Mimics of a R22(8) hydrogen-bond dimer motif: Synthesis and influence on the crystallisation of sulfathiazole and sulfapyridine

Article abstract of DOI:10.1002/ejoc.200901042

The bis[4-(hydroxyamino)phenylsulfonyl]piperazine 5, diketopiperazine 10 and benzene 14 were synthesised as mimics of an R₂²(8) motif, which occurs in one crystal polymorph of sulfathlazole and in several polymorphs of sulfapyridine.

Full text of DOI:10.1002/ejoc.200901042

FULL PAPER
DOI: 10.1002/ejoc.200901042
Mimics of a R22(8) Hydrogen-Bond Dimer Motif: Synthesis and Influence on
the Crystallisation of Sulfathiazole and Sulfapyridine
Simon E. Lawrence,[a] Marie T. McAuliffe,[a] and Humphrey A. Moynihan*[a]
Keywords: Crystal polymorphism / Hydrogen bonds / Sulfathiazole / Sulfapyridine / Polymorphism / Sulfur heterocycles
The bis[4-(hydroxyamino)phenylsulfonyl]piperazine 5, dike-
topiperazine 10 and benzene 14 were synthesised as mimics
of an R22(8) motif, which occurs in one crystal polymorph of
sulfathiazole and in several polymorphs of sulfapyridine.
When present in crystallisations of sulfathiazole and sulfa-
pyridine, these mimics were found to have little or no effect
under crystallisation conditions that favour the formation of
polymorphs not containing R22(8) motifs. However, the mimics
were found to completely or partially inhibit the formation of
form I sulfathiazole, which contains the R22(8) dimer, in crys-
tallisations of sulfathiazole from 1-propanol. In crystallisa-
tions of sulfapyridine, the mimics were found to promote the
formation of form III, which does not contain the R22(8) motif.
These compounds therefore appear to act as “tailor-made”
additives, displaying polymorph-selective crystal nucleation
inhibition based on interaction with hydrogen-bond network
motifs.
Introduction
Crystal polymorphism[1] is an area of much current inter-
est, largely because of the impact of polymorphism on the
manufacture of pharmaceuticals,[2] and fine chemicals.[3]
The antimicrobial compound sulfathiazole is one of the
best studied examples of a polymorphic pharmaceutical.[4]
Five crystal polymorphs, known as forms I to V,[5] and very
many solvates[6] of this compound have been reported. The
variation in hydrogen-bonding networks[7] in the poly-
morphs of sulfathiazole 1 [Figure 1, (a)] has also been rigor-
ously analysed.[5] Four of the five crystal polymorphs of
sulfathiazole have been shown to be based on hydrogen-
bonded dimeric motifs. The crystal structure of form I sul-
fathiazole has been shown to contain dimers containing the
R22(8) motif shown in Figure 1, (b), whereas forms II, III
Figure 1. (a) Sulfathiazole, molecular structure. (b) R22(8) hydrogen-
2
and IV have been shown to contain the R2 (18) motif bonded dimer present in form I sulfathiazole. (c) R22(18) hydrogen-
bonded dimer present in forms II, III and IV sulfathiazole.
shown in Figure 1, (c). These hydrogen-bonded dimer mo-
tifs also occur in the crystal structures of other sulfanil-
amide antimicrobials, for example, R22(8) motifs analogous
to the dimer shown in Figure 1, (b) occur in four of the
crystal polymorphs of sulfapyridine[8] 2 (Figure 2). Note
that Figure 2 shows sulfapyridine in the sulfonimide tauto-
mer for ease of comparison with sulfathiazole (which ap-
pears to exist exclusively in the sulfonimide tautomer in the
solid state), but that both the sulfonimide and sulfonamide
tautomers of sulfapyridine are found in the solid state.
[a] Department of Chemistry/Analytical and Biological Chemistry
Research Facility, University College Cork,
College Road, Cork, Republic of Ireland
E-mail: h.moynihan@ucc.ie
Figure 2. (a) Sulfapyridine, molecular structure. (b) R22(8) dimer
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901042.
present in four crystal polymorphs of sulfapyridine.
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Mimics of a R22(8) Hydrogen-Bond Dimer Motif
It has been shown that crystal nucleation and growth can capabilities of the R22(8) dimer. We also report on the influ-
be influenced at the molecular level by the use of additives. ences of these compounds as additives in crystallisations of
For example, rationally-designed tailor-made additives have sulfathiazole and sulfapyridine.
been used to selectively inhibit the nucleation of specific
crystal polymorphs.[9] Polymers have been used as crystal
heteronuclei[10] and crystals of compounds related to the
Results and Discussion
crystallising material have been used as pseudo-seeds.[11]
During some recent research on the preparation of co-crys-
The three compounds, 5, 10 and 14, which mimic the R
tals, novel or unexpected crystal forms may have been ob- 22(8) hydrogen-bond dimer were prepared by the routes
tained as a consequence of putative co-crystallising com- shown in Scheme 1. In the case of each, the final step was
pounds acting as crystallisation additives.[12]
reduction of a bis(4-nitrophenylsulfonyl) precursor, that is,
Rationally designed crystallisation additives are often compounds 4, 9 and 13. Precursor 4 was obtained by reac-
based on features of the crystallising material. For example, tion of piperazine, 3, with 4-nitrobenzenesulfonyl chloride.
additives may mimic the molecular conformation present in Precursor 9 was obtained by cyclodimerisation of the acid
a particular crystal form,[13] or may exploit the symmetries chloride 8 derived from N-(4-nitrophenylsulfonyl)glycine
of different forms.[14] One possibility for crystallisation ad- (7). Precursor 13 was obtained by reaction of 1,4-dibro-
ditive design is mimicry of hydrogen-bond motifs. In the mobenzene, 11, with copper 4-nitrothiophenylate, followed
case of sulfathiazole, a single molecule which mimics the by oxidation of the resulting bis(sulfide), 12, to the bis(sulf-
supramolecular binding features for the R22(8) dimer would one) 13.
be likely to affect the processes of sulfathiazole crystal nu-
Our original intention was to reduce the bis(4-nitrophen-
cleation and growth. For instance, such additives might di- ylsulfonyl) compounds 4, 9 and 13 to the corresponding
rect the nucleation of form I by acting as templates for the bis(4-aminophenylsulfonyl) derivatives. We therefore sub-
nucleation and growth of the form I structure. Alternatively, jected compounds 4, 9 and 13 to the following standard
such additives might selectively add to pre-critical nuclei of conditions for aromatic nitro to amine reduction: Sn, HCl,
form I and inhibit their growth into mature crystals. Other reflux; Fe, HCl, reflux; Fe, NH4Cl, reflux; Na2S, NH4Cl,
additive effects might also be possible. In this paper, we NH4OH, reflux. No identifiable product was obtained from
report the preparation of three compounds, 5, 10 and 14 any of these reactions. Hydrogenation at 40 psi in ethanol
(Scheme 1),which meet the above requirement for acting as solvent over palladium on carbon gave no reaction (com-
single-molecule mimics of the sulfathiazole R22(8) dimer. All pounds 4, 9 and 13 were effectively insoluble in ethanol).
three possess the hydrogen-bond donating and accepting Transfer hydrogenation using palladium on carbon in re-
Scheme 1. Preparation of R22(8) dimer mimics 5, 10 and 14. a) 4-NO2C6H4SO2Cl (2.0 equiv.), NaOH (2.2 equiv.), H2O, acetone, reflux
(87%). b) H2, 10% Pd/C, DMF, 50 psi (55%). c) 4-NO2C6H4SO2Cl, 1  aq. NaOH (93%). d) PCl5, EtOAc (79%). e) Et3N, toluene
(60%). f) H2, 10% Pd/C, DMF, 50 psi (66%). g) 4-NO2C6H4SCu (2 equiv.) [from 4-NO2C6H4SH, Cu2O, EtOH, reflux (96%)], quinoline,
pyridine, 200 °C (68%). h) 30% aq. H2O2, AcOH, reflux (86%). i) H2, 10% Pd/C, DMF, 50 psi (64%).
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S. E. Lawrence, M. T. McAuliffe, H. A. Moynihan
FULL PAPER
fluxing ethanol – formic acid solvent also gave no reaction.
In our hands, crystallisation from 1-propanol gave nee-
To address the issue of the poor solubility of compounds 4, dle-shaped crystals, the PXRD pattern of which correlated
9 and 13 in ethanol, a 1  aqueous sodium hydroxide/ well with the theoretically simulated pattern for form I (ESI
methanol mixture was instead used as solvent in attempted Figure 1, a). Recrystallisation from ethanol or from nitro-
hydrogenations over palladium on carbon at 40 psi; how- methane gave crystals, which were identified as form II by
ever, no identifiable product was obtained. However, use of the overlay of the experimentally isolated diffraction with
DMF as hydrogenation solvent did, in each case, give clean the theoretically simulated pattern for form II (ESI Fig-
conversion to isolable products. These were found to be not ure 1, b).
the expected bis(4-aminophenylsulfonyl) compounds, but
Recrystallisation from 20% aqueous ammonia yielded
rather the bis(hydroxylamines) 5, 10 and 14. Compounds 5, truncated hexagonal crystals which were consistent in mor-
10 and 14 contain all the required features to mimic the phology with the literature[5] description of the habit dis-
supramolecular interactions of the R22(8) dimers, namely cy- played by form III. However, subsequent PXRD analysis
clic core units replacing the R22(8) hydrogen-bond motif, identified these as a mixture of forms III and IV (ESI Fig-
and all the necessary hydrogen-bond donor and acceptor ure 1, c). From water, plate-like hexagonal crystals consis-
groups. Figure 3 gives a comparison of the R22(8) dimer mo- tent with the reported morphology for form IV[5] were iso-
tif from form I sulfathiazole with the diketopiperazine lated. PXRD analysis yielded a diffraction pattern similar
mimic 10.
to that described above for the crystals isolated from 20%
aqueous ammonia, showing the isolated crystals to be a
mixture of forms III and IV. Finally, attempted isolation by
us of form V by the evaporation of boiling water yielded
cuboid-shaped crystals, which PXRD analysis identified as
form II.
The effects of the three dimer mimics, 5, 10 and 14, on
the recrystallisation of sulfathiazole 9 were subsequently
evaluated. Water and 1-propanol were selected as solvents
for these recrystallisations. Water was selected as forms III
and IV are known to crystallise successfully from it, and so
we wished to examine the possibility that the R22(8) dimer
mimics 5, 10 and 14, might act as crystal nucleation-direct-
ing templates, inducing formation of form I from water. 1-
Propanol was selected as the form I polymorph featuring
the R22(8) dimer motif reliably crystallises from this solvent,
and hence compounds, 5, 10 and 14, designed to be R22(8)
dimer mimics, may have the potential to add to crystal nu-
clei of form I and so act as form I inhibitors. Examination
of the solubilities of the additives indicated that the maxi-
mum amount of each which would dissolve in water was
Figure 3. Top: crystallographic view of the R22(8) dimer motif of
form I sulfathiazole. Bottom: model image of the R22(8) dimer
mimic 10.
Methods for the isolation of the five known polymorphs the equivalent of approximately 1.2 wt.-% of additive com-
of sulfathizole as described in the literature[4,5] involve crys- pared to sulfathiazole. As the use of a saturated solution of
tallisation from the following solvents: form I from 1-pro- the additive could result in the precipitation of the additive
panol, form II from nitromethane or from ethanol, form III before the formation of crystals of sulfathiazole 9, it was
from 20% aqueous ammonia solution and form IV from decided to use a maximum concentration of 1 wt.-% addi-
water. Isolation of form V by the evaporation to dryness tive in each case.
of a boiling aqueous solution of sulfathiazole 9 has been
In the case of all three additives, it was found that
described.[6] We thus undertook to isolate the five poly- recrystallisation of sulfathiazole from water with 1 wt.-% of
morphs of sulfathiazole 9 as reported. The materials ob- additive present gave crystals which were observed to be a
tained were analysed by powder X-ray diffraction (PXRD). mixture of needle, plate-like hexagons and truncated hexa-
Patterns were compared with the theoretical patterns gener- gon morphologies, suggesting that a mixture of forms had
ated from crystal structural data for each form obtained been isolated. The PXRD pattern isolated (ESI Figure 1, d)
from the Cambridge Structural Database (CSD). The CSD from all three experiments was found to overlay exactly
reference codes for the structures of form I, II, III, IV and with the theoretically simulated pattern of form IV with
V used are, respectively, SUTHAZ01,[15] SUTHAZ,[16] SU- only one unassigned peak. Thus, it was concluded that
THAZ02,[15] SUTHAZ04,[17] SUTHAZ06.[5] As unit-cell while the additives did appear to have an impact on the
dimensions (and consequently the positions of diffraction crystal habit, pure form IV was isolated.
peaks) are temperature dependent, room-temperature unit-
cell dimensions were used in generating theoretical patterns, in the presence of 1,4-bis[4-(hydroxyamino)phenylsulfonyl]-
so as to provide the best comparison with the room tem- piperazine was subsequently investigated. Upon
perature PXRD data we obtained. recrystallisation from a solution containing 1 wt.-% addi-
The recrystallisation of sulfathiazole 1 from 1-propanol
5
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Mimics of a R22(8) Hydrogen-Bond Dimer Motif
tive 5, it was found that brittle needle-shaped crystals were play the R22(8) motif, but differ considerably in the arrange-
isolated. PXRD analysis showed that crystals of pure ment of these within the structures. Form III, however, is
form IV were isolated. Hence, at this concentration of com- composed of R22(12) hydrogen-bonded dimers, shown in
pound 5 as additive, complete inhibition of crystallisation Figure 4.[19] It is noteworthy that the dimeric motif shown
of form I sulfathiazole from 1-propanol was achieved. The in Figure 4 relies on sulfapyridine molecules existing in the
additive concentration was subsequently reduced to 0.5 wt.- sulfonimino (RSO2N=CR-NHR) tautomer (as shown in
% and again resulted in the isolation of needle-shaped crys- Figure 2) and could not be constructed from the “classical”
tals. PXRD analysis of the isolated material suggested that sulfonamido (RSO2NH–C=NR) tautomer.
the product consisted of a mixture of forms I and IV there-
fore suggesting that partial inhibition of form I was
achieved at this concentration. When the additive concen-
tration was further reduced to 0.1 wt.-%, the crystals iso-
lated were again determined to consist of a mixture of
forms I and IV by PXRD.
In the presence of 1 wt.-% of the diketopiperazine deriva-
tive 10, needle-shaped crystals (morphology consistent with
form I) were obtained in recrystallisations from 1-propanol.
However, PXRD analysis showed a mixture of forms I and
Figure 4. R22(12) hydrogen-bonded dimers occurring in form III
sulfapyridine.
II to be present. This result suggested that a partial inhibi-
tory effect had been observed. When this procedure was
repeated with 0.5 wt.-% of additive 10, PXRD analysis
again showed a mixture of forms I and II to be present.
This mixture was again observed when 0.1 wt.-% and
0.05 wt.-% of additive 10 was used. Hence it can be con-
cluded that the diketopiperazine 10 is capable of partially
inhibiting the crystallisation of form I sulfathiazole down
to 0.05 wt.-%.
We subsequently repeated the crystallisations of sulfathi-
azole 1 from 1-propanol in the presence of 1,4-bis[4-(hy-
droxyamino)phenylsulfonyl]benzene 14. In the presence of
1 wt.-% of additive 14, the isolated crystals were observed
to be opaque brittle needles which by PXRD analysis were
found to consist of a mixture of forms II and IV. Thus at
Literature methods for the crystallisation of the poly-
morphs of sulfapyridine can be summarised as follows:[22,19]
form I from hot methanol or water; form II from 1-prop-
anol cooled from 80 °C to 40 °C; form III from 1-butanol,
2-butanol or n-amyl alcohol cooled to 35 °C; form IV from
rapidly cooled 1-propanol or by the evaporation of 1-buta-
nol;[20] form V by allowing solutions in 1- and 2-propanol
to cool to room temperature for a few hours; form VI by
the careful addition of molten sulfapyridine 23 to boiling
toluene.[21]
In our experiments, pure form III, identified by PXRD
1 wt.-% of additive 14, complete inhibition of form I was (ESI Figure 2, a) was isolated from water, ethanol, 1-propa-
achieved. Reduction of the additive concentration to nol cooled from 80 °C to 40 °C and held at this temperature
0.5 wt.-% caused no decrease in the inhibitory effects and for twenty four hours, from 1-butanol at room temperature
a mixture of forms II and IV was again observed. Upon over twenty four hours, from methanol, and by the evapora-
decreasing the additive concentration further to 0.1 wt.-% tion of 1-butanol. Pure form IV was isolated by us from
the additive effects were seen to lessen somewhat with a solutions of sulfapyridine in 1-butanol held at 35 °C over
mixture of forms I, II and IV being isolated. This suggested twenty four hours (ESI Figure 2, b). We obtained form VI
that at this concentration of compound 14, only partial by addition of the molten sulfapyridine to the toluene, as
control was exerted over the recrystallisation from 1-propa- described by Gelbrich et al.[21] The crystallographic data
nol. At 0.05 wt.-% of additive the effects of compound 14 used to simulate the theoretical pattern for form VI was
was found to have completely diminished and PXRD analy- collected at 120 K. As the PXRD pattern isolated by us
sis indicated the isolation of pure form I. Hence it can be was isolated at room temperature it is likely that there are
concluded that 1,4-bis[4-(hydroxyamino)phenylsulfonyl]- discrepancies between the unit cell dimensions of the crys-
benzene (14) is capable of completely inhibiting the crystal- tals used by us and those used by Gelbrich et al.[21] Thus,
lisation of form I of sulfathiazole down to 0.5 wt.-% with a number of the diffraction peaks in the experimental
partial inhibition possible at 0.1 wt.-%.
pattern are shifted from the corresponding peaks on the
While there have been reports of up to seven polymor- theoretical pattern (ESI Figure 2, c). We were unable to iso-
phic forms of sulfapyridine 2,[18] the crystal structures of late pure crystals of any of the other reported forms. Mix-
only five forms have been solved to date. The numbering tures of forms II and V were isolated from 1-butanol at
system used here is based on numbering used for the solved room temperature for three hours and also from a saturated
structures as follows: form II (BEWKUJ11[19]), form III solution of 1-propanol, which was rapidly cooled, on ice
(BEWKUJ12[19]), form IV (BEWKUJ05[20]), form
V
and the crystals isolated within one hour. A mixture of
(BEWKUJ13[19]) and form VI (BEWKUJ14[21]). The hy- forms II, III and IV crystallised from a saturated solution
drogen-bonding patterns of the five forms are all composed of sulfapyridine in 1-propanol at room temperature over
of hydrogen-bonded dimers. Forms II, IV, V and VI all dis- twenty four hours.
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S. E. Lawrence, M. T. McAuliffe, H. A. Moynihan
FULL PAPER
The effects of the three additives 5, 10 and 14 on the subsequently attempted recrystallisation in the presence of
recrystallisation of sulfapyridine were investigated. As with 0.1 wt.-% of the diketopiperazine derivative 10. The crystals
sulfathiazole, it was decided to carry out the recrystalli- isolated were identified as a mixture of forms II, IV and V.
sations both under conditions which favoured the forma- While form IV was not found to be present in the mixture
tion of the R22(8) dimers, and under conditions which fav- isolated from 1-butanol in the absence of an additive, this
oured the formation of the R22(12) dimers. As the R22(12) result indicates that the additive had little or no impact on
dimers occur exclusively in form III, conditions for the reli- the formation of the R22(8) dimer at this concentration.
able crystallisation of form III (cooling a solution of sulfa-
In the presence of 1 wt.-% of additive 14 in 1-butanol the
pyridine in 1-propanol to 80 °C and then further cooling to crystals isolated were identified by PXRD as a mixture of
40 °C for twenty four hours once the first crystals were seen forms II and III. This suggested that the additive 14 had a
to form) were selected. As recrystallisation from 1-butanol partial R22(8) inhibitory effect and consequently some
at room temperature for 3 h was found, in our hands, to form III crystals were permitted to grow. When the additive
give reliably forms II and V, both of which contain the concentration was reduced to 0.5 wt.-% a mixture of forms
R22(8) dimers, this method was selected to assess the impact II, III and V was isolated. This mixture was found to persist
of the additives on the formation of the R22(8) dimers.
down to 0.05 wt.-% of additive 14 suggesting that partial
In the case of all three additives, it was found that the control over the polymorphism of sulfapyridine 23 was still
recrystallisation of sulfapyridine from a solution of 1 wt.-% present.
of additive in 1-propanol which was cooled from 80 °C to
40 °C and allowed to sit undisturbed for twenty four hours
yielded cuboid-shaped crystals which were found to corre-
Conclusions
late with the theoretically simulated PXRD pattern of
Compounds 5, 10 and 14 were designed to mimic the
form III. These findings suggested that the additives had no R22(8) dimers found in form I sulfathiazole and forms II, IV,
influence on the recrystallisation from 1-propanol and V and VI sulfapyridine. When present in crystallisations of
hence had no effect on the formation of the R22(12) dimer.
sulfathiazole or sulfapyridine, these compounds might be
The effects of additives 5, 10 and 14 on the recrystalli- expected to act as crystal nucleation directors, promoting
sation of sulfapyridine from 1-butanol at room temperature the formation of R22(8)-containing forms, or as selective nu-
for three hours was subsequently examined. Upon cleation inhibitors, impeding the nucleation of R22(8)-con-
recrystallisation of sulfapyridine from 1-butanol at room taining forms, or to have other effects. The above findings
temperature for three hours in the presence of 1 wt.-% of show that the additives have little or no effect under condi-
the piperazine derivative 5 the product isolated was found tions under which R22(8) dimers do not normally form, that
(by PXRD) to consist of a mixture of forms II and III. In is, they do not display a nucleation-directing effect. How-
the presence of 0.5 wt.-% of additive 5, the material isolated ever, under conditions favouring the formation of R22(8) di-
was observed to be a mixture of forms II, III, IV and V. mers, the compounds were found to have an inhibitory ef-
When this was repeated in the presence of 0.1 wt.-% of ad- fect. For example, compounds 5 and 14 were found to com-
ditive, a mixture of forms II and V were obtained. These pletely inhibit the formation of form I sulfathiazole when
results would suggest that the piperazine derivative 5 had a present at 1% (wt./wt.) quantities in crystallisations of sul-
partial inhibitory effect on the formation of the R22(8) dimer fathiazole from 1-propanol, while compound 10 was found
at 1 wt.-% and 0.5 wt.-% as mixtures containing form III to be partially inhibitory of form I under these conditions.
was observed in both cases. The additive effect was seen to This mode of activity is markedly different from that ob-
have completely subsided at 0.1 wt.-% additive as a mixture served for “monomer-like” additives and impurities in these
of forms II and V was isolated.
systems. For example, simple N-acylsulfathiazole derivatives
In the presence of 1 wt.-% of the diketopiperazine deriva- have been found to promote the formation of form I sulfa-
tive 10, it was found that it was not possible to obtain a thiazole from water.[4] They therefore display a very dif-
consistent result. This experiment was carried out on ten ferent effect on crystallisation outcome than that observed
occasions. On three occasions, a mixture of forms II and V for the R22(8) dimer mimics described in this paper.
was obtained. On two occasions, pure form IV was ob-
The sulfapyridine system is more complex in terms of
tained. Pure form III was obtained on one occasion. On the outcomes, different crystal forms being obtainable from the
remaining four occasions, differing mixtures of at least two same solvent with small changes in conditions. However,
of forms II, III, IV, V or VI were obtained. In our experi- even in the sulfapyridine system, compounds 5, 10 and 14
ments, crystallisation of sulfapyridine (in the absence of ad- were found to affect the outcome under conditions that
ditives) normally gives a mixture of forms II and V, or normally favour the formation of R22(8) dimers. In particu-
form III over longer cooling times. Clearly, the crystallisa- lar, form III sulfapyridine, which does not contain R22(8) di-
tion of sulfapyridine from 1-butanol is finely balanced in mers, was found to be more likely to form in the presence
terms of polymorphic outcome. In the presence of additive of the additives, usually as part of a mixture containing
10, forms less easily obtained from 1-butanol, that is, IV other forms. The additives appear to have no impact under
and VI as well as a more frequent occurrence of form III, conditions that normally give sulfapyridine form III.
is observed, suggesting that this additive is affecting the nu-
Compounds 5, 10 and 14 have therefore been found to
cleation and growth of forms II and V to some extent. We act as selective inhibitors of sulfathiazole and sulfapyridine
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Mimics of a R22(8) Hydrogen-Bond Dimer Motif
forms that contain the R22(8) dimer motif and to have little
or no effect on forms that do not possess this motif. During
crystallisation, dimerisation of the sulfa molecules may well
be a process closely linked to that of nucleation and growth.
It is possible that dimers present in solution may add di-
rectly to crystal nuclei, as well as or instead of single molec-
ules. This concept is supported by NMR spectroscopic
studies on a closely related compound, sulfamerazine.[23]
An element of molecular recognition may be present, by
(ESI) positive mode using 50% acetonitrile/water containing 0.1%
formic acid as eluant; samples were made up in acetonitrile. Ele-
mental analysis was performed by the Microanalytical Laboratory
UCC, using a Perkin–Elmer 240 or an Exeter Analytical CE440
elemental analyser. Powder X-ray diffraction was performed at am-
bient temperature using a Stoe Stadi MP PXRD operating in trans-
mission mode with a linear PSD detector with an anode current of
40 mA, an accelerating voltage of 40 kV and Cu-Kα1 radiation (λ
= 1.5406 Å) over a scan range of 3.5–60° 2θ, scanning in steps of
2° for 90 s per step. Samples were held between acetate foils and
which compounds 5, 10 and 14, as R22(8) dimer-mimics, are were not ground. Calculated patterns were generated from crystal-
acceptable for binding to crystal nuclei possessing the R22(8)
lographic information files downloaded from the Cambridge Struc-
tural Database, using the THEO function on the Stoe WinXPOW
motif, but are rejected by nuclei not possessing that motif.
software with a pseudo-Voigt profile-shape function and a Gauss
Once bound to crystal nuclei, the additive inhibits further
component of 0.8.
growth of the nucleus and so inhibits formation of R22(8)-
containing crystal forms. The presence of hydroxyamino
rather than amino groups in compounds 5, 10 and 14 may
N,NЈ-Bis(4-nitrophenylsulfonyl)piperazine (4): To piperazine (0.5 g,
5.8 mmol) in acetone (5 mL) was slowly added with cooling 4-nitro-
benzenesulfonyl chloride (2.84 g, 12.8 mmol). Halfway through the
contribute to the inhibitory effect. The compounds would
addition of the 4-nitrobenzenesulfonyl chloride, a solution of so-
then be acting in a manner similar to that of tailor-made
dium hydroxide (0.51 g, 12.8 mmol) in water (5 mL) was added. An
additives.[9]
exothermic reaction resulted and a precipitate was seen to immedi-
ately form. Once the exothermic reaction had ceased, the reaction
It is also noteworthy that the compounds display inhibi-
tory effects when present in quantities of 1% (wt./wt.) or
less. Compounds 10 and 14, for example, were found to
exert observable effects in quantities of 0.05% (wt./wt.)
Monomer-like tailor-made additives are often effective only
when present in quite large quantities, for example, ca. 10%
(wt./wt.). Additives effective in a quantity of 1% (wt./wt.)
or less are more often polymeric in nature. The observation
that compounds not considerably larger than the crystallis-
ing molecule can affect the crystallisation outcome, even
when present in low quantities, is significant for “real life”
industrial crystallisation processes in which structurally
similar process impurities are often present in quantities less
than 1%.
mixture was heated at reflux for 1.5 h. The precipitate which
formed was collected by filtration and washed with warm ethanol
(2ϫ10 mL) and water (2ϫ10 mL). A yellow solid was isolated
(2.3 g, 87%); m.p. 300 °C (dec.; ref.[24] m.p. 350 °C). IR (KBr): ν
˜
max
= 1609 (aromatic C–C), 1543 and 1310 (NO2), 1351 and 1171
(SO2). C16H16N4O8S2 (456.42): calcd. C 42.10, H 3.53, N 12.27, S
14.05; found C 41.99, H 3.28, N 11.97, S 13.82.
N,NЈ-Bis(4-hydroxyaminophenylsulfonyl)piperazine (5): N,NЈ-Bis(4-
nitrophenylsulfonyl)piperazine (4, 0.5 g, 1.1 mmol) was dissolved in
DMF (50 mL) and 0.05 g 10% Pd/C was added. The reaction mix-
ture was shaken under hydrogen gas at 50 psi for 4 h. The reaction
mixture was then filtered through Celite and most of the solvent
was removed in vacuo. Water (100 mL) was added and the precipi-
tate which formed was isolated by filtration to yield a yellow solid
We would also like to note the benefits of using theoreti-
cal powder diffraction data to assign polymorphic form by
matching to the whole experimental pattern. This allows
very reliable assignment of experimental patterns to crystal
structures held in the Cambridge Structural Database,
rather than to nominal forms distinguished on the basis of
properties such as melting point or morphology. This ap-
proach is even more effective when powder diffraction pat-
terns are obtainable in the transmission mode, which avoids
the need for grinding of the sample and the accompanying
risk of solid-state transformation.
(0.24 g, 51%); m.p. 310 °C (dec.). IR (KBr): ν
= 3420 (OH),
˜
max
1
3303 (NH), 1596 (aromatic C–C), 1334 and 1155 (SO2). H NMR
(300 MHz; [D6]DMSO, 25 °C): δ = 2.88 (s, 8 H, CH2 ϫ4), 6.91 (d,
3
3JH,H = 8.7 Hz, 4 H, ArHϫ4), 7.47 (d, JH,H = 8.7 Hz, 4 H,
ArHϫ4), 8.79 (s, 2 H, OHϫ2), 9.12 (s, 2 H, NHϫ2) ppm. 13C
NMR (75 MHz; [D6]DMSO, 25 °C): δ = 45.18 [CH2], 111.30
[ArylCH], 122.55 [–C–SO2], 128.95 [ArylCH], 155.74 [–C–NHOH]
ppm. HRMS (ESI): Exact mass calculated for C16H19N4O6S2 [(M –
H)–] 427.0746; found 427.0728.
N-(4-Nitrophenylsulfonyl)glycine (7): Glycine (1.5 g, 39.96 mmol)
was suspended in 5 mL water and completely dissolved by the ad-
dition of 1  aqueous sodium hydroxide solution (10 mL). 4-Nitro-
benzenesulfonyl chloride (6.2 g, 27.97 mmol) was added followed
by the addition of further 1  aqueous sodium hydroxide solution
(20 mL) in small portions so as to keep the pH of the reaction
mixture above 9. Once all the sodium hydroxide had been added,
stirring was maintained for a further 30 min. The reaction mixture
was then filtered so as to remove any undissolved 4-nitroben-
zenesulfonyl chloride. The mother liquor was acidified with 5 
hydrochloric acid solution, until a precipitate was seen to form,
Experimental Section
General: All materials were purchased from Sigma–Aldrich. Infra-
red spectra were recorded with a Perkin–Elmer 1000 spectrometer
in the range 4000–500 cm–1. Melting points were determined with
a Reichert hot-stage microscope and are uncorrected. 1H NMR
spectra were recorded at 300 MHz wih a Bruker AVANCE 300 and was then allowed to sit overnight. The precipitate which
spectrometer. 13C NMR spectra were recorded at 75 MHz with a
Bruker AVANCE 300 spectrometer. Splitting patterns in 1H spectra
are designated as s (singlet), br. s (broad singlet), d (doublet), t
(triplet), q (quartet), dd (doublet of doublets) and m (multiplet).
High-resolution mass spectra (HRMS) were recorded with a
Waters LCT Premier LC-MS instrument in electrospray ionisation
formed was collected by filtration to yield a yellow solid (4.68 g,
90%); m.p. 167–173 °C (ref.[25] m.p. 172 °C). IR (KBr): νmax = 3296
˜
(NH), 1732 (C=O), 1332 and 1165 (SO2), 1529 and 1354 (NO2).
1H NMR (300 MHz; [D6]DMSO, 25 °C): δ = 3.64 (s, 2 H, CH2),
3
4
8.05 (dd, JH,H = 7.0, JH,H = 1.9 Hz, 2 H, ArHϫ2), 8.39 (dd,
3JH,H = 7.0, JH,H = 1.9 Hz, 2 H, ArHϫ2) ppm.
4
Eur. J. Org. Chem. 2010, 1134–1141
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1139

S. E. Lawrence, M. T. McAuliffe, H. A. Moynihan
N-(4-Nitrophenylsulfonyl)glycinoyl Chloride (8): N-(4-Nitrophen- 1,4-dibromobenzene (0.49 g, 2.09 mmol) in quinoline (15 mL) and
FULL PAPER
ylsulfonyl)glycine (7, 4.68 g, 17.99 mmol) and phosphorus penta-
chloride (5.62 g, 26.99 mmol) were suspended in ethyl acetate
(50 mL) and stirred at room temperature until all the acid had dis-
solved. Stirring was continued for a further 30 min following which
the excess phosphorus pentachloride was removed by filtration.
Hexane (80 mL) was then added to the mother liquor and the mix-
ture was set aside at 0 °C for several hours. The precipitate which
formed was isolated by filtration to yield a yellow solid (3.52 g,
pyridine (1.5 mL) was heated to 200 °C for 2 h. The reaction mix-
ture was then allowed to cool to approximately 100 °C and was
poured onto a mixture of ice (60 mL) and hydrochloric acid
(16 mL) and stirred for 2 h. The mixture was filtered and the solid
residue was dissolved in ethyl acetate (50 mL). The aqueous filtrate
was extracted with ethyl acetate (2ϫ20 mL). The combined or-
ganic washings were washed with 10% hydrochloric acid solution
(2ϫ20 mL) followed by water (1ϫ20 mL). The organic phase was
dried with magnesium sulfate, filtered and concentrated to yield a
70%); m.p. 133–138 °C. IR (KBr): νmax = 3256 (NH), 1802 (C=O),
˜
1
1312 and 1162 (SO2), 1551 and 1350 (NO2). H NMR (300 MHz. dark brown oil (1.95 g). The product was then dissolved in ethyl
3
CDCl3, 25 °C): δ = 4.37 (d, JH,H = 6.2 Hz, 2 H, CH2), 5.41 (br. t,
acetate and passed through a short silica plug yielding a sticky
orange solid (1.15 g). This was then triturated in 2-propanol to
yield a brown solid (0.55 g, 68%); m.p. 210–219 °C (ref.[26] m.p.
3
4
3JH,H = 5.3 Hz, 1 H, NH), 8.06 (dd, JH,H = 7.0, JH,H = 2.1 Hz,
2 H, ArHϫ2), 8.40 (dd, 3JH,H = 7.0, 4JH,H = 2.1 Hz, 2 H, ArHϫ2)
ppm. 13C NMR (75 MHz; [D6]DMSO, 25 °C): δ = 43.68 (CH2), 215–218 °C). IR (KBr): ν
= 1594 (aromatic C=C), 1578 and
˜
max
124.35 (ArylCH), 128.08 (ArylCH), 146.43 (–C–SO2), 149.43 (–C–
NO2), 170.09 (–COCl) ppm. C8H7ClN2O5S (278.65): calcd. C = 8.95 Hz, 4 H, ArHϫ4), 7.52 (s, 4 H, ArHϫ4), 8.14 (d, JH,H
1334 (NO2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.32 (d, 3JH,H
3
=
34.48, H 2.52, N 10.05, S 11.51, Cl 12.72; found C 34.55, H 2.55,
N 9.78, S 11.20, Cl 13.00.
8.95 Hz, 4 H, ArHϫ4) ppm.
1,4-Bis(4-nitrophenylsulfonyl)benzene (13): A mixture of 1,4-bis(4-
nitrophenylsulfenyl)benzene (12, 0.4 g, 1.04 mmol), 30% aqueous
hydrogen peroxide (0.09 mL, 8.32 mmol) and acetic acid (15 mL)
was slowly heated to reflux and maintained at this temperature
for 2 h. The reaction mixture was then allowed to cool to room
temperature and the solid which precipitated was isolated by fil-
tration to a yellow solid (0.4 g, 86%); m.p. 316–319 °C (ref.[27] m.p.
1,4-Bis(4-nitrophenylsulfonyl)piperazine-2,4-dione (9): N-(4-Nitro-
phenylsulfonyl)glycine acid chloride (8, 3.52 g, 12.64 mmol) was
suspended in dichloromethane (50 mL). To this triethylamine
(1.8 mL, 12.64 mmol) was added. The reaction mixture immedi-
ately turned yellow with the evolution of gas. The reaction mixture
was stirred at room temperature for 5 h following which the solvent
was removed in vacuo. The solid product which resulted was stirred
for 1 h in 2-propanol (50 mL). The product was isolated by fil-
tration to yield a yellow solid (2.58 g, 84%); m.p. 248 °C (dec.). IR
325 °C). IR (KBr): ν
= 1610 (aromatic C=C), 1546 and 1333
˜
max
1
(NO2), 1350 and 1161 (SO2). H NMR (300 MHz. CDCl3, 25 °C):
3
δ = 8.20 (d, JH,H = 8.8 Hz, 4 H, ArHϫ4), 8.22 (s, 4 H, ArHϫ4),
3
(KBr): ν
= 1710 (C=O), 1532 and 1350 (NO2), 1389 and 1187
8.33 (d, JH,H = 8.8 Hz, 4 H, ArHϫ4) ppm. C18H16N2O8S2
˜
max
1
(SO2). H NMR (300 MHz; [D6]DMSO, 25 °C): δ = 4.60 (s, 4 H, (448.42): calcd. C 48.21, H 2.70, N 6.25, S 14.30; found C 48.70,
3
4
CH2), 8.31 (dd, JH,H = 6.9, JH,H = 2.1 Hz, 4 H, ArHϫ4), 8.44
H 2.59, N 6.01, S 14.10.
3
4
(dd, JH,H = 6.9, JH,H = 2.1 Hz, 4 H, ArHϫ4) ppm. 13C NMR
(75 MHz; [D6]DMSO, 25 °C): δ = 48.95 (CH2), 124.29 (ArylCH),
130.43 (ArylCHr), 142.21 (–C–SO2), 150.83 (–C–NO2), 162.95
(–C=O) ppm. C16H12N4O10S2 (484.43): calcd. C 39.69, H 2.50, N
11.57, S 13.24; found C 40.06, H 2.40, N 11.23, S 13.48.
1,4-Bis[4-(hydroxyamino)phenylsulfonyl]benzene (14): 1,4-Bis(4-
nitrophenylsulfenyl)benzene 13 (0.2 g, 0.446 mmol) was dissolved
in DMF (30 mL) and to this 10%Pd/C (0.02 g) was added. The
reaction mixture was then shaken under an atmosphere of hydro-
gen gas at 50 psi for 4 h. The reaction mixture was then filtered
1,4-Bis[4-(hydroxyamino)phenylsulfonyl]piperazine-2,5-dione (10): through Celite and most of the DMF was removed in vacuo, after
1,4-Bis(4-nitrophenylsulfonyl)piperazine-2,4-dione (9, 1.5 g, 3.09
mmol) was dissolved in DMF (50 mL) and 10% Pd/C (0.015 g) was
added. The reaction mixture was shaken under hydrogen gas at
50 psi for 4 h. The reaction mixture was then filtered through Celite
and most of the DMF was removed in vacuo. Water (50 mL) was
then added and the precipitate which resulted was isolated by fil-
which water (50 mL) was added until a precipitate was seen to
form. The product was isolated by filtration to yield a yellow solid
(0.11 g, 64%); m.p. 240 °C (dec.). IR (KBr): ν
= 3427 (OH),
˜
max
1
3298 (NH), 1592 (aromatic C=C), 1305 and 1151 (SO2). H NMR
3
(300 MHz. CDCl3, 25 °C): δ = 6.77 (d, JH,H = 8.8 Hz, 4 H,
3
ArHϫ4), 7.61 (d, JH,H = 8.8 Hz, 4 H, 4ϫArH), 7.95 (s, 4 H,
tration to yield a beige solid (0.87 g, 62%); m.p. 280–283 °C. IR ArHϫ4), 8.74 (s, 2 H, OHϫ2), 9.17 (s, 2 H, NHϫ2) ppm. 13C
(KBr): ν
= 3396 (OH), 3314 (NH), 1694 (C=O), 1359 and 1165
NMR (75 MHz; [D6]DMSO, 25 °C): δ = 111.33 (ArylCH), 127.06
˜
max
1
(SO2). H NMR (300 MHz; [D6]DMSO, 25 °C): δ = 4.42 (s, 4 H, (–C–SO2), 127.88 (ArylCH), 129.28 (ArylCH), 146.38 (SO2–C–),
CH2), 6.78 (d, JH,H = 8.9 Hz, 4 H, ArHϫ4), 7.66 (d, JH,H
3
3
=
156.16 (–C–NHOH) ppm. HRMS (ESI): Exact mass calculated for
C18H15N2O6S2 [(M – H)–] 419.0372; found 419.0358.
8.9 Hz, 4 H, ArHϫ4), 8.82 (s, 2 H, OH), 9.27 (s, 2 H, NH) ppm.
13C NMR (75 MHz; [D6]DMSO, 25 °C): δ = 48.79 (CH2), 110.40
(ArylCH), 123.98 (–C–SO2), 130.22 (ArylCH), 156.57 (–C–
NHOH), 163.37 (–C=O) ppm. HRMS (ESI): Exact mass calcu-
lated for C16H15N4O8S2 [(M–H)–] 455.0331; found 455.0328.
Crystallisations: All recrystallisations were carried out in 250 mL
conical flasks for experiments at room temperature and in 100 mL
round-bottomed flasks where a higher temperature was required.
All solutions were prepared by dissolving 0.5 g of sulfathiazole or
1,4-Bis(4-nitrophenylsulfenyl)benzene (12): A mixture of 4-nitro- sulfapyridine followed by filtration to remove any undissolved ma-
thiophenol (1 g, 6.44 mmol) and copper(I) oxide (0.46 g,
3.22 mmol) in 95% ethanol (50 mL) was heated at reflux for 48 h.
The reaction mixture was cooled to room temperature and cop-
per(I) 4-nitrothiophenylate was isolated by filtration to yield a
terial. Form I sulfathiazole was obtained from a 13 gL–1 solution
of 1-propanol, form II from a 26 gL–1 solution of nitromethane
and a 10 gL–1 solution in ethanol, form III from an 83 gL–1 solu-
tion of 20% aqueous ammonia and form IV from a 22 gL–1 solu-
tion in water. With the exception of the recrystallisation from 20%
brown solid (1.35 g, 96%); m.p. 282 °C (dec.). IR (KBr): ν
=
˜
max
3093 (Ar C-H), 1594 (aromatic C=C), 1512 and 1340 (NO2). aqueous ammonia which required three days for the crystals to
C6H4CuNO2S (217.71): calcd. C 33.10, H 1.85, N 6.43, S 14.73,
Cu 29.19; found C 33.17, H 1.76, N 6.06, S 14.27, Cu 29.11. A
mixture of copper(I) 4-nitrothiophenylate (1.00 g, 4.59 mmol) and
form, all these experiments were carried out over a twenty four
hour period. In all cases the recrystallisation solutions were un-
stirred. The effects of the three R22(8) dimer mimics, 5, 10 and 14,
1140
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1134–1141

Mimics of a R22(8) Hydrogen-Bond Dimer Motif
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under investigation in the appropriate solvent.
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by dissolving 1 g of sulfapyridine in a minimum amount of the
relevant solvent in a 250 mL conical flask and allowing to sit at
room temperature. Pure sulfapyridine form VI was isolated by the
addition of 1 g of molten sulfapyridine to 30 mL of boiling toluene.
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Received: September 10, 2009
Published Online: January 5, 2010
Eur. J. Org. Chem. 2010, 1134–1141
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1141