C NMR (CDCl3) δ 14.1, 22.6, 25.7,
29.3, 31.6, 44.6, 66.7, 68.5, 111.1, 128.0, 149.7, 169.3.
Anal. Calculated for C44H66N2O6: C, 73.50; H, 9.25, N, 3.90 Found:
C, 73.75; H, 9.25, N, 4.05.
1302.7(3)
2
4474(2)
2
9447(3)
6
Z
R1 (obs data)
wR2 (all data)
GOF on F2
0.0423
0.0503
0.0992
0.1049
0.1364
0.2971
1.047
1.030
1.098
RESULTS
■
were generally lower and byproducts from ring alkylation became
more pronounced for the longer chain iodides, so THF was the
preferred solvent for these reactions. Direct tribromination of 5b,
5c, and 5f in CCl4 using NBS under free radical conditions led to
7b, 7c, and 7f in yields of 68%, 62%, and 33%, respectively. These
halogenation reactions were particularly sluggish, and so for 5d,
5e, 5g, and 5h ionic nuclear monobromination (Br2, CHCl3) was
carried out prior to side chain bromination under free radical
Synthesis of Compounds 3b−3h. Compounds 3b−3h
were prepared as depicted in Schemes 1−3 and in a manner
analogous with the published synthesis of 3a.44 Commercially
available 2,3-dimethylhydroquinone51 (4) was deprotonated
(NaOEt/EtOH or NaH/THF) and alkylated using normal alkyl
iodides of varying chain lengths, producing compounds 5b−5h
(Scheme 1). Yields ranged from 45 to 78%. In ethanol, yields
5060
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
a
Table 2. Conformational Data for Piperazinediones 3a−3c and 3g
b
b
b
c
c
d
e
compound
conformer
A
ϕ
ψ
ω
α
β
χ
δ
chain
f
3a
−10.3
−12.1
8.0
6.4
4.7
2.8
173
180
180
173
173
180
180
165
180
180
165
165
180
180
146
145
172
−165
165
a
b
c
−173
176
d
a
3b
3c
3g
B
2.2
2.0
2.3
145
145
−2.2
−2.0
−2.3
−174
174
b
c
−176
176
d
a
C
0.5
0.5
0.5
146
146
−0.5
−0.5
−0.5
−175
175
b
c
−176
157
d
a
G1
G2
G3
G4
13.0
3.9
−4.8
−13.0
5.5
148
144
−4.1
−164
169
b
c
−177
168
d
a
13.0
3.9
−4.8
−13.0
5.5
150
148
−4.1
−177
−169
−174
173
b
c
d
a
0.3
0.3
0.3
147
147
−0.3
−0.3
−0.3
−161
161
b
c
−173
174
d
a
0.3
0.3
0.3
147
147
−0.3
−0.3
−0.3
−173
173
b
c
−174
d
a
b
Values are in degrees and are given for each substructural component. The dihedral angles ϕ, ψ, and ω are the torsion angles defined for
conformational analysis of amide bonds in peptides (see ref 56). The dihedral angles α and β were previously defined (see ref 12) and are measures
c
d
of the degree of nonplanarity of the piperazinedione ring (for flat rings α = β = 180°). The dihedral χ was previously defined (see ref 44) and is a
e
measure of the degree of nonplanarity of the cyclopentene ring component of the indane system (for flat rings χ = 180°). The C6−C9−O3−C13
f
torsion angle, δ, measures the twist of the alkoxy substituent relative to the plane of the benzene ring. Data taken from ref 44.
conditions (NBS, CCl4).52 The yields to 7d, 7e, 7g, and 7h via
6d, 6e, 6g, and 6h were 88%, 90%, 96%, and 85%, respectively,
over the two steps.
9h in 19%, 24%, 46%, and 33% yields, respectively, over three
steps.
Amino esters 9b−9h were converted to the corresponding
N-Boc esters 12b−12h in yields typically ranging from 50 to 60%
(Scheme 3). Esters 12b−12h were then saponified to give N-Boc
acids 13b−13h in yields typically ranging from 85 to 95%.
Couplings of amino esters 9b−9h with the corresponding N-Boc
acids 13b−13h were effected using (benzotriazol-1-yloxy)tris-
(dimethylamino)phosphonium hexafluorophosphate53,55 (BOP
reagent) and a tertiary amine base (Et3N or DABCO) in DMF at
room temperature, affording the dipeptides 14b−14h in yields
typically ranging from 45 to 75%. Thermolysis of these dipeptides
(neat under vacuum, ca. 250 °C) produced the corresponding
piperazinediones 3b−3h in yields ranging from 60 to 78%.
Crystal Structures. NMR spectra of compounds 3b−3h
were consistent with the expected C2h point group symmetry for
Condensation of tribromides 7b, 7c, and 7f with ethyl 2-
(benzylideneamino)acetate by the method of Kotha and Kuki53
gave indanone derivatives 8b, 8c, and 8f (Scheme 2).
Hydrogenolysis of the imine and carbon−bromine bonds (10%
Pd/C, H2 @ 55 psi, EtOH) gave the amino esters 9b, 9c, and 9f
in 40%, 43%, and 36% yields, respectively, over two steps.
Condensation of tribromides 7d, 7e, 7g, and 7h with ethyl
isocyanoacetate by the method of Kotha and Brahmachany54
gave indanone derivatives 10d, 10e, 10g, and 10h. Hydrolysis of
the isonitrile functionality (aq HCl, EtOH) produced the
corresponding amino esters 11d, 11e, 11g, and 11h. Hydro-
genolysis of the carbon−bromine bonds (10% Pd/C, H2 @ 55
psi, EtOH) gave the corresponding amino esters 9d, 9e, 9g, and
5061
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
Figure 3. Two views of hydrogen-bonded 1D-tapes from the crystal structures of compounds 3a−3c. Top: A view parallel to the long axis of the tape. Bottom:
A view perpendicular to the long axis of the tape. These views serve to illustrate the conformations A−C of the piperazinediones observed in the crystals.
these molecules in solution. Crystal structure data for com-
pounds 3b, 3c, and 3g are given in Table 1. Geometric data for
the conformers resident in the crystals are given in Table 2.56
Previously it was observed that compound 3a crystallized from
hot DMSO in space group C2.44 One conformer (see Figure 3,
conformer A) possessing C1 symmetry was present in the crystal.
The piperazinedione ring of A adopted a shallow pseudoboat
conformation (see Table 2, αA = 173°, βA = 165°) and the
cyclopentene subunits of the indane rings were substantially bent
toward the proximal nitrogen in the piperazinedione ring (χA =
145°, 146°). The carbon atoms of the four methyl ether groups
were directed away from the piperazinedione core. Two were
only slightly torsionally displaced from the average planes
defined by the arenes to which they were attached (δA = 172°,
−173°) and two were more substantially displaced (δA = 165°,
−165°). Nevertheless, 2-fold rotational symmetry very nearly
exists for conformer A.
In the present study, compound 3b crystallized from hot
DMSO in space group P21/n. One conformer (Figure 3, B)
possessing Ci symmetry was present in the crystal. The
piperazinedione ring of B adopts a flat conformation (αB =
180°, βB = 180°) and the cyclopentene subunits of the indane
rings are substantially bent toward the proximal nitrogen in the
piperazinedione ring (χB = 145°, 145°). In this case, all the
carbon atoms of the ethyl ether groups are only slightly
torsionally displaced from the average planes defined by the
arenes to which they are attached. The methylene carbons point
away from the piperazinedione core (174° ≤ |δ| ≤ 176°), while
the methyl carbons point back toward the piperazinedione core.
Compound 3c crystallized from hot absolute ethanol in space
group P21/n. One conformer (Figure 3, C) possessing Ci
symmetry was present in the crystal. The piperazinedione ring
of C adopts a flat conformation (αC = 180°, βC = 180°) and the
cyclopentene subunits of the indane rings are substantially bent
5062
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
Figure 4. Two views of conformers G1-G4 found in the crystal structure of 3g. In these depictions, conformer G1 is red, G2 is lavender, G3 is light blue,
and G4 is dark blue. Top: A view parallel to the long axis of the hydrogen-bonded tape. Bottom: A view perpendicular to the long axis of the hydrogen-
bonded tape.
a
Table 3. Intermolecular Structural Parameters for Self-Association of Piperazinediones 3a−3c and 3g: Hydrogen Bonding
N−O distances
b
b
c
d
compound
ε1 (Å)
ε2 (Å)
τp (deg)
ηp (Å)
e
3a
2.85
2.84
2.80
2.88
2.82
2.88
2.86
2.84
2.80
2.88
2.91
0.0
0.0
0.04
0.23
0.40
0.37
3b
3c
0.0
f
3g
3g
0.0
g
h
21.3
0.0
na
CSD average
0.29
a
b
Values are listed for each substructural component. The distances ε1 and ε2 lie between the amide nitrogen and oxygen atoms involved in
c
hydrogen bonding. The dihedral angle τp is formed by the intersection of the average planes defined by the atoms of adjacent piperazinedione rings
in a tape. The distance ηp lies between parallel average planes defined by the atoms of adjacent piperazinedione rings in a tape. Data taken from ref
44. Interactions of conformers A and B with conformers A and B. Interactions of conformers A and B with conformers C and D. Not applicable.
d
e
f
g
h
toward the proximal nitrogen in the piperazinedione ring (χC =
146°, 146°). Two out of four butoxy chains are related by
inversion symmetry and are present in g+g+ and g−g− “pentane”
conformations (including the oxygen). The other two butoxy
chains contain a single g+ or g− twist about the ArOCH2−
CH2CH2CH3 σ bond. As was the case for conformers A and B,
the methylene carbons adjacent to the ether oxygen point away
from the piperazinedione core and are only slightly torsionally
displaced from the average planes defined by the arenes to which
they are attached (175° ≤ |δ| ≤ 176°). However, the remaining
carbon atoms of the butoxy chains project further and further
from these planes. The carbon-to-arene plane distances
proceeding from the ether oxygen are 0.12, 0.40, 1.86, and
2.87 Å for the butoxy chains with two gauche twists and 0.07,
0.10, 1.45, and 1.64 Å for the chains with a single gauche twist.
Attempts to analyze crystals of 3d, 3e, and 3f by single crystal
X-ray analysis were unsuccessful. Crystals could be grown from
hot absolute ethanol as white needles, but were too weakly
diffracting to be of use. Fortunately, compound 3g crystallized
from isopropanol in space group P21/c and a structure was
5063
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
arenes to which they are attached, while the carbon atoms of the
dodecyloxy chains of G3 and G4 lie close to these planes.
Attempts to grow crystals of 3h produced waxy solids.
Table 4. Intermolecular Structural Parameters for
Self-Association of Piperazinediones 3a−3c and 3g: Arene
a
Interactions
Previously it was observed that molecules of 3a associated in
the crystal through reciprocal amide-to-amide R22(8) hydrogen
bonding to form “one-dimensional” tapes. Lateral neighbor tapes
(LNTs) of 3a were related by screw symmetry and associated on
one edge through perpendicular edge-to-center arene inter-
actions and on the other edge through “slipped” perpendicular
edge-to-center arene interactions (i.e., a methoxy hydrogen was
closer to the arene centroid than the arene hydrogen) to produce
“two-dimensional” sheets.44 The data in Tables 3 and 4 and
depictions of 1D-tapes and 2D-sheets from the crystal structures
of compounds 3a−3c (see Figure 5) attest to the fact that
compounds 3b and 3c assemble in these two dimensions
similarly to 3a and to each other. In the case of 3b, LNTs are
related by centers of inversion and assemble on both edges
through perpendicular edge-to-center arene interactions. In the
case of 3c, LNTs are related by centers of inversion and assemble
on both edges through “slipped” perpendicular edge-to-center
arene interactions (i.e., the butoxy hydrogens attached to C1 were
closer to the arene centroid than the arene hydrogen). While
the case of 3g is complicated by the presence of multiple
conformations in the crystal, molecules of 3g associate via
reciprocal amide-to-amide R22(8) hydrogen bonding to form
1D-tapes, and LNTs of 3g are related by screw symmetry and
associate through perpendicular edge-to-center arene inter-
actions (Figure 6).
arene centroid-to-centroid distances (κ), angles between arene
rings (τ), and centroid-to-closest arene hydrogen distances (γ)
ab
,
on each tape edge
compound κ1 (Å) κ2 (Å) τ1 (deg) τ2 (deg)
γ1 (Å)
γ2 (Å)
c
d
3a
3b
3c
4.90
4.89
5.77
4.89
4.80
5.56
4.89
5.77
4.89
5.41
86.3
82.9
84.2
88.6
89.4
85.6
82.9
84.2
88.6
86.6
2.76
2.68
3.26
2.68
e
e
3.53
3.53
f
3g
3g
2.79
2.79
3.10
g
2.87
a
b
Values are listed for each substructural component. For optimal
perpendicular edge-to-center interactions, κ ≈ 5.0 Å and τ ≈ 90° (see
c
d
refs 57−60). Data taken from ref 44. On this tape edge methoxy
hydrogens are located 3.02 Å and 3.29 Å from the arene centroid.
e
Butoxy hydrogens (Ar-OCH2Pr) are located 2.83 Å and 3.23 Å from
f
the arene centroid. Interactions of conformers A and B with
g
conformers A and B. Interactions of conformers A and B with
Association of 2D-sheets of 3a to form a “three dimensional”
solid was previously attributed to van der Waals-driven sheet
complimentarity.44 Similar complimentarity is observed in the
assembly of sheets of 3b in which “bundled” alkoxy substituents
more deeply interdigitate, maximizing van der Waals contacts.
The g+ or g− twist about the ArOCH2−CH2CH2CH3 σ bond in
molecules of 3c precludes deep interdigitation, but such an
arrangement involving fully extended alkyl chains may be
possible in a crystal polymorph. To date, polymorphs of 3a,
3b, and 3c have not been observed. Association of 2D-sheets of
3g to form a 3D-solid, while more complex, clearly involves deep
interdigitation of substituent alkyl chains in extended con-
formations in order to maximize van der Waals contacts (Figure 6).
Thermochemical Studies. Thermograms from modulated
differential scanning calorimetry (DSC) of compounds 3a−3h
are given in the Supporting Information. Melting and freezing
temperatures of compounds 3b−3g are summarized in Table 5,
and a plot of the observed freezing temperatures versus alkyl
chain lengths appears in Figure 7. Freezing points were calculated
for 3a and 3h using the equation of the best fit line to the data in
Figure 7. Compound 3a melted with substantial decomposition,
and so its freezing temperature could not be determined. Sharp
transitions were not observed for 3h over the range 375−475 K.
conformers C and D.
determined using synchrotron radiation. Four conformers
(Figure 4, G1-G4) were present in a 2:2:1:1 ratio in the crystal.
Conformers G1 and G2 are similar in conformation and were
coresident at a general position, while conformers G3 and G4 are
similar in conformation and were coresident at a position with
inversion of symmetry. The piperazinedione rings of G1 and G2
adopt unsymmetrical shallow boat conformations (αG1 = αG2
=
173°, βG1 = βG2 = 165°) and the cyclopentene subunits of the
indane rings are substantially bent toward the proximal nitrogen
in the piperazinedione ring (χG1 = 148°, 144° and χG2 = 150°,
148°). The piperazinedione rings of G3 and G4 are flat (αG1 = αG2
= 180°, βG1 = βG2 = 180°) and the cyclopentene subunits of the
indane rings are substantially bent toward the proximal nitrogen
in the piperazinedione ring (χG1 = χG2 = 147°, 147°). In all cases
the methylene carbons adjacent to the ether oxygen point away
from the piperazinedione core and are slightly to moderately
torsionally displaced from the average planes defined by the
arenes to which they are attached (157° ≤ |δ| ≤ 174°). While the
dodecyloxy chains exhibit predominantly extended (antiper-
iplanar) conformations, there are significant deviations from an
extended conformation in the following positions: G1a −68°
(OC1−C2C3), G1b 138° (C1C2−C3C4) and 127° (C2C3−C4C5),
G1c 88° (C9C10−C11C12), G1d 61° (C2C3−C4C5); G2a 88°
(C9C10−C11C12), G2b 61° (C2C3−C4C5), G2c 87° (OC1−C2C3),
G2d −158° (OC1−C2C3) and 112° (C9C10−C11C12); G3a −75°
(C9C10−C11C12), G3b 153° (CArO−C1C2) and 68° (OC1−
C2C3), G3c −153° (CArO−C1C2) and −68° (OC1−C2C3), G3d
75° (C9C10−C11C12); G4a 63° (OC1−C2C3) and −154 (C1C2−
C3C4), G4b 75° (C9C10−C11C12), G4c −75° (C9C10−C11C12),
G4d −63° (OC1−C2C3) and 154 (C1C2−C3C4). As a result of
these deviations, the carbon atoms of the dodecyloxy chains of
G1 and G2 project away from the average planes defined by the
DISCUSSION
■
The syntheses of 3b−3h parallel the published synthesis of 3a.
Direct radical bromination of compounds 5d−5h produced
unacceptable mixtures of xylene methyl and ring polybromina-
tion products.52 In these cases it was more efficient to carry out
an ionic ring bromination prior to radical bromination of the
methyl groups and, later in the sequence, a ring debromination.
Formation of the indane rings by sequential displacements of the
benzylic bromides on the way to 9b−9h was inefficient.
Following the first alkylation step, intermolecular alkylations
were competitive with intramolecular alkylations, leading to
5064
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
Figure 5. Tape assembly in the crystal structures of compounds 3a−c. Hydrogen atoms are omitted for clarity. Left: A view of lateral neighbor tapes
(LNTs) perpendicular to the hydrogen bonding axis illustrating intratape reciprocal hydrogen bonding and intertape arene interactions. Right: A view of
three sheets, each consisting of three LNTs, parallel to the hydrogen bonding axis illustrating intertape arene interactions and sheet assembly via
interdigitation of hydrocarbon chains.
oligomeric byproducts.61 The remaining steps leading to
dipeptides 14b−14h were straightforward, and themolysis of
14b−14h at 250−260 °C produced 3b−3h in good to very good
yields.
While each of the compounds 3a−3h was expectedto crystallize
with unique structural “fine-tuning” leading to differences in the
details of crystal packing, our hope was that the crystal packing of
these compounds would be more similar than different, and this
appears to be the case. For 3a−3c and 3g: molecules associate
via reciprocal amide-to-amide R22(8) hydrogen bonding to form
1D-tapes; lateral neighbor tapes associate through some type of
perpendicular edge-to-center arene interaction to form 2D-sheets;
and sheets associate via interdigitation of bundled alkyl groups that
project in “rows” away from each side of the sheet in order to
maximize van der Waals contacts in the 3D-solid. An observed
In prior work with 3a and other nonpolar piperazinediones,44
DMSO had proven to be a useful solvent for growing crystals
suitable for single-crystal analysis. In the present study, solvent-
free crystals of 3b and 3c were obtained from absolute ethanol,
and solvent-free crystals of 3g were obtained from isopropanol.
Attempts to grow X-ray quality single crystals of 3d−3f and 3h
from a variety of solvents were unsuccessful.
5065
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
Figure 6. Tape assembly in the crystal structure of compound 3g. Top: A view showing reciprocal amide-to-amide R22(8) hydrogen bonding and edge-
to-center arene interactions of the molecular core. This view has been populated with conformers G1 (peripheral molecules) and G4 (central molecule).
The dodecyl groups are omitted for clarity. Bottom: A view of two sheets, each consisting of five LNTs, parallel to the hydrogen bonding axis illustrating
sheet assembly via interdigitation of hydrocarbon chains. The top sheet has been populated with conformers G2 (lavender) and G3 (light blue) and the
bottom sheet has been populated with conformers G1 (red) and G4 (dark blue) for purposes of contrast.
crystal structure may represent a local energy minimum, not the
global energy minimum for the most stable 3D assembly.
Compound 3c is of particular interest in this regard, since full
extension of all four butyl chains should permit deeper inter-
digitation and could produce a crystal polymorph more closely
resembling the packing observed for 3b.
5066
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
members of the set. Work is currently in progress to determine
the phase behaviors of these compounds and will be reported in
due course.
Table 5. Melting and Freezing Points for Piperazinediones
3a−3h
a
number of carbons
in the alkoxy chains
compound
mp (K)
fp (K)
ASSOCIATED CONTENT
* Supporting Information
b
c
■
3a
3b
3c
3d
3e
3f
1
nd
(567)
S
2
590
566
520
511
493
472
554
544
520
506
487
464
General experimental section, experimental details for the
synthesis and characterization of compounds leading to 3c and
3e−3h, 1H and 13C NMR spectra for 3b−3h, differential
scanning calorimetry profiles for 3a−3h, and X-ray crystallo-
graphic information files (CIFs) for 3b and 3c. This material is
available free of charge via the Internet at http://pubs.acs.org.
4
6
8
9
3g
3h
12
18
b
c
nd
(408)
a
Measured by modulated differential scanning calorimetry; see the
AUTHOR INFORMATION
Corresponding Author
b
■
Supporting Information for the thermograms. Not determined.
c
Calculated value, see the equation used in the legend for Figure 7.
*Address: Department of Chemistry and Biochemistry,
University of Arizona, 1306 East University, Tucson, Arizona
85721-0041, USA. Phone: (520) 621-6321. Fax: (520) 621-
8407. E-mail: emash@u.arizona.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Technical assistance from Christine Zak and Hans Zak is
acknowledged. This work was supported in part by the Office of
Naval Research through the Center for Advanced Multifunc-
tional Nonlinear Optical Polymers and Molecular Assemblies, by
the University of Arizona Office of the Vice President for
Research, and by the Donors of the Petroleum Research Fund,
administered by the American Chemical Society. The diffrac-
tometer used for data collection for compounds 3b and 3c was
purchased with funds from NSF Grant CHE 9610374. Data
collection for compound 3g was performed at the Du Pont-
Northwestern-Dow Collaborative Access Team (DND-CAT)
Synchrotron Research Center located at Sector 5 of the
Advanced Photon Source. DND-CAT is supported by the E.I.
Du Pont de Nemours & Co., The Dow Chemical Company, the
U.S. National Science Foundation through Grant DMR-
9304725, and the State of Illinois through the Department of
Commerce and the Board of Education Grant IBHE HECA
NWU 96. Use of the Advanced Photon Source was supported by
the U.S. Department of Energy, Basic Energy Sciences, Office of
Science, under Contract No. W-31-109-Eng-38. We thank DND-
CAT staff for their help.
Figure 7. Graph of freezing point versus length of carbon chain for
piperazinediones 3b−3g. The best-fit line has the equation y = −9.40x +
576.7 and a correlation coefficient of 0.993.
It is interesting that the freezing temperatures for compounds
3b−3g decrease as the length of the alkoxy chains increases.
The crystallographic data indicate that the geometries of the
hydrogen bonds, and therefore their strengths, are very similar. If
hydrogen bonds of comparable strength are the last
intermolecular interactions broken during melting, and thus
the first intermolecular interactions formed during crystalliza-
tion, the contribution of alkyl chain motion to the entropic
component of the free energy could be responsible for the
unexpected trend observed for the freezing temperatures. This
possibility is under investigation.62
CONCLUSION
■
REFERENCES
■
From studies of piperazinediones 3a−h, we conclude (1) the
thermodynamic favorability of R22(8) reciprocal amide hydrogen
bonding results in 1D-tape formation in at least the four cases
studied by X-ray crystallography, and probably in the other cases
as well, given the observed linearity in the freezing temperatures
of compounds 3b−3g and the assumption that hydrogen
bonding should be the strongest intermolecular interaction and
the first interaction established passing from an isotropic to an
ordered state; (2) arenes adopt perpendicular edge-to-center
motifs, causing 1D-tapes to form 2D-sheets; (3) the hydrocarbon
chains of the alkoxy substituents adopt more or less extended
conformations perpendicular to the 2D-sheets and interdigitate
to fill space between the sheets and maximize van der Waals
contacts. Thus, the design model for crystal packing based on
three orthogonal recognition elements appears to be valid for
this set of piperazinediones. Thermally induced crystal-to-crystal
or crystal-to-liquid crystal transitions may occur for some
(1) The Crystal as a Supramolecular Entity; Desiraju, G. R., Ed.; John
Wiley & Sons, Ltd: Chichester, England, 1996.
(2) Crystal Engineering: The Design and Application of Functional Solids;
Seddon, K. R., Zaworotko, M., Eds; Kluwer Academic Publishers:
Dordrecht, The Netherlands, 1999.
(3) Braga, D.; Grepioni, F. Crystal Engineering. In Kirk-Othmer
Encyclopedia of Chemical Technology, 5th ed.; Wiley: New York, 2004;
Vol. 8, pp 65−94.
(4) Wuest, J. D. Chem. Commun. 2005, 5830−5837.
(5) Aakeroy, C. B; Schultheiss, N. In Making Crystals By Design;
Braga, D., Greponi, F., Eds.; Wiley-VCH: New York, 2007; pp
209−240.
(6) Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering A
Textbook; World Scientific Publishing Company: Singapore, 2011.
(7) Collings, P. J. Liquid Crystals: Nature’s Delicate Phase of Matter, 2nd
ed.; Princeton University Press: Princeton, 2002.
(8) Tschierske, C. Chem. Soc. Rev. 2007, 36, 1930−1970.
(9) Yoshizawa, A. J. Mater. Chem. 2008, 18, 2877−2889.
5067
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068

Crystal Growth & Design
Article
(10) MacDonald, J. C.; Whitesides, G. M. Chem. Rev. 1994, 94, 2383−
2420.
(11) Brienne, M.-J.; Gabard, J.; Leclercq, M.; Lehn, J.-M.; Cesario, M.;
Pascard, C.; Cheve,
8157−8160.
́
M.; Dutruc-Rosset, G. Tetrahedron Lett. 1994, 35,
(12) 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.
(13) Li, W.-R.; Kao, K.-C.; Yo, Y.-C.; Lai, C. K. Helv. Chim. Acta 1999,
82, 1400−1407.
(28) Reichenbacher, K.; Suss, H. I.; Hulliger, J. Chem. Soc. Rev. 2005,
34, 22−30.
(29) Dai, C.; Nguyen, P.; Marder, T. B.; Scott, A. J.; Clegg, W.; Viney,
C. J. Chem. Soc., Chem. Commun. 1999, 2493−2494.
(30) Gung, B. W.; Xue, X.; Zou, Y. J. Org. Chem. 2007, 72, 2469−2475.
(31) Carroll, W. R.; Pellechia, P.; Shimizu, K. D. Org. Lett. 2008, 10,
3547−3550.
(32) Cozzi, F.; Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi,
L.; Baldridge, K. K.; Siegel, J. S. Org. Biomol. Chem. 2003, 1, 157−162.
(33) Budzianowski, A.; Katrusiak, A. Acta Crystallogr., Sect. B 2006, 62,
94−101 and prior structures.
(34) Oddershede, J.; Larsen, S. J. Phys. Chem. A 2004, 108, 1057−1063
and prior structures.
̈
̈
́
(14) Ridvan, L.; Budesínsky, M.; Tichy, M.; Malon, P.; Zavada, J.;
́
Podlaha, J.; Císarova, I. Tetrahedron 1999, 55, 12331−12348.
(15) Luo, T-J. M.; Palmore, G. T. R. Cryst. Growth Des. 2002, 2,
337−350.
(16) Lenev, D. A.; Lyssenko, K. A.; Kostyanovsky, R. G. Mendeleev
Commun. 2004, 14, 312−314.
(17) Gupta, S.; Macala, M.; Schafmeister, C. E. J. Org. Chem. 2006, 71,
8691−8695.
(18) The pentacyclic core of 1 is minimally flexible about the
two cyclopentene “hinges” of the indane units and the central
piperazinedione ring.
(19) In June 2012, 144 nitrogen-unsubstituted non-ionic piperazine-
diones with 3D coordinates were retrieved from the Cambridge
Structural Database (CSD, version 5.33, see Allen, F. H. Acta Crystallogr.
Sect. B 2002, 58, 380−388); 64% possess one-dimensional “ladder-like”
tapes (i), 4% form non-reciprocal hydrogen bonded networks (ii), and
32% develop alternate hydrogen bonded structures involving
piperazinedione side chains and/or included molecules.
(35) Marciniak, B.; Pavlyuk, V. Mol. Cryst. Liq. Cryst. Sci. Technol., Sect.
A 2002, 373, 237−250 and prior structures.
(36) Umezawa, Y.; Tsuboyama, S.; Honda, K.; Uzawa, J.; Nishio, M.
Bull. Chem. Soc. Jpn. 1998, 71, 1207−1213.
(37) Kim, E.; Paliwal, S.; Wilcox, C. S. J. Am. Chem. Soc. 1998, 120,
11192−11193.
(38) Nakamura, K.; Houk, K. N. Org. Lett. 1999, 1, 2049−2051.
(39) Ribas, J.; Cubero, E.; Luque, F. J.; Orozco, M. J. Org. Chem. 2002,
67, 7057−7065.
(40) Carver, F. J.; Hunter, C. A.; Livingstone, D. J.; McCabe, J. F.;
Seward, E. M. Chem. Eur. J. 2002, 8, 2847−2859.
(41) Cockroft, S. L.; Hunter, C. A. Chem. Commun. 2006, 3806−3808.
(42) Fischer, F. R.; Schweizer, W. B.; Diederich, F. Chem. Commun.
2008, 4031−4033.
(43) Tewari, A. K.; Dubey, R. Bioorg. Med. Chem. 2008, 16, 126−143.
(44) Williams, L. J.; Jagadish, B.; Kloster, R. A.; Lyon, S. R.; Carducci,
M. D.; Mash, E. A. Tetrahedron 1999, 55, 14281−14300.
(45) Williams, L. J.; Jagadish, B.; Lansdown, M. G.; Carducci, M. D.;
Mash, E. A. Tetrahedron 1999, 55, 14301−14322.
(46) Kaneko, F.; Sakashita, H.; Kobayashi, M.; Kitagawa, Y.; Matsuura,
Y.; Suzuki, M. Acta Crystallogr., Sect. C 1994, 50, 245−247.
(47) Bryan, R. F.; Hartley, P.; Miller, R. W.; Shen, M.-S. Mol. Cryst. Liq.
Cryst. 1980, 62, 281−310.
(48) For a preliminary communication, see Kloster, R. A.; Carducci, M.
D.; Mash, E. A. Org. Lett. 2003, 5, 3683−3686.
(49) The General Experimental Section is located in the Supporting
Information that accompanies this paper.
(50) Rohrich, J.; Mullen, K. J. Org. Chem. 1992, 57, 2374−2379.
̈
̈
(51) Purchased from Aldrich Chemical Co.
(20) Kitaigorodsky, A. I. Molecular Crystals and Molecules; Academic
Press: New York, 1973.
(52) Gruter, G-J. M.; Akkerman, O. S.; Bickelhaupt, F. J. Org. Chem.
1994, 59, 4473−4481.
(21) Depero, L. E. Adv. Mol. Struct. Res. 1995, 1, 303−337.
(53) Kotha, S.; Kuki, A. Tetrahedron Lett. 1992, 33, 1565−1568.
(54) Kotha, S.; Brahmachary, E. J. Org. Chem. 2000, 65, 1359−1365.
(55) Castro, B.; Dormoy, J.-R.; Dourtoglou, B.; Evin, G.; Selve, C.;
Ziegler, J.-C. Synthesis 1976, 751−752.
(22) Perlstein, J. NATO Sci. Ser. C 1999, 538, 23−42.
(23) Desiraju, G. R. Nat. Mater. 2002, 1, 77−79.
(24) Organic zeolites are exceptions; see Hertzsch, T.; Hulliger, J.; Weber,
E.; Sozzani, P. In Encyclopedia of Supramolecular Chemistry; Taylor and
Francis: New York, 2007; pp 996−1005, and references cited therein.
(25) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem. Soc.,
Perkin Trans. 2 2001, 651−669.
(56) IUPAC-IUB Commission on Biochemical Nomenclature,
Biochemistry 1970, 9, 3471−3479.
(57) Karlstrom, G.; Linse, P.; Wallqvist, A.; Jonsson, B. J. Am. Chem.
̈
̈
Soc. 1983, 105, 3777−3782.
(26) Waters, M. L. Curr. Opin. Chem. Biol. 2002, 6, 736−741.
(27) The terms “parallel center-to-center”, “parallel edge-to-center”,
and “perpendicular edge-to-center” will be used to describe arene
interaction types herein. Other terms that have been used to designate
arene interaction motifs include, for parallel center-to-center (iii), face-
to-face, face-to-face stacked, parallel stacked, and stacked; for parallel
edge-to-center (iv) face-to-face center-to-edge, parallel offset, offset
stacked, and offset nonstacked; and for perpendicular edge-to-center (v)
edge-to-face, edge-face, herringbone, and T-type.
(58) Burley, S. K.; Petsko, G. A. J. Am. Chem. Soc. 1986, 108, 7995−8001.
(59) Jorgensen, W. L.; Severance, D. L. J. Am. Chem. Soc. 1990, 112,
4768−4774.
(60) Hobza, P.; Selzle, H. L.; Schlag, E. W. J. Am. Chem. Soc. 1994, 116,
3500−3506.
(61) Ridvan, L.; Zavada, J. Tetrahedron 1997, 53, 14793−14806.
(62) Weatherhead-Kloster, R. A.; Selby, H. D.; Miller, W. B., III; Mash,
E. A. J. Org. Chem. 2005, 70, 8693−8702.
5068
dx.doi.org/10.1021/cg301003p | Cryst. Growth Des. 2012, 12, 5056−5068