Crystal structure of diethylammonium p-aminobenzoate (Nevanide)

Article abstract of DOI:10.1071/CH98164

The crystal structure of Nevanide (diethylammonium p-aminobenzoate) has been determined and refined to a residual R 0·055 for 2797 observed reflections. Crystals are monoclinic, space group C 2/c, with 32 ion pairs in a cell with dimensions a 29·510(6), b 17·150(1), c 20·473(5) A, β 115·153(9)°. The structure is made up of a network of hydrogen-bonded ions; in this network the 4-aminobenzoate anions form a primary cyclic tetramer unit in which the amine groups of two residues are linked tail to tail through hydrogen bonds to single carboxylate oxygens of the other two residues. All oxygens are then linked peripherally to layers of diethylammonium cations by strong hydrogen bonding, with all possible hydrogen bonding sites utilized, giving a three-dimensional network array.

Full text of DOI:10.1071/CH98164

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 52, 1999
© CSIRO Australia 1999
A journal for the publication of original research
in all branches of chemistry and chemical technology
w w w. p u b l i s h . c s i ro . a u / j o u rn a l s / a j c
All enquiries and manuscripts should be directed to
The Managing Editor
Australian Journal of Chemistry
CSIRO PUBLISHING
PO Box 1139 (150 Oxford St)
Collingwood
Vic. 3066
Australia
Telephone: 61 3 9662 7630
Facsimile: 61 3 9662 7611
Email: john.zdysiewicz@publish.csiro.au
Published by CSIRO PUBLISHING
for CSIRO Australia and
the Australian Academy of Science

Aust. J. Chem., 1999, 52, 625–628
.
Crystal Structure of Diethylammonium
p-Aminobenzoate (Nevanide)
Graham Smith,A Karl A. Byriel B and Colin H. L. Kennard B
A
School of Chemistry, Queensland University of Technology, G.P.O. Box 2434, Brisbane, Qld. 4001.
Author to whom correspondence should be addressed.
B
Department of Chemistry, The University of Queensland, Brisbane, Qld. 4072.
The crystal structure of Nevanide (diethylammonium p-aminobenzoate) has been determined and
re ned to a residual R 0 055 for 2797 observed re ections. Crystals are monoclinic, space group C 2/c,
with 32 ion pairs in a cell with dimensions a 29 510(6), b 17 150(1), c 20 473(5) A,
115 153(9) .
The structure is made up of a network of hydrogen-bonded ions; in this network the 4-aminobenzoate
anions form a primary cyclic tetramer unit in which the amine groups of two residues are linked tail
to tail through hydrogen bonds to single carboxylate oxygens of the other two residues. All oxygens
are then linked peripherally to layers of diethylammonium cations by strong hydrogen bonding, with
all possible hydrogen bonding sites utilized, giving a three-dimensional network array.
Introduction
products resulted, e.g., paba with 1,3,5-trinitrobenzene
(1 : 1),8 and the 3 : 1 : 1 tricrystal of paba with 2,4,6-
trinitrobenzoic acid and 1,3,5-trinitrobenzene,9 while
in a number of cases proton transfer from the car-
boxylic acid group of the complementary acid to
the amino group of paba occurred. The acids were
invariably those considered relatively strong (e.g.,
2,4,6-trinitrobenzoic acid, 5-nitrosalicylic acid, 3,5-
dinitrosalicylic acid). Subsequent hydrogen bonding,
often involving all protons of the protonated amine
Nevanide is the trade name for diethylammonium
p-aminobenzoate,1 which nds use as a sedative and
a hypnotic. The compound is one of a number of
derivatives of p-aminobenzoic acid (paba) which pos-
sess unusual physiological properties. This may be
attributed to the fact that paba itself is a biologically
important molecule, being an essential bacterial growth
factor involved in the synthesis of pteroylglutamic acid
(folic acid),2 which it has been shown to form in vitro,
in the presence of ATP and Mg2+ 3
The action of
.
sulfanilamide is considered to be directly attributable
to its competition with paba in the bacterial growth
process, antagonizing the growth promoting action of
essential metabolites.2 The two molecules are similar in
their topological features.4 In another unrelated appli-
cation, paba and its esters also nd use as sunscreen
agents.5 Additionally, paba is recognized as one of the
most useful of the small molecules which are potentially
interactive through hydrogen bonding with a variety
of organic acids and bases. This is due not only to
the presence of two associative functional groups (car-
boxylic acid and amino) but to their stereochemically
favourable sites on the benzene ring, allowing extension
into hydrogen-bonded chains and arrays. Its utility as
a means of achieving design-directed molecular assem-
bly in the production of acentric organic solids, with
additional potential for non-linear optical application,
was recognized by Etter,6 with the preparation of a
1 : 1 paba adduct with 3,5-dinitrobenzoic acid.
In a previous work7 we reviewed the general crystal
chemistry of the adducts of paba with both aromatic
carboxylic acids and aromatic nitrogen bases. The
known examples included those in which unusual neutral
Manuscript received 4 November 1998
᭧ CSIRO 1999
0004-9425/99/060625$ 05.00
10.1071/CH98164

626
Short Communications
Fig. 1. Atom naming scheme for the diethylammonium cation (molecule E) [other cations (F–H) are conformationally identical],
and for the 4-aminobenzoate anion (molecule A: molecules B–D are identical). Unless otherwise indicated, atoms are carbon.
Fig. 2. Packing in the unit cell viewed down the c axis. Hydrogen bonding interactions are shown as broken lines.

Short Communications
627
93,17 with anisotropic thermal parameters for all non-hydrogen
group, leads to stabilization of the crystal lattice hence
enhancement of the general physical properties of the
solid, e.g., hardness and melting point. In none of
the reported examples was paba the proton donor
molecule, to give the intuitively expected ‘salt’ of
paba. In an example such as the title compound,
diethylamine (pKa 10 9) would therefore be expected
to react readily with the relatively acidic acid group
of paba (pKa 2 08) to give such a salt. The crystal
structure of the title compound was determined in
an attempt to see if the hydrogen bonding might
provide an explanation for the activity associated with
Nevanide, or at least show structural similarity to the
analogous compounds, the local anaesthetics Procaine
(2-diethylaminoethylp-aminobenzoate10) or Benzocaine
(ethyl p-aminobenzoate11). A number of structures of
salts of Procaine have previously been determined in
attempts to explain the activity of this compound and
its analogues [Procaine hydrochloride,12 Procaine dihy-
drogenorthophosphate hemihydrate,13 Procaine bis(p-
nitrophenyl) phosphate,14 and Procaine penicillin G
monohydrate15]. All show substantial hydrogen bond-
ing associated with the Procaine cations. With the title
compound, the large unit cell found from preliminary
X-ray data suggested the presence of unusual packing
associations among the large number of molecular units
comprising the cell contents, and this was subsequently
con rmed in the crystal structure analysis.
atoms, gave residuals R1, wR2 and S of 0 057, 0 148 and
0 88 with a weighting scheme w = [ 2Fo
]
.
Hydrogen
2
1
atoms were included at calculated positions with positional
and thermal parameters riding. A check, prompted by the
presence of four independent ion pairs in the crystallographic
asymmetric unit, using standard reduction programs18 failed
to reveal any higher symmetry in the cell. The carbon atoms of
the ethyl substituents of some of the diethylammonium groups
(particularly molecules G and H) showed signi cant disorder.
However, no attempt was made to model these atoms over
multiple sites in the re nement.
Results
Final atomic coordinates, bond distances and angles,
anisotropic thermal parameters, and observed and cal-
culated structure factors have been deposited as an
Accessory Publication.† Molecular con gurations and
atom numbering schemes for both molecules in one of
the ion pairs [molecule A (C7H6NO2 ) and molecule E
(C4H12N+)] are shown in Fig. 1. These are essentially
identical in conformation to the other molecules of each
of the other three ion pairs in the asymmetric unit
(B,C,D and F,G,H respectively). Packing in the unit
cell showing hydrogen bonding interactions is shown
in Fig. 2.
Discussion
The network hydrogen-bonded polymer structure
of the title compound comprises all four ion pairs
in associations via all carboxylate oxygens and amine
protons of the paba anions and all protons of the diethy-
lammonium cations. The structure is best described
in terms of an unusual pseudo-centrosymmetric paba
tetramer (Fig. 2), in which the amine groups of
the A and C molecules form into a cyclic unit
bridged by single carboxylate oxygens of molecules
Experimental
The title compound was synthesized by interacting stoi-
chiometric amounts of diethylamine and 4-aminobenzoic acid
in 95% ethanol for 10 min under re ux. Colourless crystal
plates were obtained from the cooling solvent within a day.
Elemental analysis and melting point (lit. 170–173 C) veri ed
the identity of the compound as [C4H12N]+ [C7H6NO2] .
B
[O(10B)] and
2 999(7) A; N(41A)
N(41C) O(10B), 3 058(7) A; N(41C)
D [O(10D)] [N(41A) O(10B),
Crystallography
O(10D),
3 004(7) A;
O(10D),
Crystal Data
C
a 29 510(6), b 17 150(1), c 20 473(5) A,
11H18N2O2, M r 210 3, monoclinic, space group C 2/c,
3 101(7) A]. The tetramer unit is linked laterally
through these bridging oxygens, as well as the non-
bridging oxygens, to protons of four independent
diethylammonium cations which layer through the struc-
115 153(9) , V
3
9379(3) A3, F(000) 3648, Dc(Z = 32) 1 191 g cm
,
(Mo
K ) 0 83 cm 1, temperature 298(2) K.
Data Collection, Structure Solution and Re nement
ture [O(10B)
2 759(7) A;
N(1F), 2 774(7) A; O(10D) N(1G),
O(11B) N(1G), 2 750(7) A;
X-Ray di raction data were collected from a crystal of
dimensions 0 52 by 0 30 by 0 12 mm on an Enraf–Nonius
CAD-4 four-circle di ractometer by using crystal monochrom-
atized Mo K X-radiation ( 0 71073 A). Negligible change
in the intensities of three standards monitored throughout the
data collection period indicated no signi cant crystal decompo-
O(11D)
N(1H), 2 758(7) A]. One of the carboxy-
late oxygens of both molecules A and C is asso-
ciated with two amine protons and one diethylam-
monium proton [O(10A) N(41B), N(41D), N(1H),
3 007, 3 092, 2 806(7) A; O(10C)
N(1E), 3 059, 3 027, 2 742(7) A], while the other
oxygens are linked only to diethylammonium pro-
N(41B), N(41D),
sition. Of 8362 re ections collected up to 2
50 (collection
max
range: h, from 0 to 35; k, from 0 to 20; l, from 24 to 22),
8192 were unique (Rint 0 014) while 2979 with Fo > 4 (Fo)
were considered observed and were used in the expression
of the conventional re nement residual. Data were corrected
for Lorentz and polarization e ects but not for absorption.
The structure was solved by direct methods (SHELXS-86).16
Full-matrix least-squares re nement [on (Fo)2] using SHELXL-
tons [O(11A)
N(1H), N(1F), 2 596, 2 747(7) A;
O(11C) N(1E), 2 721(7) A]. The hydrogen-bonded
core (Fig. 3) is similar to what is found in the
structure of Procaine, with the exception of the lat-
Fc2)2/ w(Fo2)2]1/2
.
2
R1
=
||Fo| |Fc||/ |Fo| and wR2 = [ w(Fo
† Copies are available (until 31 December 2004) from the Australian Journal of Chemistry, P.O. Box 1139, Collingwood, Vic. 3066.

628
Short Communications
eral associations to the free diethylammonium cations,
which are absent in Procaine, being replaced by
the diethylaminoethyl side chains, which simply layer
into cavities in the structure. Local anaesthetics
are known to react with the phosphodiester groups
in acidic phospholipids, phosphoproteins, ribonucleic
acid, but not with phosphomonoesters, pyrophosphates
or triphosphates.19 The reason for the particular phys-
iological activity of Nevanide is not clear but may
be considered to be analogous to that for Procaine,
although the two substances have di erent applications.
Nevertheless such e ects could possibly be attributed
to the presence of the extensive and strong hydrogen
bonding associated with the paba residue, and equally
to the presence of the diethylamine moiety, either as
part of the Procaine molecule or as a cationic residue
in Nevanide.
crystallographic repeating unit. All cations adopt
extended conformations with the molecular skeleton
almost planar. Similarly, the paba anions are essen-
tially planar, which is similar to what is found both
in the parent acid20 and in most of the cocrystalline
adducts of paba.7
Acknowledgments
The authors acknowledge nancial support from
the Centre for Instrumental and Developmental Chem-
istry of the Queensland University of Technology, the
Australian Research Council, and the University of
Queensland.
References
1
Stecher, P. G., (Ed.) ‘The Merck Index’ 8th Edn (Merck:
Rahway, New Jersey, 1968).
Robinson, F. A., ‘The Vitamin and Co-factors of Enzyme
Systems’ (Pergamon: London 1966).
There are no conformational di erences in the diethy-
lammonium cations (E,F,G,H) or the 4-aminobenzoate
anions (A,B,C,D) which might have explained the
unusual number of independent molecules in the
2
3
Dyke, S. F., in ‘Chemistry of Natural Products’ (Ed. K. W.
Bentley) Vol. 6 ‘Chemistry of the Vitamins’ (Interscience:
London 1965).
Pauling, L., and Hayward, R., ‘The Architecture of
4
Molecules’ (W. H. Freeman: San Francisco, U.S.A., 1964).
Berkow, R., (Ed.) ‘The Merck Manual’ 16th Edn, p. 2498
(Merck: Rahway, New Jersey, 1992).
Etter, M. C., and Frankenbach, G. M., Chem. Mater., 1989,
1, 10.
Smith, G., Lynch, D. E., Byriel, K. A., and Kennard, C.
5
6
7
H. L., J. Chem. Crystallogr., 1997, 27, 307.
Lynch, D. E., Smith, G., Byriel, K. A., and Kennard, C.
8
H. L., Acta Crystallogr., Sect. C, 1994, 50, 2079.
Lynch, D. E., Smith, G., Byriel, K. A., and Kennard, C.
9
H. L., J. Chem. Soc., Chem. Commun., 1992, 300.
Kashino, S., Ikeda, M., and Haisa, M., Acta Crystallogr.,
10
Sect. B, 1982, 38, 1868; Sinha, B. K., Subramanian, E.,
Pattabhi, V., and Trotter, J., Indian J. Pure Appl. Phys.,
1984, 22, 249.
Sinha, B. K., and Pattabhi, V., Proc. Indian Acad. Sci.,
Chem. Sci., 1987, 98, 229.
11
12
Beall, R., Herdklotz, J., and Sass, R. L., Biochem. Biophys.
Res. Commun., 1970, 39, 329; Baptista, A., Ann. Acad.
Bras. Cien., 1967, 39, 257; Dexter, D. D., Acta Crystallogr.,
Sect. B, 1972, 28, 77.
Freeman, G. R., and Bugg, C. E., Acta Crystallogr., Sect.
B, 1975, 31, 96.
Sax, M., Pletcher, J., and Gusta son, B., Acta Crystallogr.,
Sect. B, 1970, 26, 114.
Dexter, D. D., and Van der Veen, J. M., J. Chem. Soc.,
Perkin Trans. 1, 1978, 185.
13
14
15
16
Sheldrick, G. M., SHELXS-86, Structure Solution Package,
University of Gottingen, Federal Republic of Germany,
1986.
Sheldrick, G. M., SHELXL-93, Program for Crystal Structure
17
Determination, University of Gottingen, Federal Republic
of Germany, 1993.
Spek, A. L., PLATON, Acta Crystallogr., Sect. A, 1990, 36,
2805.
Feinstein, M. B., and Paimre, M., Biochim. Biophys. Acta,
1966, 115, 39.
Lai, T. F., and Marsh, R. E., Acta Crystallogr., 1967, 22,
18
19
20
885; Alleaume, M., Salas-Cimingo, G., and Decap, J., C.
R. Acad. Sci., Ser. C, 1966, 262, 416.
Fig. 3. The hydrogen-bonded core.