Thiourea versus the oxyanion hole as a double H-bond donor

Article abstract of DOI:10.1016/j.tetlet.2008.06.039

A novel receptor based on the 4,5-diamine-9,9-dimethylxanthene skeleton functionalised with triflamides has been developed and its hydrogen-bonding donor ability is examined and compared with that of thiourea groups. The novel receptor also shows its potential as an organocatalyst.

Full text of DOI:10.1016/j.tetlet.2008.06.039

Tetrahedron Letters 49 (2008) 5050–5052
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thiourea versus the oxyanion hole as a double H-bond donor
Francisco M. Muñiz a, Victoria Alcázar Montero b, Ángel L. Fuentes de Arriba a, Luis Simón a,
César Raposo c, Joaquín R. Morán a,
*
a Organic Chemistry Department, Plaza de los Caídos 1-5, Universidad de Salamanca, 37008 Salamanca, Spain
b Industrial Chemistry and Environmental Engineering Department, José Gutiérrez Abascal 2, Universidad Politécnica de Madrid, 28006 Madrid, Spain
c Mass Spectrometry Service, Plaza de los Caídos, 1-5, Universidad de Salamanca, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel receptor based on the 4,5-diamine-9,9-dimethylxanthene skeleton functionalised with trifl-
amides has been developed and its hydrogen-bonding donor ability is examined and compared with that
of thiourea groups. The novel receptor also shows its potential as an organocatalyst.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 15 May 2008
Revised 5 June 2008
Accepted 9 June 2008
Available online 12 June 2008
Keywords:
Oxyanion hole
H-bond donor
Association constants
Diels–Alder catalysis
Organocatalysis is a field in rapid expansion.1 One of the key
elements of an organocatalyst is its ability to associate substrates
with a carbonyl group or another good H-bond acceptor.2 Many
of these compounds rely upon the presence of groups, such as
ureas or thioureas, capable of double hydrogen-bond donation.3
Nevertheless, natural enzymatic systems show a preference for
linear H-bonds in the oxyanion-hole structure,4 instead of the
angular H-bonds of urea or thiourea groups.
Although many thiourea derivatives have recently been devel-
oped as organocatalysts,5 no comparison between the association
properties of thioureas and oxyanion hole mimics has been carried
out.
The carbonyl group of ketones or aldehydes affords, as guests,
only weak complexes,6 and accurate measurement of the associa-
tion constants (NMR titrations) is difficult. Therefore, a better
H-bond acceptor would be desirable. Our initial results in the
search for more suitable guests amongst ketones, sulfoxides, phos-
phine oxides and triphenylarsine oxide clearly showed that this
latter compound yielded the strongest complexes. Additionally,
triphenylarsine oxide has other practical advantages: it is a com-
mercially available stable solid, it is easy to handle, and it is very
soluble in chloroform.
amine; receptors 7 and 8, derived from isophthalic acid and
receptors 9–11, derived from 4,5-diamine-9,9-dimethylxanthene.
The association constants were measured in CDCl3 at 293 K.
From the above complexation studies it was clear that thioureas
are highly efficient. Given the availability of thiourea derivatives,
the great success of organocatalysts based on this functional group
is not surprising.
Thioureas 1–4 showed better association constants than m-
xylylene bis-acetamide 5 (9 MÀ1). This latter skeleton probably
presents too many degrees of freedom to become a good scaffold.
An effective comparison of the contribution of the different scaf-
folds to the binding process is nevertheless difficult, because the
influence of the substituents is of great importance. Isophthalic
acid dibutylamide 7 showed a higher association constant (entry
7, 23 MÀ1) than dimethyl thiourea 1 (16 MÀ1), but substitution of
one of the methyl groups by a tolyl unit transformed the thiourea
1 into a better receptor (entry 2, 47 MÀ1). As expected, the more
rigid xanthene derivatives enhanced the hydrogen bonding ability
of the NH groups, showing higher association constants that
ranged from 2.0 Â 103 MÀ1 (receptor 9 functionalised with 4,5-
bis-acetamide groups) to 6.0 Â 103 MÀ1 (receptor 10 with 4,5-bis-
thioacetamide moieties).
Several substituted thioureas (1–4, Table 1) were tested to
screen their binding properties with the substrate of our choice:
triphenylarsine oxide. We also prepared seven receptors for oxyan-
ion hole mimics: receptors 5 and 6, derived from meta-xylylenedi-
However, the most spectacular effect was related to the incor-
poration of the electron-withdrawing trifluoromethyl group. The
replacement of a single methyl group in dimethyl thiourea 1 by a
bis(trifluoromethyl)phenyl group (receptor 3) increased the associ-
ation constant from 16 MÀ1 to 5.3 Â 102 MÀ1 (33-fold), and substi-
tution of the second methyl afforded the Schreiner thiourea 4, with
an association constant of 1.0 Â 105 MÀ1 (nearly 200 times better
* Corresponding author. Tel.: +34 923294481; fax: +34 923294574.
E-mail address: romoran@usal.es (J. J. R. Morán).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.039

F. M. Muñiz et al. / Tetrahedron Letters 49 (2008) 5050–5052
5051
Table 1 (continued)
Table 1
Structure of receptors 1–11 and their association constants with triphenylarsine
oxide in CDCl3
Entry
11a
a
Receptor
Kass (MÀ1
)
Kass (MÀ1
)
CF3
CF3
Entry
Receptor
S
O
O
O
S
S
NH
HN
O
O
4.5 Â 105
N
H
N
1
16
H
1
Cl
Cl
11
S
The association constant was estimated from competitive titration with 4.
2
3
47
N
N
H
H
2
than the monomethyl thiourea 3). Discovery of the Schreiner thio-
urea3h is in this respect an outstanding achievement.
CF3
We also evaluated the remarkable changes in binding when
m-xylylenediamine, isophthalic acid and 4,5-diamine-9,9-dimeth-
ylxanthene skeletons were modified using the trifluoromethyl
group. The flexible m-xylylenediamine receptor now functional-
ised with triflamides (6) displayed an association constant as
high as 4.5 Â 102 MÀ1 (50-fold compared to 5). An even more
impressive effect was observed for the binding of receptor 8 and
triphenylarsine oxide: the previously reported Kass = 23 MÀ1 for
S
5.3 Â 102
F3C
N
H
N
H
3
CF3
CF3
S
4
5
1.0 Â 105
F3C
N
N
CF3
the isophthalic acid dibutylamide
7
increased up to 4.2 Â
H
H
104 MÀ1 (1800-fold) when bis(trifluoromethyl)phenyl groups were
introduced through thioamide junctions.
4
Also as expected, receptor 11 with triflamide moieties on the
xanthene framework provided the highest complexation constant,
yielding a complex 4 times stronger than the Schreiner thiourea.
Given the excellent binding properties of receptors 11 and 4
with triphenylarsine oxide, we decided to extend our study to
other guests, performing competitive titrations (Table 2):
O
NH
HN
O
9
5
CF3
CF3
S
In most cases, the xanthene triflamide 11 proved to be a better
H-bond donor than the Schreiner thiourea, affording stronger com-
plexes. Nevertheless, receptor 11 had a hindered cleft, and in the
case of the sterically demanding triphenylphospine oxide the thio-
urea 4 formed a stronger associate (Table 2, entry 3). The data
reported for As–O and P–O bond distances7 support these
experimental results: the shorter P–O bond involves steric hin-
drance between the phosphine oxide phenyl rings and the xan-
thene receptor 11, hindering the binding process. However, when
the less sterically hindered substrate trioctylphosphine oxide was
used, the bistriflamide receptor 11 formed a stronger complex than
the Schreiner thiourea (sixfold). The absolute association constants
S O
O
O
NH
HN
O
6
7
4.5 Â 102
6
NH
HN
O
O
23
7
for the phosphine and arsine oxides were in the range of 105 MÀ1
–
104 MÀ1 8
.
CF3
CF3
Sulfoxides and ketones are poorer H-bond acceptors, displaying
lower association constants that change from 7.8 Â 103 MÀ1
(tetramethylenesulfoxide and receptor 11) to only 53 MÀ1 (cyclo-
hexanone and receptor 4). In all cases, there is excellent agreement
between the absolute association constants and the data obtained
from competitive titrations.
8
4.2 Â 104
F3C
NH
HN
CF3
S
S
8
Since the Schreiner thiourea proved to be a good catalyst of the
Diels–Alder reaction and since receptor 11 was able to bind
ketones, we examined the reaction between methyl vinyl ketone
(12) and cyclopentadiene (13) under conditions similar to those
reported by Schreiner9 (Fig. 1).
O
NH
HN
HN
O
O
9
2.0 Â 103
Cl
Cl
Table 2
9
Competitive binding studies with receptors 11 and 4 in CDCl3
Entry
Guest
Krel (K11/K4)
S
NH
S
1
2
3
4
5
Ph3As@O
Oc3P@O
Ph3P@O
Tetramethylenesulfoxide
Cyclohexanone
4.3
6
0.43
7.1
1.9
O
10
6.0 Â 103
Cl
Cl
10

5052
F. M. Muñiz et al. / Tetrahedron Letters 49 (2008) 5050–5052
the Junta de Castilla y León (JCL) (SA 52/03) for their support in this
O
work. The Spanish Ministerio de Educación y Ciencia (MEC) is
acknowledged for the fellowships (F.M.M., L.S.).
5% mol cat.
CDCl3
+
12
13
O
References and notes
Figure 1. Diels–Alder reaction between methyl vinyl ketone and cyclopentadiene.
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ketone concentration).
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In sum, the xanthene receptor 11 reveals the efficiency of the
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Acknowledgements
8. The evaluated association constants in CDCl3 at 293 K for trioctylphosphine
oxide and receptors 11 and 4 are 1.3 Â 105 MÀ1 and 2.5 Â 104 MÀ1, respectively.
9. Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407.
The authors thank the Spanish Dirección general de Investiga-
ción, Ciencia y Tecnología (DGICYT)(CTQ-2005-074007BQU) and