(Thio)urea organocatalyst equilibrium acidities in DMSO

Article abstract of DOI:10.1021/ol300307c

Bordwell's method of overlapping indicators was used to determine the pK_a values of some of the most popular (thio)urea organocatalysts via UV spectrophotometric titrations. The incremental effect of CF₃ groups on acidic strength was

Full text of DOI:10.1021/ol300307c

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1724–1727
(Thio)urea Organocatalyst Equilibrium
Acidities in DMSO
Gergely Jakab, Carlo Tancon, Zhiguo Zhang, Katharina M. Lippert, and
Peter R. Schreiner*
Institute of Organic Chemistry, Justus-Liebig University Giessen, Heinrich-Buff-Ring 58,
35392 Giessen, Germany
prs@org.chemie.uni-giessen.de
Received February 7, 2012
ABSTRACT
Bordwell’s method of overlapping indicators was used to determine the pKa values of some of the most popular (thio)urea organocatalysts via UV
spectrophotometric titrations. The incremental effect of CF3 groups on acidic strength was also investigated. The pKa’s are in the range of
8.5ꢀ19.6. The results may lead to a better understanding of noncovalent organocatalysis and may aid in future catalyst development.
The 3,5-bis(trifluoromethyl)phenyl moiety is a common
structural motif in a great number of (thio)urea organo-
catalysts (Figure 1).1 The apparently privileged role of the
3,5-bis(trifluoromethyl)phenyl moiety has been rationalized
by its ability to increase the acidity of double H-bonding
organocatalysts,2 thereby strengthening the catalystꢀsub-
strate interactions that are akin to Lewis acid activation.3
The 3,5-bis(trifluoromethyl)phenyl group also increases the
polarity as well as the polarizability of a catalyst and, there-
by, modulates the critical H-bonding interactions in the
required transition state stabilization.4 Much to our sur-
prise, many of the pKa values of common thiourea organo-
catalysts are unknown. The pKa values of a selection of
bifunctional dialkyl amino and cinchona-derived thioureas
recently were determined in DMSO and correlated with
their relative activity in some Michael addition re-
actions.5 The tested catalysts were generally less acidic
(pKa = 13.2ꢀ21.1) than those reported here, and a
structure-activity-enantioselectivity relationship could
be established.5 While hydrogen bonding interactions,
(1) (a) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7,
4293–4296. (b) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa,
K. Tetrahedron Lett. 2004, 45, 5589–5592. (c) Vakulya, B.; Varga, S.;
ꢀ
ꢀ
Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967–1969. (d) Zhang, Z.;
Lippert, K. M.; Hausmann, H.; Kotke, M.; Schreiner, P. R. J. Org.
Chem. 2011, 76, 9764–9776. (e) Klausen, R. S.; Jacobsen, E. N. Org. Lett.
2009, 11, 887–890. (f) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A.
Angew. Chem., Int. Ed. 2005, 44, 6576–6579. (g) Cao, C.-L.; Ye, M.-C.;
Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901–2904. (h) Okino, T.;
Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672–12673. (i)
Wittkopp, A.; Schreiner, P. R. Chem.;Eur. J. 2003, 9, 407–414.
(2) (a) Hof, K.; Lippert, K. M.; Schreiner, P. R. In Science of
Synthesis. Asymmetric Organocatalysis 2. Brønsted Base and Acid Cat-
alysis and Additional Topics; Maruoka, K., Ed.; Thieme: Stuttgart, NY,
2012, pp 296ꢀ412.(b) Li, X.; Deng, H.; Luo, S.; Cheng, J.-P. Eur. J.
Org. Chem. 2008, 4350–4356. (c) Schreiner, P. R.; Wittkopp, A. Org.
Lett. 2002, 4, 217–220. (d) Wang, X.-S.; Zheng, C.-W.; Zhao, S.-L.;
Chai, Z.; Zhao, G.; Yang, G.-S. Tetrahedron: Asymmetry 2008, 19,
2699–2704.
(4) (a) Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315–
4317. (b) Weil, T.; Kotke, M.; Kleiner, C. M.; Schreiner, P. R. Org. Lett.
2008, 10, 1513–1516. (c) Kotke, M.; Schreiner, P. R. Synthesis 2007, 779–
790. (d) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434–439.
(5) Li, X.; Deng, H.; Zhang, B.; Li, J. Y.; Zhang, L.; Luo, S. Z.;
Cheng, J. P. Chem.;Eur. J. 2010, 16, 450–455.
(6) (a) Etzenbach-Effers, K.; Berkessel, A. In Asymmetric Organo-
catalysis; List, B., Ed.; Springer-Verlag: Berlin, 2009; Vol. 291, pp 1ꢀ27. (b)
Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20678–20685. (c) Kotke, M.; Schreiner, P. R. In Hydrogen Bonding in
Organic Synthesis; Pihko P., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA:
2009; pp 141ꢀ351.
(3) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259–3261.
r
10.1021/ol300307c
Published on Web 03/21/2012
2012 American Chemical Society

Table 1. Indicators Used and Their pKa Values in DMSO
no.
compounda
abbreviation
pKa
1
2
3
4
5
6
7
8
9
9-cyanofluorene
CN-FH
8.3
2-bromo-9-(phenylsulfonyl)fluorene 2-Br-PhSO2-FH 9.6
9-carbomethoxyfluorene
4-nitrophenol
MeOOC-FH
PNP
10.35
10.8
9-(phenylsulfonyl)fluorene
9-(ethylsulfonyl)fluorene
2-bromo-9-phenylthiofluorene
9-phenylthiofluorene
9-ipropylthiofluorene
PhSO2-FH
EtSO2-FH
2-Br-PhS-FH
PhS-FH
11.55
12.30
13.2
15.4
iPrS-FH
16.9
10 9-phenylfluorene
Ph-FH
17.9
11 4-chloro-2-nitroaniline
4-Cl-2-NO2-AN 18.9
a For further details see Supporting Information.
Figure 1. 3,5-Bis(trifluoromethyl)phenyl structural motif com-
mon to many organocatalysts.
We adopted the spectrophotometric method of over-
lapping indicators, developed by Bordwell.9 The basis of
the pKa determination is an acidꢀbase equilibrium (eq 1)
between an arbitrary weak acid (HA) and an appropriate
indicator (HInd) that obeys Beer’s law.
and not proton transfer, play the key role in noncovalent
organocatalysis,6 itisquiteclear thatthe availabilityof pKa
values for these catalysts helps in the understanding of
catalytic activity and catalyst design, keeping in mind,
however, that an equilibrium quantity has its limitations
for a kinetic property such as transition state stabilization.
As we demonstrated recently that the most common
achiral catalyst, 3,5-bis(trifluoromethyl)phenyl thiourea
(1) can readily be deprotonated with common bases such
as diethylpropyl amine (DIPEA),7 it is imperative to know
the pKa values of such catalysts to rationalize the under-
lying reaction mechanisms.
Although most organic reactions are being carried out in
organic solvents, the first acidity scale was established in
water with a limited practical pKa range of 0ꢀ12.8 As
many organic compounds are either sparingly soluble in
aqueous media or significantly weaker acids than water,
new acidity scales in organic solvents needed to be estab-
lished. Polar non-H-bond-donor solvents proved to be
very capable media for this purpose, since they suppress
ion pairing,9 and thus the obtained pKa values were termed
“absolute”.8,10 Bordwell and co-workers determined the pKa
values of over 1200 compounds in DMSO,8 establishing an
excellent basis for comparison. Inspired by this as well as
Berkessel and O’Donoghue’s report on the pKa values of
some important chiral Brønsted acid organocatalysts,11 we
decided to determine the acidic dissociation constants of
some of the most popular (thio)urea organocatalysts in
DMSO.
HA þ Indꢀ h Aꢀ þ HInd
ð1Þ
A precondition for accurate measurements is a relatively
similar acidity of the two participants; in our experience a
pKa difference no greater than 1.5 units is acceptable to
keep the errors small. Addition of the weak acid yields a
new equilibrium with a lower concentration of the indica-
tor anion, resulting in a decrease of the UV absorption at a
certain wavelength. In the absence of a proton source other
thanthe weak acid, the following equation applies (charges
were omitted for clarity).
Δ[Ind] ¼ Δ[HA]
ð2Þ
Since the initial amount of each species is known, the
equilibrium constant (Keq) of eq 1 can be calculated, which
leads to the pKa value of the weak acid in question:
pKa ¼ pKInd ꢀ logKeq
ð3Þ
In order to achieve maximum accuracy, the concentration
of the K-dimsyl base solution and the molar extinction
coefficient of the indicator in use were determined in each
titration. Dilution effects were taken into account, and
moisture and oxygen exposure were minimized. Ion asso-
ciation was neglected due to the low concentration of
participants (10ꢀ3ꢀ10ꢀ4 M).9 The (thio)urea derivatives
investigated in this study were initially assumed to have
pKa values in the rangeof 9ꢀ18; hence a series ofindicators
covering the aforementioned range anchored to the Bord-
well acidity scale was synthesized (Table 1). We used
benzoic acid and N,N0-diphenylthiourea as test com-
pounds to verify our approach. Benzoic acid is prone to
self-association and the presence of water in solution has a
serious influence on its pKa value, so this resulted in being a
challenging task. To our delight, repeated measurements
with two different indicators showed close agreement with
the literature values of these two test compounds (BzOH:
11.09( 0.07, lit. 11.0( 0.1; 8: 13.38( 0.06, lit. 13.4( 0.1).8
€
(7) Hrdina, R.; Muller, C. E.; Wende, R. C.; Lippert, K. M.; Benassi,
M.; Spengler, B.; Schreiner, P. R. J. Am. Chem. Soc. 2011, 133, 7624–
7627.
(8) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(9) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006–7014.
(10) Bordwell, F. G.; Branca, J. C.; Hughes, D. L.; Olmstead, W. N.
J. Org. Chem. 1980, 45, 3305–3313.
€
(11) Christ, P.; Lindsay, A. G.; Vormittag, S. S.; Neudorfl, J.-M.;
Berkessel, A.; O’Donoghue, A. C. Chem.;Eur. J. 2011, 17, 8524–8528.
(12) (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964–12965. (b) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
1998, 120, 4901–4902.
Org. Lett., Vol. 14, No. 7, 2012
1725

We also measured one catalyst against three different
indicators, furnishing basically the same pKa value (see
Supporting Information).
Table 2. pKa Values of Some Popular Chiral (Thio)urea Orga-
nocatalysts in DMSO
With a reliable method in hand we decided to investigate
first the effect of the CF3 groups on (thio)urea acidity
(Figure 2). Bordwell’s measurements already revealed that
replacing the urea oxygen by a sulfur atom increases the
acidity by 6 orders of magnitude; aryl substitution adds
another 108 units to the acidity, which is due to DMSO
lacking ion stabilizing effects. Thus, the ability of intra-
molecular charge distribution is critical to acidic strength,
and unsubstituted (thio)urea (5 and 6) has a much higher
pKa value (26.9and 21.1, respectively) thanN,N0-diphenyl-
(thio)urea (7 and 8) (18.7 and 13.4, respectively). Introdu-
cing CF3 groups to the aromatic rings further increases
acidity, owing to their strong σ-electron withdrawing
ability. We find that the pKa increase corresponds well
with the overall number of CF3 groups attached to the aro-
matic rings; each CF3 group decreases the pKa by approxi-
mately 1.2 pKa units. The combined effect of four CF3
groups thus results in a pKa value of 8.5, which is well
below the common expectation for a thiourea derivative.
This low pKa is in line with the literature value2b and
underscores our finding that relatively weak organic bases
(e.g., DIPEA) are able to deprotonate 1.7
Figure 2. Substituent effects on a selection of achiral (thio)urea
derivative pKa values in DMSO.
Another conclusion is that both aromatic rings are in-
volved in the stabilization of the anion, as indicated by the
similar pKa values of two isomeric thiourea compounds
(Figure 2, 112b and 121i). A plausible explanation involves
dynamic proton exchange between the two thiourea nitro-
gens, creating an average partial negative charge on both;
this is in line with the fast H/D exchange of 1 in deuterated
solvents (Mike Kotke, Dissertation, Justus-Liebig Univer-
sity Giessen, 2009). Most of the popular (thio)urea orga-
nocatalysts lack a second aromatic moiety, which would
lead to somewhat higher pKa values according to our
hypothesis. Indeed, Wang’s binaphthyl catalyst (Table 2,
entry 1) inherits the acidic strength of the parent system
a Jacobsen originally presented a large number of catalysts based on
this general motif with various amino acids as well as variations in the
substituentsatthe terminalamino groupand thephenolmoiety. b ThepKa
presented is an apparent value, a result of the similar acidity of the
thiourea group and the phenolic OH. c The depicted catalyst is the one
preparedbyListetal.;13b Jacobsenprepared various catalystsofthismotif
differing in the dialkyl substituents (Me, Ph, i-Bu) at the terminal amino
group and the di-ortho substituents at the imidazol moiety (Me, Ph).13a
1726
Org. Lett., Vol. 14, No. 7, 2012

(ꢀ2.2 pKa units), while the pKa values of other commonly
employed catalysts are 2ꢀ3 pKa units higher (Table 2,
entries 2ꢀ8). Without aromatic substituents the pKa values
converge to that of parent thiourea (Table 2, entry 10, 11).
An important inclusion is that N-aryl thioureas have
intrinsically lower pKa values and may therefore be more
useful as organocatalysts; exceptions are Jacobsen’s cata-
lysts 20 and 21 with pKa’s of 18.3 and 19.4. Intramolecular
hydrogen bonds may also be responsible for an enhance-
ment of acidic strength. For instance, while Nagasawa’s
thiourea 2 and the Takemoto catalyst 3 share the same
chiral backbone, a second thiourea group is in close proxi-
mity to stabilize the incipient anion via H-bonding interac-
tions in 2, leading to a lower pKa.
A survey of the literature yielded some examples where
the increasing acidic strength of a series of catalysts had a
beneficial effect on their activity in the given reactions.
Turnover frequencies (TOF) were calculated in each case
to quantify catalyst performance. In a MoritaꢀBaylisꢀ
Hillman reaction of 2-cyclohexen-1-one with phenylpropio-
naldehyde Takemoto’s catalyst (3, pKa = 13.65, TOF =
0.04 hꢀ1) exhibited moderate activity compared to that of
Wang’s (14, pKa = 10.72, TOF = 0.17 hꢀ1).1a Similarly, in
a vinylogous aldol addition of γ-butenolide to benzalde-
0.08 hꢀ1).14 The same three catalysts were involved
in another study concerning an azaꢀMoritaꢀBaylisꢀ
Hillman type reaction with turnover frequencies of 0.13,
0.19, and 0.16 hꢀ1, respectively.15 This finding suggests that
a thiourea derivative with an optimal pKa value (∼13.7)
may be suitable to achieve maximum acceleration in this
transformation. It is quite clear, however, that the acidic
strength of the (thio)urea moiety is only one of several key
features defining catalytic properties. pKa Values and cata-
lyst activity do not necessarily correspond well, as shown in
the case of transfer hydrogenations of nitroolefins.16 This is
not unexpected as catalystꢀsubstrate interactions and tran-
sition-state stabilization can be energetically quite different.
In the current study we report the pKa values of some of
the most popular (thio)urea organocatalysts in DMSO.
The UV-spectrophotometric indicators synthesized and
used for this purpose were introduced by Bordwell; thus
the obtained results are embedded within his extensive
acidity scale. The strongly acidifying effect of CF3 groups
was also investigated and found to be very predictable by
the number of groups attached to an aryl moiety. The data
provided here are likely to contribute to future cat-
alyst development and to a deeper understanding of non-
covalent, hydrogen bonding organocatalysis.
ꢀ
hyde, the best results were obtained with the Soos catalyst
(4, pKa = 12.39, TOF = 0.16 hꢀ1), and decreasing acidity
of the thiourea moiety resulted in slightly lower reaction
rates in the case of Takemoto’s catalyst (3, pKa = 13.65,
TOF = 0.13 hꢀ1) and for a derivative of 3 without the CF3
groups attached to the phenyl ring (pKa = 17.0,5 TOF =
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft. We thank Hans-
Peter Reisenauer (Institute of Organic Chemistry, Justus-
ꢀ
ꢀ
Liebig University) for fruitful discussions and Julia Denes
(Institute of Inorganic and Analytical Chemistry, Justus-
Liebig University) for HRMS measurements.
(13) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558–10559. (b) Pan, S. C.; Zhou, J.; List, B. Angew. Chem., Int. Ed.
2007, 46, 2971.
(14) Yang, Y.; Zheng, K.; Zhao, J.; Shi, J.; Lin, L.; Liu, X.; Feng, X.
J. Org. Chem. 2010, 75, 5382–5384.
Supporting Information Available. Detailed description
of the spectrophotometric titrations, synthetic protocols,
and characterization of materials. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(15) Wang, X.; Chen, Y.-F.; Niu, L.-F.; Xu, P.-F. Org. Lett. 2009, 11,
3310–3313.
(16) Martin, N. J. A.; Ozores, L.; List, B. J. Am. Chem. Soc. 2007,
129, 8976–8977.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
1727