Stacking of a benzenehexacarboxylic acid core in the crystal structure of benzenehexacarboxylic acid α-aminomethyl isobutyrate amide (MA-Aib6)-sodium nitrate complex

Article abstract of DOI:10.1039/b109465n

MA-Aib₆ forms discrete stacks with sandwiched water, sodium and nitrate ions, presenting a novel profile, where nine out of the 12 binding sites, of the six amides present, are involved in bonding with water, sodium and nitrate ions, with no in

Full text of DOI:10.1039/b109465n

Stacking of a benzenehexacarboxylic acid core in the crystal structure
of benzenehexacarboxylic acid a-aminomethyl isobutyrate amide
(MA-Aib6)–sodium nitrate complex†
Subramania Ranganathan,*ab K. M. Muraleedharan,a C. H. Chandrashekhar Rao,a
M. Vairamani,c Isabella L. Karled and Richard D. Gilardid
a Discovery Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Jawaharlal Nehru Center for Advanced Scientific Research, Bangalore 560 007, India
c
Mass Spectrometry Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
d Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC 20375-5341, USA
Received (in Columbia, MO, USA) 20th August 2001, Accepted 4th October 2001
First published as an Advance Article on the web 22nd November 2001
MA-Aib6 forms discrete stacks with sandwiched water,
sodium and nitrate ions, presenting a novel profile, where
nine out of the 12 binding sites, of the six amides present, are
involved in bonding with water, sodium and nitrate ions,
with no inter-amide hydrogen bonding. This is the first
example of the stacking of a benzenehexacarboxylic acid
core.
14.3 Å. Each stack is quite independent of the others and there
are no hydrogen bonds between stacks or any interdigitation.
In the stack, shown with a central MA-Aib6 flanked by two
neighbors as presented in Fig. 2, the aromatic rings are tilted
slightly along the two-fold screw axis by 2.9°. The sodium ion
is penta-coordinated to two proximate carbonyls of the upper
layer (Na…O30, 2.472 Å; Na…O40, 2.488 Å) and a single
carbonyl from the middle layer (Na…O0, 2.255 Å), as well as
to both water molecules (Na…W3, 2.463 Å, Na…W4, 2.415
Å). The short Na…O0 distance of 2.255 Å is found in penta-
coordinated Na+ complexes7 but not for tetra- or hexa-
complexes. The water molecules are, in addition, bonded to
carbonyls from the middle layer (W3…O10, 2.872 Å;
W4…O50, 2.813 Å), the NH of the upper layer (W3…N21,
3.011 Å; W4…N51, 2.996 Å) and the nitrate ion (W3…O1S,
3.102 Å; W4…O2s, 2.824 Å). In turn, the nitrate ion is an
acceptor for the NH of the middle layer (N31…O1s, 2.984 Å)
and NH in the upper layer (N1…O2S, 2.805 Å). Thus, of the
twelve binding sites available in the hexa-amide 1, five carbonyl
groups and four NH units are used in a unique manner; while
N11 and N41 do not participate in any manner. The absence of
any inter amide hydrogen bonding and the strong involvement
of the nitrate counter ion in the assembly are particularly
noteworthy.
The design and synthesis of conformationally constrained
organic scaffoldings/templates that can potentiate controlled
growth to protein secondary structure motifs, is of current
interest.1 Such structural mimics are important for the design of
simple, low molecular weight pharmaceutical agents.2 The
present communication reports the synthesis of benzenehex-
acarboxylic acid a-aminomethyl isobutyrate amide (MA-Aib6,
C6[CONHC(CH3)2COOMe]6 (1) and the determination of its
structure by X-ray crystallography. The choice of a-aminome-
thyl isobutyrate as the first spacer was logical because of the
known ability of the Aib residue to control the growth of
secondary structures.3
The tertiary carbon center present in Aib resisted the
introduction of all the six units in a single step. The best
conditions afforded only MA-Aib5 mono imide (2), which, on in
situ treatment with further Aib gave 1. Thus, the reaction of
hexamellitoyl chloride4 with Aib-OMe under carefully defined
conditions followed by chromatography on silica gel column
and elution with ethylacetate–hexane afforded nearly pure MA-
Aib6 in 41% yield.5 Re-chromatography under the same
conditions afforded fine needles, mp 256–258 °C, that separated
from the eluent (Fig. 1).
A schematic profile of the stacking is presented in Fig. 3.
The crystal structure6 of MA-Aib6 (1) (Fig. 2) shows its
assembly to layered stacks along a two-fold screw axis where
molecules of MA-Aib6 on the one hand and water and sodium
nitrate on the other, form alternate layers (Fig. 2). The ester
groups, projected vertically, do not participate in the assembly.
The twelve a-methyl groups from each molecule form a neat
ring around the stack. The pattern of the stack is repeated every
2
Fig. 2 The crystal structure of 1. A Na+ ion, NO3 ion and two water
Fig. 1 Structure of 1 and 2.
molecules (W3 and W4) are also indicated. The columnar stacking of
molecules 1 alternating with Na+ and NO32 ions and two water molecules.
The dashed lines indicate the five ligands to Na+ and hydrogen bonds
between water molecules, the NO32 ion and 1.
† Respectfully dedicated to Darshan Ranganathan, who passed away on
June 4, 2001, her sixtieth brithday.
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Chem. Commun., 2001, 2544–2545
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b109465n

3 E. Benedetti, Biopolymers (Peptide Sci.), 1996, 40, 3; I. L. Karle,
Biopolymers (Peptide Sci.), 1996, 40, 157; I. L. Karle, Acc. Chem. Res.,
1999, 32, 693
4 Mellitic acid [1.62 g, 4.73 mmol] was digested with PCl5 [9.8 g, 47
mmol] at 150 °C for 24 h, excess reagent and POCl3 distilled off, the
residue triturated with dry benzene [5 3 10 ml] and dried to give 1.8 g
[84%] of hexamellitoyl chloride mp 245–247 °C, whose structure was
confirmed by methanolysis to mellitic acid hexamethyl ester and
comparison with an authentic sample.
5 A solution of hexamellitoyl chloride [0.48 g, 1.1 mmol] in dry CH2Cl2
(20 mL) and triethylamine (1 mL, 6.7 mmol) were simultaneously
added, in drops, over a period of 0.5 h to an ice cooled and stirred
solution of a-amino isobutyric acid methyl ester, generated in situ by
addition of triethylamine (1 mL, 6.7 mmol) to an ice cooled and stirred
solution of a-amino isobutyric acid methyl ester hydrochloride (1.48 g,
9.67 mmol) in dry CH2Cl2 (65 mL). The reaction mixture was left sitrred
at room temperature for two days. After this period another batch of a-
amino isobutyric acid methyl ester, precisely generated as described
above from the hydrochloride (1.48 g, 9.67 mmol) in dry CH2Cl2, was
introduced, the mixture left stirred for 2 d at rt, washed successively with
saturated NaHCO3 (2 3 15 mL), 2 N H2SO4 (2 3 15 mL), water (2 3
15 mL), dried (MgSO4) and the residue chromatographed on silica gel.
Elution with hexane–EtOAc = 8+2 afforded 0.420 g (41%) of nearly
pure MA-Aib6 (1), mp 247–250 °C; dH (200 MHz, DMSO-d6) 1.68 (s,
36H), 3.71 (s, 18H), 7.00 (br, 6H); FAB-MS (m/z) (%) 959 (M + Na+)
(60), 820 (M + H+ 2 Aib) (44), 703 (M + H+ 2 2Aib) (100), 586 (M +
H+ 2 3Aib) (8). Further elution gave 0.100 g (11%) of 2, mp 203–205
°C. When the second batch was not added, work up afforded exclusively
33% of 2, mp 203–205 °C; dH (200 MHz, CDCl3) 1.66, 1.77, 1.88 (s, s,
s, 30H), 3.68, 3.73, 3.78 (s, s, s, 15H), 7.13 (br, 4H); FAB-MS (m/z) (%)
842 (M + Na+) (77), 703 (M + H 2 Aib) (100%), 586 (M + H+ 2 2Aib)
(24).
Fig. 3 Schematic drawing of the layered structure in a stack.
Using a sample of the crystal, the presence of sodium nitrate
was confirmed by using positive and negative ion mass
spectrometry. By negative ion mass spectrometry, the source of
sodium nitrate was traced to the silica gel used for chromatog-
raphy.8 Chromatographically pure MA-Aib6, freed of nitrate9
when allowed to stand in ethyl acetate with dissolved sodium
nitrate, deposited needles identical to that used for crystallo-
graphic studies.10
Futher experiments have shown that in the complexation of 1,
the nature of the metal ion is important. Thus, under identical
conditions lithium nitrate formed the complex whereas po-
tassium nitrate did not.11 However it is very likely that in the
assembly of 1 the nitrate ion, being large and with dispersed
charge, plays a controlling role to the extent that the expected
hydrogen bonding involving the amide bonds is not seen.
To the best of our knowledge, this is the first report of
achieving the stacking of a benzenehexacarboxylic acid core.
Crystallographic data currently available relating to mellitic
acid, its esters and metal salts are unexceptional.12
6 Crystal data for 1: C42H60N6O18·2H2O·NaNO3, space group Pna21, a =
14.286(1) Å, b = 14.614(1) Å, c = 24.800(5) Å, V = 5177.9 Å3, Dc
=
1.352 g cm23, Cu-Ka radiation, l
= 1.54178 Å. Least squares
refinement on F2, R1 = 0.0512 for 4480 data [|F| > 4.0s (F)] and wR2
= 0.1388 for all data. Data collection at 293 °C. CCDC 173157. See
http://www.rsc.org/suppdata/cc/b1/b109465n/ for crystallographic files
in .cif or other electronic format.
7 I. L. Karle, Biochemistry, 1974, 13, 2155.
8 Silica gel (2.0 g), used for chromatography, was triturated with ethyl
acetate (5 mL), filtered and the clear filtrate evaporated. Negative ion
Ms of the residue clearly showed presence of nitrate and the positive ion
Ms that of sodium ion.
9 Chromatographically pure MA-Aib6 (0.005 g, mp 247–250 °C) was
triturated with distilled water (3 3 2 mL), centrifuged and dried in vacuo
to afford sample, mp 238–239 °C which was shown to be totally free of
sodium nitrate by Ms.
10 Sodium nitrate (0.005 g) in water (2 mL) was shaken with ethyl acetate
(2 mL), the layers separated and the organic layer filtered through cotton
to give a clear solution in which salt freed MA-Aib6 from the above
experiment was dissolved and left aside. Fine needles, mp 256–258 °C,
identical to that used for crystallographic studies were slowly deposited.
These were demonstrated to contain sodium nitrate by positive and
negative ion mass spectrometry.
11 The conditions used were similar to that described above. Unlike
sodium nitrate, crystals were not deposited with lithium nitrate and
potassium nitrate, on standing. Solvents were evaporated, the residue
washed with water to remove uncomplexed salts, centrifuged, dried and
the resulting fine powders, when analyzed by both positive and negative
ion mass spectra, clearly showed complexation with lithium nitrate and
the absence of this with potassium nitrate. In view of the exclusive
preference of the amide groups for hydrogen bonding with nitrate ions
seen with 1, the lithium nitrate complex is likely to have a structure
similar to that with sodium nitrate.
12 K. A. Bezja and D. Grdenic, Nature, 1960, 185, 756; S. F. Darlow,
Nature, 1960, 186, 542; S. F. Darlow, Acta Crystallogr., 1961, 14, 159;
V. A. Uchtman and R. Jandacek, J. Inorg. Chem., 1980, 19, 350; H. A.
Endres and A. Knieszner, Acta. Crystallogr., Sect. C., 1984, 40, 770; C.
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S. Hentschel, Z. Naturforsch. Teil B, 1991, 46, 1188; C. Robl and S.
Hentschel, Z. Naturforsch. Teil B, 1992, 47, 1561; L. P. Wu, M.
Munakata, M. Yamamoto, T. K. Sowa and M. Maekawa, J. Coord.
Chem., 1996, 37, 361; L. P. Wu, M. Munakata, M. Yamamoto, T. K.
Sowa, M. Maekawa and Y. Suenaga, Inorg. Chem. Acta, 1996, 249,
183; J. A. Harnisch, L. M. Thomas, I. A. Cuzei and R. J. Angelici, Inorg.
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Financial support was provided by the National Institutes of
Health Grant GM-30902, the Office of Naval Research and the
Department of Science and Technology, New Delhi.
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Chem. Commun., 2001, 2544–2545
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