Orthohalogen substituents dramatically enhance hydrogen bonding of aromatic ureas in solution

Article abstract of DOI:10.1039/c3cc47447j

The phenylurea moiety is a ubiquitous synthon in supramolecular chemistry. Here we report that the introduction of chlorine or bromine atoms in the ortho positions to the urea unit is a simple and very efficient way to improve its intermolecular hydrogen bond (HB) donor character. This effect was demonstrated in solution both in the context of self-association of bis-ureas and hydrogen bonding of mono-ureas to strong HB acceptors. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc47447j

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Orthohalogen substituents dramatically enhance
hydrogen bonding of aromatic ureas in solution†
Cite this: Chem. Commun., 2014,
50, 611
Ilaria Giannicchi,a Benjamin Jouvelet,bc Benjamin Isare,bc Mathieu Linares,d
Antonella Dalla Corta and Laurent Bouteiller*bc
Received 29th September 2013,
Accepted 4th November 2013
DOI: 10.1039/c3cc47447j
www.rsc.org/chemcomm
The phenylurea moiety is a ubiquitous synthon in supramolecular However, in the case of fluorine, an interesting conformational
chemistry. Here we report that the introduction of chlorine or effect has been described: the presence of a single fluorine
bromine atoms in the ortho positions to the urea unit is a simple atom in the ortho position enforces a coplanar conformation of
and very efficient way to improve its intermolecular hydrogen bond the aromatic and urea moieties, whereas the presence of two
(HB) donor character. This effect was demonstrated in solution fluorine atoms in 2,6 positions is responsible for the clear loss of
both in the context of self-association of bis-ureas and hydrogen coplanarity. This is attributed to the electrostatic repulsion
bonding of mono-ureas to strong HB acceptors.
between the oxygen and both fluorine atoms, which therefore
forbids the formation of a weak N–HÁ Á ÁF intramolecular HB.14
Developing supramolecular synthons with an improved efficiency Although the strength of the intermolecular HB cannot be
and selectivity is an important endeavour in the context of the deduced from the crystalline structures reported, it is note-
current increasing complexity of self-assembled systems.1 A well- worthy that the bisfluorinated urea forms the usual bifurcated
known strategy to enhance the HB donor ability of receptors is to intermolecular HB, whereas the monofluorinated analogue
introduce electron withdrawing substituents, but a careful design does not. This conformational effect is particularly relevant in
is required to avoid establishing competing intramolecular inter- the context of self-association, because the phenylurea moiety
actions. Here, we focused our attention on the phenylurea moiety, usually displays a strong conformational change on self-
which is a ubiquitous synthon in supramolecular chemistry. Its assembly to avoid steric clash between the aromatic groups
direct synthetic accessibility and its HB donor ability have been and to allow some p-stacking interactions.15,16 We therefore
exploited in the fields of anion complexation,2 organocatalysis3 reasoned that the presence of two halogen atoms in the ortho
and foldamer conformational control.4 Moreover, the self- position to the urea group could have a favourable influence on
complementarity of the phenylurea synthon is a reliable design intermolecular hydrogen bonding, due to a better conformational
motif for crystal engineering,5 organogelators,6 liquid crystals,7 preorganization of the monomer. In this communication, we report
supramolecular polymers,8 nanostructured polymers,9 self- that indeed the presence of halogen atoms in the ortho positions to
assembled capsules10 and monolayers.11 The effect of various the urea considerably improves intermolecular hydrogen bonding
electron withdrawing substituents on urea assembly is well- and that, surprisingly, in the case of chlorine and bromine, this
known,12 but the case of halogen atoms in the ortho position of effect is accompanied by the formation of an intramolecular HB.
the phenylurea moiety has rarely been investigated, probably
We consider the 2,4,6-trihalogenated bis-ureas presented in
because such substitution was shown to favour intramolecular Scheme 1 together with the unsubstituted and trimethylated
HBs. The intramolecular HB to an ortho chlorine atom totally bis-ureas as references. At low concentration (2 Â 10À5 mol LÀ1
)
suppresses the intermolecular HB for a trisubstituted urea.13 in chloroform, FTIR spectra show that all these compounds are
monomeric and that an intramolecular interaction between
N–Ha (Scheme 1) and the halogens in the ortho position is
a
`
Dipartimento di Chimica and IMC-CNR, Universita La Sapienza, 00185 Roma,
Italy
b
`
UPMC Univ Paris 06, UMR 7610, Chimie des Polymeres, F-75005 Paris, France.
E-mail: laurent.bouteiller@upmc.fr
c
`
CNRS, UMR 7610, Chimie des Polymeres, F-75005 Paris, France
d
¨
Department of Physics, Chemistry and Biology (IFM), Linkoping University,
¨
SE-58183 Linkoping, Sweden
† Electronic supplementary information (ESI) available: Additional data and
Scheme 1
experimental procedures. See DOI: 10.1039/c3cc47447j
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Fig. 2 SANS intensity (I) versus scattering vector (q) for bis-urea solutions
in CDCl3 at a concentration of 15 g LÀ1 (ca. 0.03 mol LÀ1) at 22 1C. The plain
curves are fits according to a model for long rigid filaments with a circular
cross-section (characteristic dimensions are provided in Table S3, ESI†).
Fig. 1 FTIR spectra of bis-ureas at 10À2 mol LÀ1 in chloroform (20 1C).
present in the case of the chlorinated bCl3 and brominated bBr3
bis-ureas (see ESI†). Ab initio calculations on model mono-ureas
support these results and highlight the significant influence of the
substituents on the dihedral angle (j) between the urea and aromatic
groups (see ESI†). In the absence of substituents (bH3) the most stable
conformation is coplanar (j = 0). With fluorine (bF3) or methyl (bMe3)
substituents, the most stable conformations correspond to a dihedral
angle of 601 to 1201, separated by a small barrier (1 kcal molÀ1) at
j = 901. With chlorine (bCl3) or bromine (bBr3) substituents, the
energy surface is completely flat from j = 601 to 1201.
At higher concentration (10À2 mol LÀ1), FTIR shows that inter-
molecular HBs are formed (Fig. 1). In fact, at this concentration, the
free N–H vibration band (3420–3450 cmÀ1)8 is small in the case of
bH3 and bMe3 and is barely detectable in the case of bF3, bCl3 and
bBr3, which qualitatively hints at the positive effect of the halogens
on the strength of intermolecular association. The structure of the
assemblies was examined by Small Angle Neutron Scattering (SANS).
All compounds yield very similar scattering profiles in deuterated
chloroform (Fig. 2): the low angle region shows a qÀ1 dependence
over more than a decade, which is characteristic of long and rigid
fibrillar objects. In principle, the specific dimensions of the scatter-
ing objects can be deduced from a fit to a form factor calculated
according to a suitable geometrical model. In the present case the
Fig. 3 ITC enthalpograms of bis-urea solutions in chloroform injected
into chloroform versus total bis-urea concentration in the cell (T = 20 1C).
use of a form factor for infinitely long rigid filaments (with a circular be reduced to induce full dissociation. To quantify this effect, the
cross-section and a uniform scattering length density profile)17 yields experiments were reproduced with optimized initial concentrations
an excellent fit over the whole q range (Fig. 2). The values deduced and injection volumes, and the heat signal was integrated and plotted
from the fits are summarized in Table S3 (ESI†). According to these versus the concentration in the calorimetric cell (Fig. 3). From these
results, all five bis-ureas form very similar assemblies,‡ with a curves, it is possible to determine graphically the critical concen-
relatively low linear density (nL E 0.25 ÅÀ1), which corresponds to tration (c*)18 below which the assemblies dissociate into monomers:
the presence of a single bis-urea in the cross-section.17
the stability of the assemblies increases very strongly from the
The fact that all five bis-ureas self-assemble into long filaments reference bis-ureas bH3 (c* = 1.6 mM) and bMe3 (c* = 0.6 mM) to
with the same structure makes the comparison of their association the halogenated bis-ureas bF3 (c* = 0.1 mM), bBr3 (c* = 0.056 mM)
strength particularly relevant. Therefore, their stability to dilution was and bCl3 (c* = 0.041 mM). Moreover, the exact shape of the titration
probed by Isothermal Titration Calorimetry (ITC). Fig. S5 (ESI†) shows curves can be accounted for by a simple mass action law model
the heat effect produced when a drop of a solution containing a self- describing the evolution of the concentration of monomers (M) and
assembled bis-urea is diluted with chloroform. The endothermic filaments (Fn) of any degree of polymerisation (n).19 The values
signal results from the breaking of hydrogen bonds consequent to deduced from the fit for the association constants and the enthalpy
the dilution. Qualitatively, it is possible to see that the halogenated of association are presented in Table S4 (ESI†).
bis-ureas are more strongly self-associated than bH3 and bMe3
These results show that the replacement in the ortho positions
because in their case the concentration of the experiment had to of methyl groups with chlorine or bromine atoms stabilizes the
612 | Chem. Commun., 2014, 50, 611--613
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In conclusion, we have shown by FTIR and ab initio calcula-
tions that an intramolecular HB is formed when phenylureas
are functionalized by chlorine or bromine atoms in ortho
positions. Remarkably, the involvement of the aromatic N–H
group in an intramolecular HB does not weaken the inter-
molecular hydrogen bond capacity of the urea group. In contrast,
the association constant of aromatic bis-ureas (measured by
ITC) is improved by one order of magnitude when chlorine
atoms replace methyl groups or even more when they replace
hydrogen atoms in the ortho positions to the urea unit. This
effect was demonstrated both in the context of self-association
of bis-ureas and hydrogen bonding of mono-ureas to strong HB
acceptors. We suggest that this halogen effect is due at least in
part to conformational constraints resulting from the repulsion
between the oxygen and halogen atoms that favourably orientates
Fig. 4 Free N–H fraction determined by FTIR for mixtures of mono-ureas
(5 Â 10À3 mol LÀ1) and DMSO in chloroform (20 1C). The curves are fits to a the N–H groups for hydrogen bonding.
1 : 1 association model.
`
I.G. acknowledges financial support from the Universita
La Sapienza, COST Action ‘‘Supramolecular Chemistry in
Water’’ and Egide. M.L. thanks SERC (Swedish e-Science
Research Center) for funding and SNIC for providing computer
assemblies by more than one order of magnitude. This huge
effect may potentially be due to several factors:
´
resources. We thank François Boue (LLB, Saclay) for assistance
– the electron withdrawing effect of the halogen atom which
should enhance the HB donor character of N–Ha, as confirmed
by ab initio calculations on model mono-ureas (see ESI†);
– the polarization of the aromatic ring by the halogen atom
which could increase p-stacking interactions;
with SANS experiments.
Notes and references
‡ The vertical shift between the curves results from the significant
differences in specific contrast among the bis-ureas (see Table S3, ESI†).
– the repulsion between oxygen and halogen atoms which
may induce a conformational effect.
´
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structurally simpler mono-ureas (Fig. 4) and probed their association
with strong hydrogen bond acceptors such as dimethylsulfoxide
(DMSO) and triphenylphosphine oxide (TPPO). Sufficiently
dilute solutions of the mono-ureas were prepared to ensure that
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mMe2-NH to mCl2-NH (and from mMe2-NMe to mCl2-NMe)
reveals the presence of intramolecular HB between N–Ha and
chlorine atoms, as in the case of bis-ureas. The free N–H band
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donor than mMe2-NH. This experiment rules out the enhance-
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and mCl2-NMe are HB donors of similar magnitude. Therefore,
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for hydrogen bonding. However, in the case of N–Ha, the intra-
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This journal is ©The Royal Society of Chemistry 2014
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