Hydrogen-bonding between benzoic acid and an N,N′-diethyl-substituted benzamidine

Article abstract of DOI:10.1016/S0040-4020(02)00301-0

The synthesis and crystal structure of 4,N,N′-triethylbenzamidinium benzoate is reported in which the benzoate anion and the (E,E)-configured amidinium group are linked through two hydrogen bonds (with an N·middot;middot;O distance of 2.723A?). Since an a

Full text of DOI:10.1016/S0040-4020(02)00301-0

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3499±3505
Hydrogen-bonding between benzoic acid and an
N,N0-diethyl-substituted benzamidine
Arno Kraft,a,b,p Lars Petersb and Harold R. Powellc
aDepartment of Chemistry, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, UK
b
È
È
Department of Organic Chemistry and Macromolecular Chemistry, University of Dusseldorf, 40225 Dusseldorf, Germany
cMRC Laboratory of Molecular Biology, MRC Centre, Hills Road, Cambridge CB2 2QH, UK
Received 8 January 2002; accepted 14 March 2002
AbstractÐThe synthesis and crystal structure of 4,N,N0-triethylbenzamidinium benzoate is reported in which the benzoate anion and the
Ê
(E,E)-con®gured amidinium group are linked through two hydrogen bonds (with an N´´´O distance of 2.723 A). Since an amidine (E,E)
isomer was also observed for chloroform solutions of the complex, the binding mode in the crystal and in solution was analogous to that
reported for unsubstituted amidines. The strong basicity of the N,N0-diethyl-substituted benzamidine (pKa 11.99^0.02 in water±dioxane,
1:1) was evident from potentiometric titrations. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
as well as more soluble in nonpolar solvents. It should be
noted that the hydrogen-bonding arrangement of a phos-
phate, and presumably also that of a phosphonate, closely
resembles the binding of a carboxylate to an amidinium
group.12 Complexes of a polymerisable amidine, N,N0-
Like guanidines, amidines are strong organic bases. The
biological activity of many amidines is attributed to a
cationic hydrogen-bond donor group that can act as binding
site for both carboxylates and phosphates. The amidine
pharmacophore is found in a range of pharmaceutical
drugs. Benzamidines, in particular, have replaced arginine
in various synthetic analogues of natural hormones.1
Whereas most amidine-based drugs are unsubstituted at
the amidine nitrogen site, N-substituted amidines have
only recently gained interest in drug design. For example,
certain N-isopropyl and N-cycloalkyl amidines tend to bind
to the minor groove of oligonucleotides with an af®nity
larger than their parent analogues.3,4 However, few crystal
structures of N-alkyl- and N-aryl-substituted amidines have
been reported so far: p-(dimethylamino)-N,N0-dimethyl-
benzamidine,2 various N,N0-diarylbenzamidines5±8 and
semicyclic amidines, generally in the form of the free
base or the hydrochloride,9,10 and just one example of an
amidinium carboxylate.11
diethyl-4-vinylbenzamidine (1), and
a
phosphonate
template were recently used by Wulff and co-workers in
the preparation of molecularly imprinted polymers that, by
mimicking catalytic antibodies, were able to hydrolyse
esters.13,14
An N,N0-diethyl-substituted amidine can exist in two con®g-
urations\scale100% with either an (E,E) or an (E,Z) stereo-
chemistry at the partial C±N double bond (Fig. 1), whereas
the (Z,Z) isomer is not possible for steric reasons.11,15±17
Although this seems to be a complication at a ®rst glance,
the two isomers can be easily differentiated by NMR. The
N-ethyl substituents serve as an NMR marker and, thus,
provide important information about the binding mode in
solution. Previous solution NMR studies have shown that a
dynamic equilibrium between (E,E) and (E,Z) con®gura-
tional isomers is frequently observed for protonated N,N0-
disubstituted benzamidines.11,16,17 The isomer ratio depends
N-Substituted amidines have a number of advantages: (i)
they are more stable towards hydrolysis compared to
unsubstituted analogues, allowing the amidine base to be
isolated and puri®ed; (ii) aggregation through intermolecu-
lar hydrogen bonds is generally suppressed; and (iii) the
extra substituents make these amidines more hydrophobic
Keywords: amidine; supramolecular; complexation; binding; crystal
structure.
p
Corresponding author. Address: Department of Chemistry, Heriot-Watt
University, Riccarton, Edinburgh EH14 4AS, UK;
e-mail: a.kraft@hw.ac.uk
Figure 1. Polymerisable amidine 1 and the two isomers observed for a
protonated N,N0-diethyl-substituted benzamidine.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00301-0

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A. Kraft et al. / Tetrahedron 58 (2002) 3499±3505
crucially on solvent, concentration, and counteranion. Wulff
È
and Schonfeld found that association constants between
protonated 1 and 4-methylbenzoate were large in chloro-
form (.106 M21 at 258C) and involved an exclusively
(E,E)-con®gured amidine.15,16 We report in this paper the
crystal structure of a benzoic acid complex of 4,N,N0-
triethylbenzamidine (4) that provides further insight into
the amidinium-carboxylate binding arrangement.
2. Results and discussion
2.1. Synthesis
Benzamidine 4 was obtained in three steps from 4-ethyl-
benzoyl chloride (Scheme 1). Reaction of the acid chloride
with aqueous ethylamine gave 2. The amide was then
converted to benzimidate 3 by treatment with triethyl-
oxonium tetra¯uoroborate. Stirring with ethylamine
hydrochloride produced the N,N0-diethyl-substituted benza-
midine 4 in good yield. Prior to complexation the crude
amidine was puri®ed by gradient sublimation, a method
that has been known to furnish photoconducting and
charge-transporting organic compounds in the high purity
required for device applications.18 This was necessary since
amidine 4 had a tendency to slowly hydrolyse in the
presence of moisture.
Amidinium groups typically have pKa values .11, whereas
the pKa of a protonated primary amine tends to be much
lower (between 9 and 10). Potentiometric titrations of
amidine 4 in 0.1M aqueous KCl at 25 8C indicated no
detectable ionisations at pH,11. Under these conditions,
the pKa of N,N0-diethyl-substituted benzamidine 4 could
only be estimated roughly from the experimental data as
12.2^0.5. We therefore repeated the titration in a dioxane±
water (1:1) mixture in which the ion product of water is
much smaller than in aqueous KCl and contributes little to
the hydroxide ion concentration at pH,13. Analysis of the
titration data by a difference plot19 then yielded a pKa of
11.99^0.02, con®rming the strong basicity of amidine 4
(Fig. 2).
Figure 2. (a) Titration curve and (b) difference plot19 for N,N0-diethyl-
substituted benzamidine 4 in dioxane±water (1:1) to which KCl was
added to maintain a constant ionic strength Iˆ0.1. Titrations were carried
out at 25.08C with 0.4905 M NaOH in 0.01mL steps. The solid line is the
®tted Bjerrum function. The pKa can be read from the difference plot at
nHˆ0.5 (50% protonation).
in hexane. According to differential scanning calorimetry
(DSC) measurements, the complex had a melting point of
1418C. A crystal±crystal phase transition was observed at
398C, indicating the possibility of polymorphism. Although
crystals could also be obtained from heptane, these were of
lower quality and seemed to consist of a different
polymorph.
2.2. Crystal structure of amidine±benzoic acid complex
A 1:1 mixture of amidine 4 and benzoic acid dissolved
easily in hot ethanol, and complex 5 was isolated in
analytical purity after one recrystallization from hexane.
Crystals of complex 5 were grown from a saturated solution
The crystal structure of complex 5 (crystallized from
hexane) is shown in Fig. 3. In the space group C2/c the
Figure 3. Crystal structure of benzoic acid±amidine complex 5 showing the
hydrogen bonding arrangement between amidinium and carboxylate ion.
Displacement ellipsoids are at 50% probability levels. The structure has a
C2 symmetry axis through atoms C2, C3, C6, C7, C10, C11, and C14. Only
NH hydrogen atoms (calculated) are shown. Hydrogen bonds are indicated
Ê
Ê
by dashed lines; the NH´´´O distance is 1.85 A (N±H 1.055 A), and the
N±H´´´O angle is 176.58.
Scheme 1. Preparation of amidine 4 and its benzoic acid complex 5.

A. Kraft et al. / Tetrahedron 58 (2002) 3499±3505
3501
Figure 4. Molecular arrangement of benzoic acid±amidine complex 5 in the unit cell.
complex lies on a crystallographic 2-fold axis. This is a
much higher symmetry than previously found for
4-bromo-N,N0-diethylbenzamidinium benzoate.11 The
C-ethyl group is disordered around this diad, the two sites
having an occupancy of 0.5 each. We note that the C1±C2
con®gured 4-bromo-N,N0-diethylbenzamidinium tetrazolate
(668),11 or even in the (E,E)-con®gured N,N0-diphenyl-
benzamidinium nitrate (61.48)7 is much smaller. A packing
diagram con®rms that the large dihedral angle is not a
consequence of crystal packing constraints and long-range
interactions between adjacent molecules (Fig. 4). The
substantial increase in torsion angle hence re¯ects the steric
bulk of the N,N0-diethyl-substituted amidine group. In
comparison, the planes of the carboxylate and the phenyl
group of the benzoate are oriented at an angle of 26.98 with
respect to each other. The dihedral angle between the planes
de®ned by the amidinium and carboxylate atoms is 15.38 in
the salt bridge, which is again larger than for carboxylate
complexes of unsubstituted amidines (3.8±8.48).21±23
Ê
distance of 1.266(7) A is unusually short for a C±C single
bond; furthermore, the C1±C2±C3 angle of 127.68 would
also have ®tted more a vinylbenzene derivative. However,
both synthesis and NMR data left no doubt about the
identity of the 4-ethylbenzamidine structure. We suspected
therefore that this peculiarity in the structural data could be
attributed to the presence of disorder and a high anisotropic
thermal motion. A search through the Cambridge Structural
Database (CSD) revealed indeed a number of ethylbenzene
derivatives with equally short C±C distances, which in most
cases proved to be associated with disordered terminal
carbons.20
2.3. Comparison of crystal and solution structure
The NH chemical shift of dH<12.9 in the 1H NMR spectrum
of 5 in chloroform is characteristic of a strongly hydrogen-
bonded complex in solution (Fig. 5). Both N-ethyl sub-
stituents give rise to a triplet and a quartet (in addition to
another triplet and quartet from the C-ethyl group) indica-
tive of an exclusively (E,E)-con®gured amidine. No signi®-
cant line-broadening or frequency dependence of the NMR
signals was noted as one would expect if the substituted
amidine isomerised at the NMR timescale. A dynamic
process, which has been reported for other N-substituted
amidinium salts with chloride or tetrazolate counter-
anions,11,16,17 can therefore be excluded. This is clearly a
consequence of strong binding interactions between
amidine and benzoate. A carboxylate ligand is obviously
able to force the N,N0-diethyl-substituted amidine into an
(E,E) con®guration that is perfect for binding. In contrast,
benzamidinium salt 7 (prepared from the corresponding
hydrochloride 6 by ion exchange (Scheme 2)) with its
non-coordinating tetrakis[3,5-bis(tri¯uoromethyl)phenyl]-
borate24 counteranion prefers the (E,Z) isomer in CDCl3Ð
most likely for steric reasons.
As a result of the symmetry of the crystal structure, the two
C±N bond lengths of the amidine are identical at
Ê
1.306(7) A, the length being consistent with an amidinium
salt con®guration. The benzoate forms a salt bridge to the
amidinium group. Hydrogen atoms in the H-bonds are
calculated and are bound to the nitrogen. They make up a
symmetry-related pair, and N±H bond lengths are identical
(as are the hydrogen-bonding distances and angles). The
Ê
N´´´O distance of 2.723(1) A is indicative of a strong hydro-
gen bond; slightly larger values have been reported in the
21
Ê
literature for 3-amidinium benzoate (2.766 and 2.791A ),
benzamidinium pyruvate (2.837 and 2.824 A),22 and benza-
midinium bromoacetate (2.804 and 2.846 A). The (E,E)
Ê
23
Ê
con®guration of the N,N0-diethyl-substituted amidinium
group in complex 5 ensures that binding interactions closely
resemble those of unsubstituted amidines. The N,N0-diethyl-
amidinium ion as a whole displays an approximate zig-zag
conformation, while the CH3 groups point above and below
the NCN plane. With a C5±C6±C7±N1torsion angle of
80.88, the amidinium group and adjacent aromatic ring are
almost perpendicular to each other, whereas the rotation of
the amidine relative to the plane of the aromatic ring in
unsubstituted amidinium carboxylates (30.0±35.28),21±23 in
an N,N0-dimethylbenzamidine base (628),2 in an (E,Z)-
The binding constant for a related complex between 1 and
4-methylbenzoic acid has been previously reported to
exceed 106 M21 in CDCl3 at 258C.15 While complex 5

3502
A. Kraft et al. / Tetrahedron 58 (2002) 3499±3505
Figure 5. 1H NMR spectra (500 MHz, 258C, CDCl3) of complex 5 (left) and of a benzamidinium salt 7 with the non-coordinating tetrakis[3,5-bis(tri¯uoro-
methyl)phenyl]borate counteranion (right). The quintet multiplicity of the N±CH2CH3 signals of 7 is due to coupling with the vicinal NH as well as CH3
protons. Solvent signals are marked by X.
shows a single set of amidine NMR signals in chloroform,
this is no longer the case if the salt is dissolved in a more
3. Conclusions
1
polar solvent such as DMSO-d6 in which the H and 13C
N,N0-Diethylsubstituted amidines are known to form strong
noncovalent complexes with carboxylic acids in nonpolar
solvents such as chloroform. The crystal structure of model
complex 5 con®rms that this is due to two almost linear
hydrogen bonds between benzoate and the (E,E)-con®gured
protonated amidine. Such a binding arrangement is also
noted for the solution structure of the complex in
chloroform. Comparison with previous studies led us to
conclude that only strongly binding ligands are able to
force the amidine into the sterically more hindered (E,Z)
con®guration.
NMR signals for the N-ethyl group as well as the aromatic
protons are broadened owing to isomerisation of the
amidine on the NMR timescale. Amidine±tetrazole
complexes show such a dynamic behaviour already in
chloroform, and binding constants were found to be con-
siderably lower than for typical carboxylic acid
complexes.11 Although the (E,Z) isomer of the amidine
can, in principle, bind through a single hydrogen bond to
a suitable counteranion, such a binding mode is unfavorable.
Benzamidinium chloride 6 exists therefore as a concentra-
tion- and temperature-dependent mixture of (E,E) and (E,Z)
amidine even in chloroform. No complexation is observed
in protic solvents in any of the above-mentioned cases so
that the thermodynamically more stable (E,Z)-con®gured
amidine prevails under these conditions. We note that
there seems to be a distinct correlation between the strength
of complexation and the preferred con®guration of the
N-substituted amidine. Mixtures of (E,E) and (E,Z) isomer
are therefore always dominant in the presence of weakly
binding ligands (chloride, tetrazolate) that cannot bind to
the amidine through two linear (i.e. strong) hydrogen
bonds.11,15±17
4. Experimental
4.1. General methods
All solvents were distilled prior to use. Mp (DSC): Mettler
TC 11 (melting enthalpies are given in brackets). NMR:
Bruker AC 200, DRX 500. TMS was used as standard in
the NMR measurements. The multiplicities of 13C signals
were determined by DEPT experiments. IR: Bruker Vector
22 FT-IR. CI-MS: Finnigan INCOS 50. ESI-MS: Thermo-
quest Automass benchtop LC/GC MS. Elemental analyses:
È
Pharmazeutisches Institut der Heinrich±Heine-Universitat
DuÈsseldorf.
4.1.1. 4,N-Diethylbenzamide (2). 4,N-Diethylbenzamide
(2) was prepared by the addition of aqueous ethyl amine
(70%, 20 mL, 0.31mol) to an ice-cold solution of 4-ethyl-
benzoyl chloride (5.06 g, 30.0 mmol) in ether (20 mL),
followed by stirring at room temperature for 24 h. Water
(100 mL) was added, and the mixture stirred for another
2 h. The resulting precipitate was collected by suction ®ltra-
tion and recrystallized from acetone. Yield: 5.50 g (97%).
Mp 1028C (143 J g21). 1H NMR (500 MHz, CDCl3): d 1.25
(,t, Jˆ7.5 Hz, 6H), 2.69 (q, Jˆ7.5 Hz, 2H), 3.50 (quin,
Scheme 2.

A. Kraft et al. / Tetrahedron 58 (2002) 3499±3505
3503
Jˆ6.8 Hz, 2H), 6.05 (br s, 1H), 7.25, 7.68 (AA0XX0, 4H).
13C NMR (125 MHz, CDCl3): d 15.0, 15.3 (CH3), 28.8, 34.9
(CH2), 126.9, 128.0 (CH), 132.2, 147.9, 167.4 (ipso-C,
CvO). MS (CI, NH3): m/z 195 (M1NH41, 100%), 178
(M1H1, 100). IR (KBr, cm21): n 3326, 2968, 1634,
1548, 1505, 1309, 1144, 854, 675. Anal. Calcd for
C11H15NO (177.24): C, 74.54; H, 8.53; N, 7.90. Found: C,
74.38; H, 8.41; N, 7.93.
Calcd for C20H26N2O2 (326.43): C, 73.59; H, 8.03; N, 8.58.
Found: C, 73.37; H, 8.15; N, 8.58.
4.1.5. 4,N,N0-Triethylbenzamidinium chloride (6).
Hydrochloride 6 was obtained as a colourless solid by
freeze-drying a solution of 4 in methanolic HCl. Mp
1
1148C (82 J g21). H NMR (500 MHz, DMSO-d6): d 1.09
(br t, Jˆ7.3 Hz, 3H), 1.21 (t, Jˆ7.6 Hz, 3H), 1.22 (br t,
Jˆ7.3 Hz, 3H), 2.70 (q, Jˆ7.6 Hz, 2H), 3.15 (br q,
Jˆ7.3 Hz, 2H), 3.49 (br q, Jˆ7.3 Hz, 2H), 7.45, 7.50
(AA0BB0, 4H), 9.65 (br s, 2H). 13C NMR (50 MHz,
CD3OD): d 12.9, 15.1, 15.2 (CH3), 27.9, 37.7, 39.9 (CH2),
128.0, 128.3 (CH), 125.8, 148.0, 162.8 (ipso-C, CvN). IR
(KBr, cm21): n 3156, 3032, 2977, 2932, 1639, 1568, 1385,
752. Anal. calcd for C13H21ClN2 (240.77): C, 64.85; H, 8.79;
N, 11.63. Found: C, 64.81; H, 8.67; N, 11.62.
4.1.2. 4,N,O-Triethylbenzimidate (3). Amide 2 (4.43 g,
25.0 mmol) was dissolved in a 1.0 M solution of triethyl-
oxonium tetra¯uoroborate in CH2Cl2 (30 mL). After stirring
at room temperature under Ar for 24 h, the solvent was
removed in vacuum. The residue was treated with ice-cold
aqueous NaOH (3 M, 20 mL) and extracted with ice-cold
ether (100 mL). The organic extract was dried over Na2SO4
and concentrated. Crude benzimidate 3 was distilled once
(Kugelrohr, 1608C/0.02 mbar) and used without further
puri®cation. Yield: 4.25 g (83%). 1H NMR (500 MHz,
CDCl3): d 1.14 (t, Jˆ6.9 Hz, 3H), 1.24 (t, Jˆ7.6 Hz, 3H),
1.32 (q, Jˆ6.9 Hz, 2H), 2.66 (q, Jˆ7.6 Hz, 2H), 3.29 (q,
4.1.6.
4,N,N0-Triethylbenzamidinium
tetrakis[3,5-
bis(tri¯uoromethyl)phenyl]borate (7). A mixture of 6
(120 mg, 0.500 mmol) and potassium tetrakis[3,5-bis(tri-
¯uoromethyl)phenyl]borate24 (451mg, 0.500 mmol) were
dissolved in methanol (25 mL) and concentrated in a
vacuum. The residue was then suspended in a 1:1 mixture
of CHCl3±MeCN (20 mL) and passed through a membrane
®lter. The ®ltrate was concentrated in a vacuum to furnish 7
Jˆ6.9 Hz, 2H), 4.21(q,
Jˆ6.9 Hz, 2H), 7.22, 7.26
(AA0BB0, 4H).
4.1.3. 4,N,N0-Triethylbenzamidine (4). A solution of 3
(2.67 g, 13.0 mmol) and ethylamine hydrochloride (1.30 g,
16.0 mmol) in dry ethanol (30 mL) was stirred for 5 days at
room temperature under Ar. The solvent was removed in
vacuum, and the residue suspended in ice-cold ethyl acetate
(100 mL). The mixture was then washed with ice-cold
aqueous NaOH (6 M, 20 mL). The organic phase was
collected, dried over Na2SO4, and concentrated. Gradient
sublimation (908C/1024 mbar) gave 4.10 g (98%) of
amidine 4. Mp 698C (93 J g21). 1H NMR (500 MHz,
CDCl3): d 1.13 (br s, 6H), 1.25 (t, Jˆ7.6 Hz, 3H), 2.67 (q,
1
as a colourless amorphous solid. Yield: 250 mg (71%). H
NMR (500 MHz, CDCl3) major (E,Z) isomer: d 1.19 (t,
Jˆ6.9 Hz, 3H), 1.26 (t, Jˆ7.6 Hz, 3H), 1.29 (t, Jˆ6.9 Hz,
3H), 2.74 (q, Jˆ7.6 Hz, 2H), 3.31( ,quin, Jˆ6.9 Hz, 2H),
3.36 (,quin, Jˆ6.9 Hz, 2H), 6.29 (br s, 1H), 6.60 (br s, 1H),
7.25, 7.39 (AA0XX0, 4H), 7.53 (br s, 4H), 7.69 (br s, 8H); an
additional set of smaller signals could be assigned to the
(E,E)-con®gured amidine isomer: d 1.13 (t, Jˆ6.9 Hz,
6H), 1.26 (t, Jˆ7.6 Hz, 3H), 2.74 (q, Jˆ7.6 Hz, 2H), 3.07
(,quin, Jˆ6.9 Hz, 4H), 7.20, 7.43 (AA0XX0, 4H), 9.18 (br
s, 2H). Anal. Calcd for C45H33BF24N2 (1068.53): C, 50.58;
H, 3.11; N, 2.62. Found: C, 50.97; H, 3.26; N, 2.73.
1
Jˆ7.6 Hz, 2H), 3.20 (br s, 4H), 7.17±7.23 (br m, 4H). H
NMR (200 MHz, CD3OD): d 1.10 (t, Jˆ7.2 Hz, 6H), 1.24
(t, Jˆ7.6 Hz, 3H), 2.68 (q, Jˆ7.6 Hz, 2H), 3.14 (q,
Jˆ7.2 Hz, 4H), 7.20, 7.28 (AA0BB0, 4H). 13C NMR
(50 MHz, CD3OD): d 16.2, 16.3 (br) (CH3), 29.7, 41.2
(br) (CH2), 128.88, 128.94 (CH), 134.4, 146.7, 162.8
(ipso-C, CvN). MS (CI, NH3): m/z 205 (M1H1, 100%).
IR (KBr, cm21): n 3210, 2966, 2929, 2862, 1622, 1539,
1312, 833. Anal. Calcd for C13H20N2 (204.31): C,
76.42; H, 9.87; N, 13.71. Found: C, 76.57; H, 10.06; N,
13.93.
4.2. Determination of pKa
Amidine 4 (20±30 mg, ca. 0.13 mmol) and KCl (221 mg,
3.0 mmol) were dissolved in a mixture of water (15.0 g) and
dioxane (15.0 g) to which a known amount of 0.5 M hydro-
chloric acid was added to lower the pH to about 3. Potentio-
metric studies were conducted with a Metrohm 702 Titrino
autotitrator using a Metrohm 6.0222.100 combined pH glass
electrode with a 3 M KCl internal ®lling. Titrations were
carried out at 258C with 0.4905 M NaOH, and about 100
data points were collected for each titration. The ion product
of water (pKw 15.4) in the mixed solvent was determined by
a Gran plot.25 The equivalents of H1 bound (Eq. (1)) were
calculated from the activity-corrected pH,19b the amount of
amidine base (L) used in the titration, added strong acid (A),
the concentration (Cb) and added volume (v) of NaOH
titrant, and the starting volume (V0).19 The pKa was obtained
after ®tting the experimentally determined values (Eq. (1))
to the theoretical Bjerrum function (Eq. (2)) by an
unweighted nonlinear least-squares regression method
using Microsoft Excel.
4.1.4. 4,N,N0-Triethylbenzamidinium benzoate (5).
Benzoic acid (122 mg, 0.982 mmol) and 4 (200 mg,
0.982 mmol) were dissolved in hot ethanol (10 mL). The
solution was then concentrated in vacuum, and the residue
was recrystallized from hot hexane to give colourless
needles of complex 5 (121 mg, 92%). DSC: 398C
1
(9 J g21), 1418C (82 J g21). H NMR (500 MHz, CDCl3):
d 1.17 (t, Jˆ7.2 Hz, 6H), 1.30 (t, Jˆ7.6 Hz, 3H), 2.75 (q,
Jˆ7.6 Hz, 2H), 3.05 (br q, Jˆ7.2 Hz, 4H), 7.24, 7.39
(AA0XX0, ArH amidine), 7.36±7.41, 8.09±8.12 (m, ArH
benzoate), 12.93 (br s, 2H). 13C NMR (125 MHz, CDCl3):
d 15.1, 15.5 (CH3), 28.8, 39.6 (CH2), 127.0, 127.6, 129.0,
129.4, 130.0 (CH), 124.6, 137.9, 147.9, 166.8, 175.0 (ipso-
C, CvN, CvO). IR (KBr, cm21): n 2972, 1646, 1596,
1552, 1377, 718. ESI-MS (CH3CN): m/z 531( 421benzoic
acid1H1, 100%), 409 (421H1, 10), 205 (41H1, 10). Anal.
w1pH
L 1 A 2 Cbv 2 ꢀ102pH 2 102pK
†ꢀV0 1 v†
nꢀH ˆ
ꢀ1†
L

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A. Kraft et al. / Tetrahedron 58 (2002) 3499±3505
9. Hartmann, S.; Weckert, E.; Frahm, A. W. Acta Crystallogr.,
10pK 2pH
a
nꢀH
ˆ
ꢀ2†
Sect. C 1999, 55, 806±808.
1 1 10pK 2pH
a
10. McNally, J. J.; Youngman, M. A.; Lovenberg, T. W.;
Nepomuceno, D. H.; Wilson, S. J.; Dax, S. L. Bioorg. Med.
Chem. Lett. 2000, 10, 213±216.
4.3. X-Ray crystallographic study of 5
È
11. Peters, L.; Frohlich, R.; Boyd, A. S. F.; Kraft, A. J. Org. Chem.
2001, 66, 3291±3298.
Crystals suitable for X-ray crystallography were grown
from a solution of 5 (5±7 mg) in hexane (2 mL) that was
kept in a sample vial (sealed with a polypropylene lid) and
left to stand at room temperature for several days. Crystal
data: C20H26N2O2, colourless needle 0.23£0.12£0.09 mm3,
È
12. Gobel, M. W.; Bats, J. W.; Durner, G. Angew. Chem., Int. Ed.
È
Engl. 1992, 31, 207±209.
13. Wulff, G.; Groû, T.; Schonfeld, R. Angew. Chem., Int. Ed.
È
Engl. 1997, 36, 1962±1964.
monoclinic, space group C2/c (No. 15), aˆ9.717(2),
14. Strikovsky, A. G.; Kasper, D.; GruÈn, M.; Green, B. S.; Hradil,
J.; Wulff, G. J. Am. Chem. Soc. 2000, 122, 6295±6296.
È
15. (a) Wulff, G.; Schonfeld, R. Adv. Mater. 1998, 10, 957±959.
(b) Baumstark, R.; Wildburg, G.; Hauûling, L.; Wulff, G.;
Ê
bˆ22.074(4),
cˆ9.258(2) A,
bˆ106.76(3)8,
Vˆ
1901.4(7) A , Zˆ4, rcalcdˆ1.140 g cm23, Tˆ230 K. Data
Ê 3
collection: 2416 re¯ections (^h, ^k, ^l) were collected
È
Ê
on a NoniusKappa diffractometer, lˆ0.71073 A (Mo Ka
È
Schonfeld, R.; Grun, M. German Patent DE 19720345, 1997.
È
16. Schonfeld, R. PhD Dissertation, University of Dusseldorf,
radiation), 1637 independent and 895 observed re¯ections
È
1998.
È
[I$2s(I)]. The structure was re®ned against F2 (program
È
SHELXL-97, G. M. Sheldrick, University of Gottingen) to
17. Hammond, G. S.; Neuman, R. C. J. Phys. Chem. 1963, 67,
1655±1659.
give Rˆ0.065 and wR2ˆ0.170 for 114 parameters, max.
Ê 23
residual electron density 0.23 (20.22) e A . Crystallo-
18. (a) Yeretzian, C.; Wiley, J. B.; Holczer, K.; Su, T.; Nguyen, S.;
Kaner, R. B.; Whetten, R. L. J. Phys. Chem. 1993, 97, 10097±
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graphic data (excluding structure factors) for the structure
in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC-176872. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: 144-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
19. (a) Avdeef, A.; Kearney, D. L.; Brown, J. A.; Chemotti, A. R.
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Chemists: A Comprehensive Guide; 2nd ed; Wiley-VCH: New
York, 2001; Chapter 22.
20. The following examples are a selection of ethylbenzenes with
Ê
C±C bond lengths ,1.32 A, excluding poor structures and
Acknowledgements
organometallics (C±C distance, CAr±C±C angle, and CSD
reference code given in brackets): (a) N,N0-Bis(4-ethyl-
We thank Dr John E. Davies and the X-ray laboratory of
Cambridge University Chemical Laboratory for carrying
out the crystal structure determination, Ms S. Johann for
assistance in preparing the starting materials, and Professor
Dr G. Wulff for support. Financial support by the Deutsche
Forschungsgemeinschaft, Heriot±Watt University and the
Royal Society is gratefully acknowledged.
Ê
benzenesulfuryl)-p-phenylenediamine (1.093 A, 126.58,
disordered, GOWSIU): Bock, H.; Nagel, N.; Eller, P. Z.
Naturforsch 1999, B54, 491±500. (b) A 1,3,5-triethylbenzene
Ê
derivative (1.231 A, 131.48, disordered, NAWXEO): Bisson,
A. P.; Lynch, V. M.; Monahan, M.-K. C.; Anslyn, E. V.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2340±2342. (c) Ethyl-
benzene solvent included in a metalloporphyrin crystal
Ê
(1.231 A, 110.18, disordered, YEKHIF): Guilard, R.; Brandes,
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