Chiral enantiopure bis(thio)ureas derived from TADDOL and their carboxylate complexation capacity

Article abstract of DOI:10.2478/s11532-012-0011-8

New chiral enantiopure ureas and thioureas with (R,R)-TADDOL backbone were synthesized. Bis-(thio)ureas with C2 symmetry were obtained from TADDOL iso(thio)cyanates and bifunctional amino-(thio)ureas from TADDAMINE, respectively. These were tested for car

Full text of DOI:10.2478/s11532-012-0011-8

Cent. Eur. J. Chem. • 10(4) • 2012 • 1066-1072
DOI: 10.2478/s11532-012-0011-8
Central European Journal of Chemistry
Chiral enantiopure bis(thio)ureas derived
from TADDOL and their carboxylate
complexation capacity
Research Article
Dragos Gherase1,2*, Christian Roussel1
1Université Paul Cézanne, UMR ISM2: Chirosciences,
Marseille 13397 CEDEX 20, France
2‘‘C.D. Nenitzescu’’ Center of Organic Chemistry,
Romanian Academy, 060023 Bucharest, Romania
Received 28 November 2011; Accepted 7 January 2012
Abstract:
New chiral enantiopure ureas and thioureas with (R,R)-TADDOL backbone were synthesized. Bis-(thio)ureas with C2 symmetry
were obtained from TADDOL iso(thio)cyanates and bifunctional amino-(thio)ureas from TADDAMINE, respectively. These were tested
for carboxylate recognition capacity and the association constant was determined for the most stable complex.
Keywords: TADDOL • Enantiopure (thio)urea • Carboxylate recognition
© Versita Sp. z o.o.
1. Introduction
best of our knowledge, ureas and thioureas derived from
TADDAMINEs have not been reported. Aiming to take
Chiral (thio)ureas and amino(thio)ureas have found advantage of the TADDOL backbone properties and our
many applications in organocatalysis [1-4] and molecular experience in working with these diols [15], we started
recognition [5-8].
to prepare a library of chiral (thio)urea hosts to evaluate
The success of the recognition process depends their anion recognition capacity [16].
on two factors: hydrogen bonding due to the acidity of
the NH protons and the topology of the binding site.
2. Experimental procedure
Ureas and thioureas are some of the best receptors for
Y-shaped oxoanions, such as carboxylates [5,9-11]. One
noticeable application is the enantioselective molecular
recognition of carboxylate group of aminoacids when
the (thio)urea receptor is chiral. The ability of these
compounds to recognize carboxylate anions is due
to a double hydrogen bonding formation between
the carboxylate group and the two hydrogen atoms of
the receptor. Even though most of the time thioureas
have better complexation capacity compared to their
oxygenated analogs due to the higher acidity of the NH
found in the former, the difference in orientation, syn
or anti, of the two acidic protons can favor the ureas,
as previously reported by our group [8]. TADDOLs are
extraordinary versatile chiral auxiliaries [12-14] derived
from tartaric acid. Bis-amino analogues of TADDOLs:
TADDAMINEs have been far less studied and, to the
Chemicals were obtained from commercial suppliers
and used without further purification. The acetonitrile
used for the UV-Vis titrations was purified by distillation
from calcium hydride, in an inert atmosphere. All the new
compounds were characterized and their preparations
are described in the supplementary material. Melting
points were determined on a Boëtius hot plate and are
uncorrected. The measurements of optical rotation were
performed on a 241 Perkin Elmer polarimeter using a
quartz cell with the length of 1 dm. The NMR spectra
were recorded on a BRUKER Avance 400 NANO (400
MHz for 1H) in deuterochloroform (CDCl3) at room
temperature. The chemical shift (δ) values are given in
ppm, tetramethylsilane (TMS) was used as an internal
standard. The High Resolution Mass Spectra (HRMS)
* E-mail: dragos@cco.ro
1066

D. Gherase, Ch. Roussel
were measured on a QStar Elite (Applied Biosystems Table 1. Synthesis of the hosts.
SCIEX) spectrometer equipped with a time-of-flight
Entry
X
R
Yield (%)
Host
(TOF) detector. UV-Vis spectra were recorded on a
Shimadzu UV-2401PC using a quartz cell with the
length of 1 cm. For the acquisition and treatment of the
UV-Vis spectra a UV Probe version 2.0 from Shimadzu
was used.
Bis(thio)ureas
1
S
S
S
O
Me
iPr
Bn
iPr
94
98
97
96
H1
H2
H3
H4
2
3
4
Amino-(thio)ureas
5
S
S
S
S
S
S
O
Me
Ph
89
98
95
95
84
90
99
H5
H6
3. Results and discussion
6
7
4-NO2-Ph
4-Cl-Ph
3,5(CF3)Ph
iPr
H7
8
H8
3.1. Synthesis of the chiral selectors
9
H9
The chiral thioureas and ureas were obtained by the
nucleophilic addition of an amine to isothiocyanates and
isocyanates, respectively [17]. There are two possible
approaches for this synthesis: either using an iso(thio)
cyanate derived from TADDOL 1 and a commercially
available amine, or using TADDAMINE 2 (the primary
amine derived from TADDOL) with commercially
available iso(thio)cyanates.
10
11
H10
H11
Ph
hosts H5-H11 was performed at room temperature in
diethylether. The product could be isolated after three
hours in very high yields (84-99%). With aliphatic
isothiocyanates, such as methyl and isopropyl, the
reaction time was longer (up to 3 days) due to their lower
electrophilicity. Moreover, the reaction of TADDAMINE 2
with 2 equivalents of isothiocyanates, even in the same
energetic conditions, stopped at amino-thioureas and
the bis-thioureas were not obtained. These results are
also presented in Table 1. We obtained six thiourea
derivatives with various substituents, as well as, for the
sake of comparison, one urea derivative.
Interestingly enough, prolonged heating of
TADDAMINE 2 with some aromatic iso(thio)cyanates, at
reflux in acetonitrile leads to the formation of guanidine
derivatives. For example, heating for 3 days the host
molecule H7 with two equivalents of 4-nitrophenyl
isothiocyanate, in the presence of DMAP, yielded
guanidine derivative H12; 4-nitroaniline was formed as
a by-product. The guanidine can be obtained through a
more elegant (and shorter) two-step, one-pot pathway
from TADAMINE 2. In the first step a carbodiimide is
formed by dehydrosulfuration of H7, which takes place in
the presence of iodine and triethylamine in ethylacetate
at 0°C [21]; the second step yields the guanidine
through intramolecular addition of the free amino group
to the carbodiimide, at room temperature. The guanidine
hydrochloride is finally separated by precipitation with
hydrochloric acid from diethylether solution. Since
guanidines and their salts can also be used as hosts
for the molecular recognition of carboxylates [22] we
added these two compounds (guanidine H12 and its
hydrochloride H13) to our library.
We first synthesized the (R,R) TADDOL 1 as
previously reported [18]. From TADDOL 1, in a two
step synthesis we obtained the isothiocyanate 3a using
Seebach’s procedure [19,20]. (S,S) TADDAMINE 2 was
synthesized from (R,R) TADDOL 1 in a classic three
step synthesis [19]. The isocyanate 3b was obtained by
carbonylation of the TADDAMINE 2 with triphosgene,
(CCl3O)2CO, in dichloromethane. The reaction takes
place with a quantitative yield at room temperature.
For the synthesis of bis-(thio)ureas we have chosen
thefirstapproach:thereactionofamineswithcompounds
3a or 3b as presented in Scheme 1. When diethylether is
used as a solvent the reaction product precipitates and
can be isolated in very high purity by a simple filtration.
Results for the synthesis of bis-thioureas and bis-ureas
are summarized in Table 1.
Very good yields (94-98%) are obtained when
using aliphatic amines. For instance, bis-thioureas with
R = methyl H1, isopropyl H2 and benzyl H3 were
obtained from isothiocyanate 3a in 94%, 97% and
98%, respectively, while the corresponding urea with
R = isopropyl H4 was formed in 96% yield from
isocyanate 3b. Unfortunately, the use of aromatic amines
did not match the same success rate. Even under more
energetic conditions, such as microwave irradiation,
reflux in acetonitrile or toluene, or in the presence of
various catalysts (DMAP, DBU, LiClO4) the reaction
between iso(thio)cyanates 3 and aromatic amines did
not succeed; we could recover the unreacted iso(thio)
cyanate 3.
3.2. Complexation study by UV-Vis titration
The carboxylate complexation is an equilibrium
process between the host molecule H (bis-thioureas,
bis-ureas and guanidines H1-H13) and the guest G
For the amino-(thio)ureas we used an alternative
pathway, involving TADDAMINE
2 and aromatic
iso(thio)cyanates (Scheme 1). The synthesis of amino-
1067

Chiral enantiopure bis(thio)ureas derived from TADDOL
and their carboxylate complexation capacity
Scheme 1. Synthesis of host molecules H1-H11.
Scheme 2. Synthesis of guanidine H12 and guanidine hydrochloride H13.
(the carboxylate) in a polar solvent, with the formation different solvents: acetonitrile, dimethyl sulfoxide and
of a complex C. The process is characterized by its dichloromethane.As observed in the absorption spectra,
association (or binding) constant, K, which represents the complexation occurred in the first two solvents, while
the ratio of the concentrations of the complex [C] and in dichloromethane no change was recorded in the UV
the free species [H] and [G] at equilibrium:
spectra, even after adding increments of TBAA solution.
The experiments were performed by adding 50, 200 and
600 µL of a 2×10-3 M solution of TBAA guest to 100 µL,
5×10-4 M, solution of H7 host in 1.9 mL of solvent. In this
[C]
K
a H + b G
C
K =
[H]a x [G]b
The progress of the complexation process was case we used a host/guest ratio of 1:2, 1:8 and 1:24.
observed through UV-Vis spectroscopy, due to the After selecting acetonitrile as solvent of choice,
simplicity and fast response of this method. Moreover, we tested the rest of the library (ureas, thioureas and
this technique uses small quantities of host and guest guanidines) in the same conditions as presented above.
molecules (10-4-10-6 M solutions of the two partners).
The chosen partner molecules were H7 as the
The results are presented in Table 2.
UV-Vis spectra are useful for following up the
host and tetra-n-butylammonium acetate (TBAA) complexation process. For instance, for H7 we observed
as guest. We attempted the complexation in three a bathochromic effect, its characteristic absorption band
1068

D. Gherase, Ch. Roussel
Table 2. Complexation study with TBAA in acetonitrile at H : G ratio 314 nm. For the guanidine H12 and its hydrochloride
of 1:24.
H13 we obtained the same bathochromic effect
(354→375 nm). The presence of hydrochloric acid has
no influence in this complexation.
Entry
Host
λmax (nm) λmax (nm)
free host complex
R
It was interesting to observe that the bis-thioureas
H1-3 and bis-urea H4 did not undergo complexation.
In the amino series of thioureas H5-H10 and urea H11,
the complexation occurred only for compounds H7 and
H9. Electronic effects can indeed offer an explanation,
since compounds H7 and H9 contain a strong electron
withdrawing group (-NO2 and –CF3, respectively), which
increases the acidity of the –NH– group vicinal to the
aryl group.
The resulting complexes (Table 2) are moisture
sensitive and special precautions have to be taken.
The most stable complex proved to be the H7-TBAA
complex. In this case, we could calculate the association
constant.
1
H1
H2
H3
H4
Bis-thiourea
Bis-thiourea
Bis-thiourea
Bis-urea
Me
iPr
Bn
iPr
Me
Ph
251
255
-
2
-
3
255
-
4
255
-
6
H5 Amino-thiourea
H6 Amino-thiourea
-
-
-
7
242
8
H7 Amino-thiourea 4-NO2-Ph
H7 Amino-thiourea 4-NO2-Ph
H7 Amino-thiourea 4-NO2-Ph
348
468
489
-
9*
10**
11
12
13
14
15
16
366
304 & 333
247
H8 Amino-thiourea
4-Cl-Ph
-
H9 Amino-thiourea 3,5(CF3)Ph
280
314
-
H10 Amino-thiourea
iPr
Ph
253
H11
H12
Amino-urea
Guanidine
243
-
4-NO2-Ph
354
375
381
H13 Guanidine HCl 4-NO2-Ph
356
* solvent – DMSO; ** solvent – dichloromethane
The review by Hirose [23] and the paper by
Hargrove [24] are very useful resources for the
calculation of binding constants. The steps involved in
this process are: a) determination of the stoichiometry;
b) evaluation of the complex concentration [C];
c) setting up the concentration conditions for the host
and guest, d) data treatment. The stoichiometry was
determined using the Continous Variation Method, the
following four steps being observed: 1) keeping the sum
of [H]t and [G]t constant (α); 2) variation of [H]t from
0 to α; measuring the concentration of the complex, [C]
and 4) data treatment (Job’s Plot – complex formation
vs. host/guest ratio).
Table 3. Absorbance of the complex measured for different ratio
H/G.
Entry
___[H]t___
([H]t+[G]t)
Aobs at 468 nm
(Au)
1
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0.0000
0.0232
0.0344
0.0456
0.0658
0.0510
0.0462
0.0384
0.0456
0.0178
0.0000
2
3
4
5
6
7
8
9
10
11
According to the Lambert-Beer law, the absorbance
is the product of the extinction coefficient and the
molar concentration of the studied compound:
AC = εC · [C], where AC is the absorbance and εC is the
molar extinctions of the complex.
In our case, since neither the host nor the guest are
showing any absorption bands at 468 nm, this value can
be attributed to the sole complex and the concentration
of the complex becames [C] = Aobs/εC.
By measuring the absorbance of the complex at
ratios H/G varying from 1:0 to 0:1, at constant sum of
concentrations (Table 2), a modified Job’s plot can be
created (Fig. 1).
The stoichiometry of the complexation is determined
on the x ordonate at the maximum of the curve and in our
case is at x = 0.5 corresponding to a 1:1 stoichiometry.
Theconcentrationofthecomplexcanbecalculatedusing
the equation [C] = Aobs/εC. Since the molar absorption of
the complex (εC) cannot be measured directly, a titration
experiment and a regression are needed. The titration
experiment (Fig. 2) consists in a progressive increase of
Figure 1. Modified Job’s Plot for complexation of H7 with TBAA
by UV-Vis spectroscopy.
at 348 nm diminishing, while another band at 468 nm
was appearing, upon addition of TBAA. The 468 nm
band was attributed to the orange complex H7-TBAA.
Another amino-thiourea which underwent complexation
is H9 gave a shift in absorption band from 280 nm to
1069

Chiral enantiopure bis(thio)ureas derived from TADDOL
and their carboxylate complexation capacity
of the complex and from its value the absorbance
Acalc. Knowing the extinction coefficient and [C], the
minimum condition is reached for K = 7500 mol-1 L-1.
Comparison with other association constants reported
for thiourea and tetra-n-butylammonium acetate
(ca 105-106 mol-1 L-1) [25,26] reveals that the association
constant we observed is small.
The complexation capacity of the tested ureas,
thioureas and guanidines can be explained by
their conformation and by the proton availability
in these compounds. The bis-derivatives (H1-H4)
and amino-derivatives (H5-H11) have totally different
conformational states.
The X-ray structure of bis-thiourea H2 (Fig. 4a)
offers important informations about the conformation of
this compound in solid state. The two NH of the thiourea
have an anti orientation, which is not favourable for
efficient carboxylate recognition. It is also noticeable
that one of the NH necessary for the complexation is
already involved in an intramolecular NH···O hydrogen
bond. This bond is created between the NH protons
neighboring the aliphatic moiety and the oxygen atoms
fromthedioxolanering.Thehydrogenbondsstabilizethe
molecule by changing the conformation from “current” to
“un-current” [15] and thus the acetate approach is highly
unlikely, due to steric hindrance. The same pattern can
be observed for the other bis-thioureas (H1-H3). The
occurrence of an intramolecular hydrogen bond for one
NH and the steric hindrance of the other NH account
for the lack of complexation of the carboxylate anion by
bis-(thiourea) H1-H4.
Figure 2. Absorption spectra of H7 (2×10-5 M) in the presence
of increasing amounts of TBAA (4×10-6 → 1.2×10-3 M,
0.2 → 60 eq) in acetonitrile.
0.3
0.25
0.2
0.15
0.1
0.05
0
0
10
20
30
40
50
60
No Eq of TBAA
Figure 3. Titration of H7 with TBAA in acetonitrile.
Table 4. Titration of H7 with TBAA in acetonitrile.
Entry
No. eq. of guest
Aobs (AU)
Aminothioureas
different conformational
to their bis-substituted analogues.
intramolecular NH···NH2
hydrogen
(H5-H11)
have
a
very
orientation
compared
A
1
2
0
0.2
0.5
1
0.000
0.009
0.036
0.045
0.068
0.111
0.162
0.208
0.237
0.251
strong
bond,
3
4
2.111 Å in length, can be observed in the X-ray of H7
(Fig. 4b). This bond is formed between the hydrogen
from the NH group bearing the chiral moiety of the
thiourea and the nitrogen of the NH2 group.
This hydrogen bond is probably strong and prevents
any complexation of the carboxylate anion by the NH
involved in such an intramolecular H-bonding. The anti
5
2
6
4
7
10
20
40
60
8
9
10
the guest/host ratio until the maximum of absorbance is conformation of the thiourea is not favorable for double
reached. In our case it was observed at 60 equivalents hydrogen bonding however the hydrogen of the second
of TBAA.
NH bearing the aryl group is accessible to carboxylate
At the maximum of absorbance the concentration of anion and its acidity is tuned by the substituents on the
the complex is approximately equal to the concentration aryl. In the lattice of H7 we observed two molecules
of the host, [C] = [H]t = 2×10-5 M. Thus, the molar of acetone; one of them being involved in a hydrogen
extinction coefficient of the complex is calculated as bond with the NH2. This supplementary intermolecular
εC = 14500 L mol−1 cm−1. The value of the association hydrogenbondingispossiblyduetotheacidificationofthe
constant is obtained by linear regression minimizing two protons from the amino group by the intramolecular
Σ(Acalc-Aobs)2 for all Aobs. From the initial concentration of hydrogen bond. In summary, the observed complexation
the guest, it is possible to calculate the concentration capacity of the two aminothioureas (H7 and H9) rests on
1070

D. Gherase, Ch. Roussel
(a)
(b)
Figure 4. X-Ray structures of the (S,S) bis-thiourea H2 (left - 4a) and (S,S) amino-thiourea H7 (right – 4b) obtained from (R,R) TADDOL.
the sole availability and the acidity of the hydrogen of simple methods from TADDOL derivatives, such as
the NH bearing the aryl moiety of the thiourea group.
isothiocyanates, isocyanates, and TADDAMINE, in high
The occurrence of the intramolecular N-H···NH2 yields.
hydrogen bond in aminothiourea H7 was also observed
in solution by H NMR spectroscopy: the singlet that recognition was tested using tetra-n-butylammonium
Their complexation capacity toward carboxylate
1
appears at 12.71 ppm in CDCl3 can be assigned acetate as a guest. Four compounds, namely the two
to a hydrogen atom involved in a strong hydrogen aminothioureas (H7 and H9), one guanidine (H12)
bond. The signal belongs to the closest –NH- group and its hydrochloric salt (H13), complex with TBAA in
to the TADDAMINE moiety. The chemical shift for acetonitrile. This process was investigated by UV-Vis
the NH group involved in the hydrogen bond ranges spectroscopy and for one of the aminothioureas (H7)the
from 11.93 ppm for H5 to 12.71 ppm for H7. association constant was determined as K = 7500 mol-1
The chemical shift of the proton of the second L-1. The weak complexation capacity was explained by
NH is highly sensitive to the nitrogen substituent. electronic and conformational factors.
It ranges from 4.90 ppm for the methyl substituted one
to 6.92 ppm for the 4-NO2-C6H4- one monitoring
the acidity of the protons attached to the nitrogen
atoms.
Acknowledgements
We thank Dr. Michel Giorgi for the X-ray structure
determinations and Dr. Valerie Monnier for the HRMS
4. Conclusions
measurements. We also thank Dr. Cornelia Uncuta
and Dr. Emeric Bartha for their help. D.G. is grateful to
We created a focused library of new chiral enantiopure CNCSIS–UEFISCSU, Romania (Project Number PNII –
bis-thioureas, bis-ureas, amino-thioureas, amino-ureas IDEI 53/2007) and to EGIDE, France (Eiffel scholarship)
and guanidines with (S,S) configuration derived from for financial support.
(R,R)-TADDOL. These compounds were obtained by
References
[1] J.A.J. Breuzard, M.L. Christ-Tommasino, M. Lemaire, [5] G.M. Kyne,
M.E.
Light,
M.B.
Hursthouse,
P. Mangeney, Chiral Ureas and Thiroureas in
Asymmetric Catalysis (Springer, Berlin & Heidelberg,
2005) 231-270
J. de Mendoza, J.D. Kilburn, J. Chem. Soc., Perkin
Trans. 1, 1258 (2001)
[6] G. Qing, T. Sun, Z. Chen, X. Yang, X. Wu, Y. He,
Chirality 21, 363 (2009)
[2] R.M. Steele, C. Monti, C. Gennari, U. Piarulli,
F. Andreoli, N. Vanthuyne, C. Roussel, Tetrahedron: [7] P.D. Beer, P.A. Gale, Angew. Chem., Intl. Ed. 40,
Asymmetry 17, 999 (2006)
486 (2001)
[3] H. Pellissier, Tetrahedron 63, 9267(2007)
[4] M.S. Taylor, E.N. Jacobsen, Angew. Chem., Intl. Ed.
45, 1520 (2006)
[8] C. Roussel, M. Roman, F. Andreoli, A. Del Rio,
R. Faure, N. Vanthuyne, Chirality 18, 762 (2006)
[9] T. Gunnlaugsson, A.P. Davis, J.E. O’Brien,
1071

Chiral enantiopure bis(thio)ureas derived from TADDOL
and their carboxylate complexation capacity
M. Glynn, Org. Biomol. Chem. 3, 48 (2005)
[10] A.F. Li, J.H. Wang, F. Wang, Y.B. Jiang, Chem.
Soc. Rev. 39, 3729 (2010)
[11] P. Dydio, D. Lichosyt, J. Jurczak, Chem. Soc. Rev.
40, 2971 (2011)
[12] D. Seebach, A.K. Beck, A. Heckel, Angew. Chem.,
Intl. Ed. 40, 92 (2001)
[13] H. Pellissier, Tetrahedron 64,10279 (2008)
[14] H.W. Lam, Synthesis, 2011 (2011)
[15] C. Uncuta, E. Bartha, D. Gherase, F. Teodorescu,
[19] D. Seebach, M. Hayakawa, J.I. Sakaki,
W.B. Schweizer, Tetrahedron 49, 1711 (1993)
[20] D. Seebach, A.K. Beck, M. Hayakawa,
G.Jaeschke,F.N.M.Kuhnle,I.Nageli,A.B.Pinkerton,
P.B. Rheiner, R.O. Duthaler, P.M. Rothe,
W. Weigand, R. Wunsch, S. Dick, R. Nesper,
M. Worle, V. Gramlich, Bull. Soc. Chim. Fr. 134,
315 (1997)
[21] A.R. Ali, H. Ghosh, B.K. Patel, Tetrahedron Lett. 51,
1019 (2010)
C. Draghici, D. Cavagnat, N. Daugey, D. Liotard, [22] V.D. Jadhav, F.P. Schmidtchen, J. Org. Chem. 73,
T. Buffeteau, Chirality 22, E115 (2010)
1077 (2007)
[16] V. Amendola, M. Bonizzoni, D. Esteban-Gomez, [23] K. Hirose, J. Incl. Phenom. Macro. 39, 193 (2001)
L. Fabbrizzi, M. Licchelli, F. Sanchenon, A. Taglietti, [24] A.E.Hargrove, Z. Zhong, J.L. Sessler, E.V. Anslyn,
Coord. Chem. Rev. 250, 1451 (2006)
[17] X-G.Liu,J-J.Jiang,M.Shi, Tetrahedron:Asymmetry [25] A. Misra, M. Shahid, P. Dwivedi, Talanta 80, 532
18, 2773 (2007)
(2009)
[18] A.K. Beck, B. Bastani, D.A. Plattner, W. Petter, [26] S. Kondo, M. Nagamine, S. Karasawa, M. Ishihara,
New J. Chem. 34, 348 (2010)
D. Seebach, H. Braunschweiger, P. Gysi,
L. La Vecchia, Chimia 45, 238 (1991)
M. Unno, Y. Yano, Tetrahedron 67, 943 (2011).
1072