Recognition of chiral carboxylates by 1,3-disubstituted thioureas with 1-arylethyl scaffolds

Article abstract of DOI:10.1039/c3nj00644a

Chiral thioureas with 1-arylethyl and 1-arylethyl-2-2-2-trifluoroethyl (Ar = Ph, 1-Napht, 9-Anthr) scaffolds were used as hosts to recognize acetate and chiral mandelates. The higher binding obtained with the trifluoromethyl analogue is also reflected in

Full text of DOI:10.1039/c3nj00644a

NJC
View Article Online
View Journal | View Issue
LETTER
Recognition of chiral carboxylates by 1,3-disubstituted
thioureas with 1-arylethyl scaffolds†
Cite this: NewJ.Chem., 2013,
37, 2610
´
Karla Elisa Trejo-Huizar, Ricardo Ortiz-Rico, Mar´ıa de los Angeles Pen˜a-Gonzalez
Received (in Porto Alegre, Brazil)
15th June 2013,
´
´
and Marcos Hernandez-Rodrıguez*
Accepted 19th June 2013
DOI: 10.1039/c3nj00644a
www.rsc.org/njc
Chiral thioureas with 1-arylethyl and 1-arylethyl-2-2-2-trifluoro-
The chiral amines used for the synthesis of the thioureas are
ethyl (Ar = Ph, 1-Napht, 9-Anthr) scaffolds were used as hosts to commercially available or easily prepared through Ellman’s
recognize acetate and chiral mandelates. The higher binding sulfinamide methodology.9 The C2 symmetric 1,3-disubstituted
obtained with the trifluoromethyl analogue is also reflected in thioureas 1–4 and 6–8 were prepared by the reaction of the
the higher selectivity factor for one enantiomer. The C2 symmetry corresponding amine and thiophosgene. Thiourea 5 was obtained
was also indispensable to obtain selectivity.
from the reaction between (S)-phenylethylamine and 3,5-bistrifluoro-
phenylisothiocyanate. The aryl groups studied were phenyl,
Anion recognition is a process with direct applications in sensing 1-naphthyl, and 9-anthracenyl. We considered that a comparison
and biological activities.1 The (thio)urea moiety plays an important between thioureas 1–3 and 6–8 with nearly the same steric
role in the recognition of anions because of its ability to donate two demand but different NH acidity would show the importance
hydrogen bonds to the anion.2 (Thio)ureas are also an active of this factor in the complexation process (Scheme 1).
research topic in organocatalysis through activation of substrates
We first studied the complexation of thioureas with acetate
by hydrogen bonding or by complexing with an anion.3 The as a model to explain the stability of the supramolecular adducts.
complexation with carboxylates creates the possibility of chiral The stoichiometry of the adduct between thiourea 1 and acetate was
counterion catalysis4 and kinetic resolutions.5 Enantiomers of chiral determined to be 1 : 1 using Job’s continuous variation10 (Fig. 1).
amino acids and drugs which have a carboxylate ion (at physiologi-
The binding studies were performed using 1H NMR titration
cal pH) could exhibit different properties in biological systems, thus in DMSO-d6 and the data were processed by WinEQNMR2
making the mechanisms of recognition of enantiomers an impor- (ref. 11) to obtain the binding constant. As an example, during
tant endeavour. In earlier examinations of the recognition of chiral the titration of thiourea 1 with tetrabutylammonium acetate,
carboxylates by different hosts, little attention has been paid to the the chemical shift of the NH moved from 7.27 ppm to a steady
mechanisms responsible for the enantiorecognition.6,7 In a previous value of 10.77 ppm (Fig. 2).
report, 1,3-disubstituted thioureas were used as chiral solvating
This NMR experiment also provided structural information
agents of carboxylates which not only allowed measurement of about the involved species. Thiourea 1 signals were broad due
the enantiomeric purity of the sample but also permitted the to conformational changes. In sharp contrast, at the end of the
assignment of the absolute configuration.8 In this paper, we describe
the process of enantiodiscrimination using simple 1,3-disubstituted
thioureas with 1-arylethyl groups.
´
´
´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico, Circuito Exterior,
´
´
´
Ciudad Universitaria, Del. Coyoacan, 04510, Mexico, D.F., Mexico.
E-mail: marcoshr@unam.mx; Tel: +52 55-5622-4402
† Electronic supplementary information (ESI) available: Synthesis of chiral
thioureas, 1H NMR of the titration of thioureas with carboxylates and graphs of
the value of NH obtained during the titration. Internal coordinates and calculated
energy of the diastereomers of thiourea 8 with chiral mandelates. CCDC 921521.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3nj00644a
Scheme 1 Thioureas employed in this study.
c
2610 New J. Chem., 2013, 37, 2610--2613
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
Letter
NJC
Fig. 1 Job’ plot of thiourea 1 and tetrabutylammonium acetate (Dd = dNH(obs.) À
dNH(free thiourea), To = Total concentration of thiourea).
Fig. 3 Titration of thiourea 6 with tetrabutylammonium acetate.
Fig. 2 Titration of thiourea 1 with tetrabutylammonium acetate.
Fig. 4 Titration of thiourea 7 with (R)-tetrabutylammonium mandelate.
titration, hydrogen signals appeared as defined multiplets.
Thus, the supramolecular adduct is conformationally more
rigid. Another observation was that the ortho hydrogens were
shifted to higher frequency. A similar trend was observed with
the other thioureas where the hydrogens of the aryl group in
proximity to the acetate showed a displacement to higher
chemical shift: ortho hydrogens of phenyl groups, hydrogens
in position 2 of the naphthyl and hydrogens in positions 1 and
8 of the anthracenyl group (see ESI†). This change in chemical
shift is even more pronounced with thioureas with the trifluoro-
methyl group 6–8. As an example, in the thiourea 6-acetate
complex, the ortho hydrogens are completely separated from
Table 1 Binding constant between chiral thioureas and acetate and mandelate salts
Exp.
Thiourea
AcOÀ
(R)-Mand.
(S)-Mand.
Sa
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
227
197
140
88
260
3440
8705
2288
10
14
8
12
18
9
1.20
1.28
1.12
1
1.13
1.64
2.08
1.38
4
4
176
171
447
76
198
104
205
55
a
Selectivity factor KS/KR for thioureas 1–4 and 8 and the inverse ratio for
their meta and para counterparts (Fig. 3). These observations thioureas 5–7.
might suggest a secondary hydrogen bond between the aromatic
C–Hs and the oxygen of the carboxylate.12
After the studies with acetate, we examined the recognition the strength of the binding,13,14 since thioureas with the trifluoro-
of mandelate salts with both configurations, as an example in methyl group have 10 times higher binding (exp. 1–3 vs. 6–8); (4)
the titration of thiourea 7 with (R)-mandelate is shown in Fig. 4. higher binding means higher recognition of one enantiomer, as
We made the following observations on the binding of the thio- exemplified by thioureas 2 and 7 with almost identical steric
ureas to the chiral carboxylates in Table 1: (1) the opposite properties but thiourea 7 has higher enantiodiscrimination; (5)
enantiomer recognition of thioureas 1–3 vs. 6–8 is due to the the non-C2 thiourea 5 has almost no selectivity between the
opposite spatial arrangement; (2) the optimal size of the aromatic enantiomers because the rotation between the carboxyl and the
group is naphthyl; (3) the acidity of the NH has a direct impact on asymmetric carbon of the mandelate forms two different adducts.
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 2610--2613 2611

View Article Online
NJC
Letter
mandelates were also modelled in B3LYP/6-31G(d,p) and showed a
higher stability of the (S,S-R) by 0.69 kcal molÀ1 with a conformation
similar to that explained above (Fig. 6).
Taking into account this mechanism a receptor with C2
symmetry and a conformationally restricted guest, we conclude
that the combined interactions of hydrogen bonds with the
carboxylate and p–p interaction between the aryl rings explain
the discrimination of diastereomeric pairs. There are also
other fields that can be benefited from our findings like
organocatalysis, in which the ubiquitous 3,5-bis-trifluoro-
methylphenyl shows lower capacity for hydrogen bonding than
our chiral trifluormethylthioureas, thus providing the possibility
of having an acidic hydrogen with a chiral scaffold.
Fig. 5 X-ray structure of the urea analogue of thiourea 4.
In one adduct the OH of the mandelate is on the same side of
the aryl group but in the other the OH is on the same side of the
phenylethyl group; and (6) the thiourea with the tetrahydro-
naphthyl group has the weakest binding because this thiourea
has no additional C–H–O interaction due to the half-chair
conformation of the cyclohexene ring. Comparison of the
X-ray analysis of the urea analogue of 4 (ref. 15) (Fig. 5) with
the urea analogue of 1 (ref. 16) and thiourea 2 (ref. 17) shows
that this conformation is also responsible for the null enantio-
recognition of this thiourea.
Conclusions
In conclusion, in simple 1,3-disubstituted thioureas a C2 symmetry
is necessary to achieve enantiodiscrimination. Higher acidity of
the N–H of the thiourea confers higher binding and higher
selectivity. We also concluded that the ideal combination was
the 1-naphthyl group and trifluoromethyl (thiourea 7) for the
enantiodiscrimination of carboxylates.
In order to elucidate the mechanism of recognition of the
enantiomers, the nature of the supramolecular adducts must
be explained. The two hydrogen bonds between thiourea and the
carboxylate are linear, constraining thiourea, the carboxylate and
the carbon next to these functional groups in nearly the same plane.
The intramolecular hydrogen bonding of the mandelate salt is in the
same plane orienting the phenyl and the hydrogen of the mandelate
outside the plane. In thiourea, because of the 1,3-allylic strain17,18
the C–H of the stereocenter is syn-periplanar to the N–C(S) bond and
by the same effect, the aryl group is perpendicular to the same C–H
bond. With these considerations in mind, we can propose that in
the (S,S-R) diastereomers of thioureas 6, 7 and 8 the aryl groups of
the thiourea and the phenyl group of the mandelate are located
on the same side of the adduct and a favorable T-shaped p–p
interaction takes place,19,20 forming a more stable adduct that leads
to higher binding. On the other hand, for diastereomers (S,S-S) the
aryl groups are on opposite sides and therefore this interaction is not
possible. The supramolecular adducts of thiourea 8 and chiral
We thank DGAPA for generous financial support (IB201312),
and DGCTIC, UNAM for supercomputer time. We also like to
´
´
thank J. Perez, L. Velasco, I Chavez, E. Huerta, B. Quiroz,
´
˜
˜
´
´
H. Rıos, R. Gavino, R. Patino, C. Marquez, E. Garcıa, S. Hernandez
and A. Toscano for technical support.
Notes and references
1 (a) J. L. Sessler, P. Gale and W.-S. Cho, Anion Receptor Chemistry,
Royal Society of Chemistry, London, UK, 2006; (b) M. Wenzel,
J. R. Hiscock and P. A. Gale, Chem. Soc. Rev., 2012, 41, 480;
(c) Chem. Soc. Rev. 2010, 39, Issue 10, Supramolecular chemistry
of anionic species themed issue.
2 V. Amendola, L. Fabbrizzi and L. Mosca, Chem. Soc. Rev.,
2010, 39, 3889.
3 (a) P. M. Pinko, Hydrogen Bonding in Organic Synthesis,
Wiley-VCH, Weinheim, 2009; (b) A. G. Doyle and
E. N. Jacobsen, Chem. Rev., 2007, 107, 5713.
4 (a) Z. Zhang and P. R. Schreiner, Chem. Soc. Rev., 2009,
`
38, 1187; (b) J.-F. Briere, S. Oudeyer, V. Dalla and
V. Levacher, Chem. Soc. Rev., 2012, 41, 1696; (c) K. Brak
and E. N. Jacobsen, Angew. Chem., Int. Ed., 2013, 52, 534.
5 (a) C. K. De, E. G. Klauber and D. Seidel, J. Am. Chem. Soc.,
2009, 131, 17060; (b) R. P. Singh, B. M. Foxman and L. Deng,
J. Am. Chem. Soc., 2010, 132, 9558; (c) C. K. De and D. Seidel,
J. Am. Chem. Soc., 2011, 133, 14538; (d) S. M. So, H. Kim,
L. Mui and J. Chin, Eur. J. Org. Chem., 2012, 229.
6 Some recent examples are (a) X. Wu and S. D. Starnes, Org.
Lett., 2012, 14, 3652; (b) Y. Li, V. Tamilavan and M. H. Hyun,
Chirality, 2012, 24, 406; (c) D. Gherase and C. Roussel, Cent.
Eur. J. Chem., 2012, 10, 1066.
7 Some examples with (thio)ureas: (a) A. Tejeda, A. I. Oliva,
´
´
L. Simon, M. Grande, M. C. Caballero and J. R. Moran,
Fig. 6 Structure of diastereomeric supramolecular adducts.
Tetrahedron Lett., 2000, 41, 4563; (b) G. M. Kyne, M. E. Light,
c
2612 New J. Chem., 2013, 37, 2610--2613
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
Letter
NJC
M. B. Hursthouse, J. de Mendoza and J. D. Kilburn, J. Chem.
Soc., Perkin Trans. 1, 2001, 1258; (c) T. Gunnlaugsson,
C. Tancon, Z. Zhang, K. M. Lippert and P. R. Schreiner,
Org. Lett., 2012, 14, 1724.
A. P. Davis, G. M. Hussey, J. Tierney and M. Glynn, Org. Biomol. 14 Guanidinium and thiouronium salts being more acidic have
Chem., 2004, 2, 1856; (d) A. Ragusa, S. Rossi, J. M. Hayes,
M. Stein and J. D. Kilburn, Chem.–Eur. J., 2005, 11, 5674;
(e) C. Roussel, M. Roman, F. Andreoli, A. del Rio, R. Faure
and N. Vanthuyne, Chirality, 2006, 18, 762; ( f ) K. M. K. Swamy,
N. J. Singh, J. Yoo, S. K. Kwon, S.-Y. Chung, C.-H. Lee and
J. Yoon, J. Inclusion Phenom. Macrocyclic Chem., 2010, 66, 107;
higher binding as reported in: (a) A. Echavarren, A. Galan,
J. M. Lehn and J. de Mendoza, J. Am. Chem. Soc., 1989,
111, 4994; (b) V. D. Jadhav and F. P. Schmidtchen, J. Org.
Chem., 2008, 73, 1077; (c) M. B. Foreiter, H. Q. N. Gunaratne,
P. Nockemann, D. R. Seddon, P. J. Stevenson and
D. F. Wassell, New J. Chem., 2013, 37, 515.
(g) A. Sirikulkajorn, T. Tuntulani, V. Ruangpornvisuti, 15 The urea analog of thiourea 4 is deposited in CCDC with
B. Tomapatanaget and A. P. Davis, Tetrahedron, 2010, 66, 7423. deposition number 921521.
8 M. Hernandez-Rodrıguez and E. Juaristi, Tetrahedron, 2007, 16 The X-ray crystallography structure of the urea analog of thiourea
´
´
´
´
´
63, 7673.
1 is reported in: M. Hernandez-Rodrıguez, R. Melgar-Fernandez
and E. Juaristi, J. Phys. Org. Chem., 2005, 18, 792, with deposition
number CCDC 263119.
9 (a) G. K. S. Prakash, M. Mandal and G. A. Olah, Angew.
Chem., Int. Ed., 2001, 40, 589; (b) M. Hernandez-Rodrıguez,
´
´
´
T. Castillo-Hernandez and K. E. Trejo-Huizar, Synthesis, 17 With deposition number CCDC 605751 in: H. D. P. Ali,
2011, 2817.
S. J. Quinn, T. McCabe, P. E. Kruger and T. Gunnlaugsson,
New J. Chem., 2009, 33, 793 (this paper also describes the
binding between 2 and acetate).
10 L. Fielding, Tetrahedron, 2000, 56, 6151.
11 M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311.
12 Shreiner found interactions between ortho hydrogens of the 18 R. W. Hoffmann, Chem. Rev., 1989, 89, 1841.
3,5-bistrifluoromethylphenyl radical and oxygens of neutral 19 The distance between the center of both rings is 5.8 Å
molecules. In this case the interaction is between unactivated
aromatic C–H and anionic oxygen of the carboxylate.
K. M. Lippert, K. Hof, D. Gerbig, D. Ley, H. Hausmann,
(phenyl of the mandelate and the terminal ring of anthra-
cene). The optimal distance is 5.0 Å for this interaction with
high level of theory (ref. 20a).
S. Guenther and P. R. Schreiner, Eur. J. Org. Chem., 2012, 5919. 20 (a) S. Tsuzuki, K. Honda, T. Uchimaru and M. Mikami,
13 The acidity of the NH also correlates with the capacity for
hydrogen bonding found in organocatalysis: G. Jakab,
J. Chem. Phys., 2005, 122, 144323; (b) M. O. Sinnokrot and
C. D. Sherrill, J. Phys. Chem. A, 2006, 110, 10656.
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 2610--2613 2613