Counterion effects in iminium-activated electrophilic aromatic substitutions of pyrroles

Article abstract of DOI:10.1039/c0cc04295a

Electrophilic substitution of pyrroles by α,β-unsaturated iminium ions is slow in acetonitrile when only weakly basic counterions are present. When the reactions are carried out in the presence of KCF ₃CO₂, fast deprotonation of the intermediate σ-adducts occurs, and the rate constant for the rate-determining CC bond-forming step can be predicted from the electrophilicity parameter E of the iminium ion and the N and s parameters of the pyrroles.

Full text of DOI:10.1039/c0cc04295a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Counterion effects in iminium-activated electrophilic aromatic
substitutions of pyrrolesw
Sami Lakhdar and Herbert Mayr*
Received 8th October 2010, Accepted 9th November 2010
DOI: 10.1039/c0cc04295a
Electrophilic substitution of pyrroles by a,b-unsaturated iminium
ions is slow in acetonitrile when only weakly basic counterions
are present. When the reactions are carried out in the presence of
KCF3CO2, fast deprotonation of the intermediate r-adducts
occurs, and the rate constant for the rate-determining CC
bond-forming step can be predicted from the electrophilicity
parameter E of the iminium ion and the N and s parameters of
the pyrroles.
Iminium activation has become one of the most important
methods for the enantioselective formation of CC bonds.1
Recently, much attention has been paid to the mechanism of
these reactions including the isolation and characterisation of
the intermediates.2
In previous work, we have studied the kinetics of a series of
a,b-unsaturated iminium ions with ketene acetals in order to
determine their electrophilicity parameters
E according
to eqn (1)3 where electrophiles are characterised by one
parameter (E), while two parameters (N and s) are used for
the characterisation of nucleophiles.4
Scheme 1 Mechanism of the reactions of different iminium salts 1–X
with p-nucleophiles.
log k (20 1C) = s(N + E)
(1)
We now report on the applicability of eqn (1) for predicting
the scope and limitations of iminium-activated electrophilic
aromatic substitutions.5 As the rate constants accessible by
eqn (1) refer to the electrophile–nucleophile combination step,
knowledge of the rate-determining step of this reaction
cascade was needed. Paras and MacMillan reported that
imidazolidinone-catalysed reactions of a,b-unsaturated
aldehydes with pyrroles proceed well with CF3CO2H as a
cocatalyst, but give low yields and enantioselectivities, when
strong acids such as CF3SO3H, TsOH or HCl are employed.6
As this observation may be due to reversible formation of the
s-adduct from the iminium ion 1 and the pyrroles,6 we have
systematically studied the effect of the counterions on the rates
of these reactions.
Table
1
Counterion effect on the second-order rate constants
ꢀ1) for the reactions of the iminium salts 1–X with the
k2 (Mꢀ1
s
ketene acetal 2a in CH2Cl2 and the apparent second-order rate
constants k02 (Mꢀ1 ꢀ1) for the reactions of 1–X with kryptopyrrole
2b in CH3CN at 20 1C
s
1–X
k2 (2a)
k02(2b)
1–PF6
1–BF4
1–OTf
1–Br
1.14 ꢁ 104
1.19 ꢁ 104
9.06 ꢁ 103 a
4.53 ꢁ 103
6.76 ꢁ 103
6.27 ꢁ 101
5.60 ꢁ 101
2.32 ꢁ 101
6.43 ꢁ 101
5.94 ꢁ 102
b
1–CF3CO2
a
b
From ref. 3. 1–CF3CO2 was generated by addition of an equimolar
amount of cinnamaldehyde to imidazolidinium trifluoroacetate in
acetonitrile.
The kinetics of the reactions of the iminium ion 1 with
the ketene acetal 2a and the pyrrole 2b (Scheme 1) were
determined photometrically by following the disappearance
of the absorbance of 1 at 360 nm according to the procedure
described previously.3,7
1–X with the ketene acetal 2a showed monoexponential decays
over more than 4 half-lives. Deviations from the first-order
rate law were observed for the reactions of 1–X with 2b at
conversions above 70%. The second-order rate constants k2
and k02 listed in Table 1 are the slopes of the linear plots of the
observed first-order rate constants kobs vs. [2].
All kinetic experiments were performed under first-order
conditions using 25 to 800 equivalents of 2. The reactions of
Table 1 shows the different counterion effects on the reac-
tions with the nucleophiles 2a and 2b. While the second-order
rate constants of the reactions of 1–X with 2a vary by less than
a factor of 3, the rates of the reactions of 1–X with 2b are
significantly affected by the counterions; in the concentration
range investigated, the iminium trifluoroacetate 1–CF3CO2
reacts 26 times faster with 2b than the iminium triflate 1–OTf.
Department Chemie, Ludwig-Maximilians-Universitat Munchen,
¨
Butenandtstr. 5–13 (Haus F), 81377 Munchen, Germany.
¨
¨
E-mail: Herbert.Mayr@cup.uni-muenchen.de;
Fax: +49 89 2180 77717
w Electronic supplementary information (ESI) available: Details of the
kinetic experiments, synthetic procedures and product characterisa-
tion. See DOI: 10.1039/c0cc04295a
c
1866 Chem. Commun., 2011, 47, 1866–1868
This journal is The Royal Society of Chemistry 2011

View Article Online
This behaviour may be rationalised by the reversible attack
of 1 at the pyrrole 2b and subsequent deprotonation of thꢀe
intermediate s-adduct.8 Due to its higher basicity,9 CF3CO2
can be assumed to abstract the proton faster than the other
anions investigated, all of which are conjugate bases of very
strong acids.
Table
2
Comparison of calculated and experimental second-
order rate constants (Mꢀ1 ꢀ1) of the reactions of pyrroles 2b–g
s
with the iminium ion
added trifluoroacetate
1 (20 1C, CH3CN) in the presence of
N, sa
k2
k2
k2calcd/k2
calcd b
exp c
exp
Pyrroles 2
In line with this hypothesis, first-order kinetics over more
than four half-lives have been observed when the reaction of
the iminium salt 1–BF4 with 2b was studied in the presence of
high concentrations of potassium trifluoroacetate. With the
11.63, 0.95
2.3 ꢁ 104
2.1 ꢁ 103
1.3 ꢁ 104
3.5 ꢁ 103
1.8
ꢀ
assumption that CF3CO2 serves as the base to deprotonate
the intermediate s-adduct, the rate law for the reaction of
1–BF4 with 2b is given by eqn (2), where the last term
corresponds to the ratio of deprotonation of the intermediate
k1[CF3CO2ꢀ] divided by the sum of the forward plus back-
ward reaction (the meaning of the rate constants is specified in
Scheme 1). For [2b] c [1], the concentration of [2b] can be
considered to be constant, and one obtains eqn (3).
10.67, 0.91
0.60
8.69, 1.01
8.01, 0.96
5.85, 1.03
3.9 ꢁ 101
5.3
3.6
7.4
1.6
d½1ꢂ
dt
k1½CF3COꢀ2 ꢂ
ꢀ
¼ k2½1ꢂ½2bꢂ
ð2Þ
k1½CF3COꢀꢂ þ k
ꢀ2
5.9
2
1
1
k
1
ꢀ2
¼
þ
ð3Þ
kobs k2½2bꢂ k1k2½2bꢂ ½CF3COꢀ2 ꢂ
4.1 ꢁ 10ꢀ2
2.7 ꢁ 10ꢀ3
7.2 ꢁ 10ꢀ3
6.8 ꢁ 10ꢀ4
5.7
4.0
According to eqn (3), the intercept of the plot of 1/kobs vs.
1/[CF3CO2ꢀ] yields the rate constant for the first step
of the reaction cascade (Fig. 1). Comparison of this value
4.63, 1.00
(k2 = 1.3 ꢁ 104 Mꢀ1
s
ꢀ1) with the entries 1 to 4 in the right
column of Table 1 shows that the rate constants k02 observed in
the absence of CF3CO2ꢀ are 202 to 560 times smaller than k2,
indicating that triflate, tetrafluoroborate, hexafluorophosphate,
and bromide ions are poor bases for the removal of protons
from the pyrrolium species. It should be noted that also the
last entry in the right column of Table 1 is 22 times smaller
than the second-order rate constant derived from Fig. 1,
indicating that at low ion concentrations, also the first step
of the reaction of 1–CF3CO2 with 2b is reversible.
a
b
From ref. 10. Calculated by eqn (1) by using the electrophilicity
c
parameters E = ꢀ7.2 for 1 from ref. 3. Derived from the intercepts
of the linear correlations of 1/kobs with 1/[CF3CO2ꢀ]. Details are given
in the ESI.w
those calculated from eqn (1), i.e., the E, N, and s parameters
can be employed for determining the scope and limitations of
iminium-catalysed reactions.
As the N and s parameters of the pyrroles 2b–g10 have
been derived from their reactions with benzhydrylium ions
(reference electrophiles) and the parameter E for 1 has been
derived from its reactivity toward ketene acetals,3 this agree-
ment is further evidence for the power of the three parameter
eqn (1) to provide reliable estimates for second-order rate
constants in a reactivity range presently covering 40 orders of
magnitude.
The method described in Fig. 1 for determining the second-
order rate constant k2 for the attack of 1 at the pyrrole 2b has
analogously been employed for determining the rate constant
of attack of 1 at the pyrroles 2c–g. Table 2 shows that the
experimental rate constants k2 agree within a factor of 8 with
Accordingly, treatment of an acetonitrile : water (1 : 1)
solution of the iminium salts 1–PF6 with 5 equivalents of
the pyrroles 2b–g in the presence of 5 to 6 equivalents of
potassium trifluoroacetate and subsequent reduction with
NaBH4 allowed us to isolate the alcohols 3b–g in 78 to 99%
yield (Table 3).11 In contrast, the reaction of 2b with 1–PF6
gave only 15% of 3b when the reaction was carried out under
the same conditions but without potassium trifluoroacetate.
These observations show clearly that the presence of base is
essential for the success of the reaction.12
The high reversibility of the attack of the iminium ions at
pyrroles in the absence of CF3CO2ꢀ not only accounts for the
lower conversion rates of 1–X (X = PF6, BF4, OTf, Br) but
also for the erosion of enantioselectivity which was reported
Fig. 1 Exponential decay of the absorbance at 360 nm during the
reaction of 1–BF4 (5.0 ꢁ 10ꢀ5 M) with 2b (1.0 ꢁ 10ꢀ2 M) and
CF3CO2 (5.0 ꢁ 10ꢀ3 M). Inset: determination of the second-order
ꢀ
rate constant k2.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1866–1868 1867

View Article Online
Table 3 Products of the reactions of 1–PF6 with pyrroles 2b–g in the
presence of potassium trifluoroacetatea
Notes and references
1 For reviews on asymmetric iminium catalysis, see: (a) J. Seayad
and B. List, Org. Biomol. Chem., 2005, 3, 719; (b) B. List, Chem.
Commun., 2006, 819; (c) G. Lelais and D. W. C. MacMillan,
Pyrrole
Product
Yieldb (%)
94 (15)c
Aldrichimica Acta, 2006, 39, 79; (d) A. Erkkila, I. Majander and
¨
P. M. Pihko, Chem. Rev., 2007, 107, 5416; (e) S. B. Tsogoeva, Eur.
J. Org. Chem., 2007, 1701; (f) D. Alma-si, D. A. Alonso and
C. Najera, Tetrahedron: Asymmetry, 2007, 18, 299; (g) B. Brazier
´
2b
3b
and N. C. O. Tomkinsson, Top. Curr. Chem., 2010, 291, 281;
(h) for a review on organocatalysed Friedel–Crafts reactions, see:
V. Terrasson, R. M. De Figueiredo and J. M. Campagne, Eur. J.
Org. Chem., 2010, 2635.
2 (a) D. Seebach, U. Groselj, D. M. Badine, W. B. Schweizer and
A. K. Beck, Helv. Chim. Acta, 2008, 91, 1999; (b) U. Groselj,
D. Seebach, D. M. Badine, W. B. Schweizer, A. K. Beck,
I. Krossing, P. Klose, Y. Hayashi and T. Uchimaru, Helv. Chim.
Acta, 2009, 92, 1225; (c) C. Sparr, W. B. Schweizer, H. M. Senn and
R. Gilmour, Angew. Chem., 2009, 121, 3111 (Angew. Chem., Int. Ed.,
2009, 48, 3065); (d) U. Groselj, W. B. Schweizer, M.-O. Ebert and
D. Seebach, Helv. Chim. Acta, 2009, 92, 1; (e) D. Seebach, U. Groselj,
2c
2d
3c
3d
97
83
W. B. Schweizer, S. Grimme and C. Muck-Lichtenfeld, Helv. Chim.
¨
Acta, 2010, 93, 1; (f) J. B. Brazier, G. Evans, T. J. K.
Gibbs, S. J. Coles, M. B. Hursthouse, J. A. Platts and N. C. O.
Tomkinson, Org. Lett., 2009, 11, 133; (g) C. Sparr and R. Gilmour,
Angew. Chem., 2010, 122, 37 (Angew. Chem., Int. Ed., 2010, 49, 37);
(h) I. Fleischer and A. Pfaltz, Chem.–Eur. J., 2010, 16, 1.
3 S. Lakhdar, T. Tokuyasu and H. Mayr, Angew. Chem., 2008, 120,
8851 (Angew. Chem., Int. Ed., 2008, 47, 8723).
4 (a) H. Mayr and M. Patz, Angew. Chem., 1994, 106, 990 (Angew.
Chem., Int. Ed. Engl., 1994, 33, 938); (b) H. Mayr, T. Bug,
M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B. Kempf,
R. Loos, A. R. Ofial, G. Remennikov and H. Schimmel, J. Am.
Chem. Soc., 2001, 123, 9500; (c) H. Mayr, B. Kempf and
A. R. Ofial, Acc. Chem. Res., 2003, 36, 66; (d) H. Mayr and
A. R. Ofial, Pure Appl. Chem., 2005, 77, 1807; (e) H. Mayr and
A. R. Ofial, J. Phys. Org. Chem., 2008, 21, 584.
5 For the application of eqn (1) in organocatalysis, see:
(a) P. G. Cozzi, F. Benfatti and L. Zoli, Angew. Chem., 2009,
121, 1339 (Angew. Chem., Int. Ed., 2009, 48, 131); (b) F. Benfatti,
E. Benedetto and P. G. Cozzi, Chem.–Asian J., 2010, 5, 2047;
(c) M. G. Capdevila, F. Benfatti, L. Zoli, M. Stenta and
P. G. Cozzi, Chem.–Eur. J., 2010, 16, 11237; (d) A. R. Brown,
W.-H. Kuo and E. N. Jacobsen, J. Am. Chem. Soc., 2010, 132,
9286.
2e
2f
3e
99
3f
78d
80
2g
3g
a
Reaction conditions: iminium salt 1–PF6 (0.50 mmol), pyrroles 2b–g
(2.46 mmol), potassium trifluoroacetate (2.63 mmol) in acetonitrile–
water mixture 1 : 1 at ꢀ20 1C, 30 min. Then, in situ reduction of the
aldehydes by NaBH4 to the corresponding primary alcohols 3b–g.
b
Yield of isolated product after column chromatography on silica
c
gel. Without potassium trifluoroacetate. ee > 99% (for details see
d
p S31 of the ESIw).
by Paras and MacMillan for the imidazolidinium catalysed
reaction of cinnamaldehyde with 2f.6 Only when high concen-
trations of the more basic trifluoroacetate counterion are
present, are the s-adducts formed irreversibly. As a con-
sequence, the high enantioselectivity of the addition step,
which has been studied computationally by Houk et al.,13 is
fully transmitted into the final product. In line with this
interpretation, the reaction of 2f with 1–PF6 gave 3f with
>99% ee, when the reaction was carried out in CH3CN–H2O
(1 : 1) in the presence of KCF3CO2 (Table 3). Presently, we are
investigating the effect of the co-catalyst on the formation of
the iminium ion, in order to achieve a quantitative description
of the whole organocatalytic cycle.
6 N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2001,
123, 4370.
7 (a) S. Lakhdar, R. Appel and H. Mayr, Angew. Chem.,
2009, 121, 5134 (Angew. Chem., Int. Ed., 2009, 48, 5034);
(b) S. Lakhdar, A. R. Ofial and H. Mayr, J. Phys. Org. Chem.,
2010, 23, 886.
8 N. F. Austin, PhD thesis, California Institute of Technology, 2006.
9 A. Albert and E. P. Serjeant, The Determination of Ionization
Constants, Chapman and Hall, New York, 3rd edn, 1984.
10 T. A. Nigst, M. Westermaier, A. R. Ofial and H. Mayr, Eur. J.
Org. Chem., 2008, 2369.
11 In the case of 2d and 2e, the intermediate aldehydes 3d0 and
3e0 were also isolated as described in the ESIw.
12 Ref. 2g shows, however, that in methanol solution basic counter-
ions are not needed, because the reaction of 1–SbF6 with 2f in
methanol (rt, 90 min) yielded 86% of 3f after in situ reduction of
the intermediate aldehyde by NaBH4.
13 R. Gordillo, J. Carter and K. N. Houk, Adv. Synth. Catal., 2004,
346, 1175.
We thank Dr Armin R. Ofial and Dr Tanja Kanzian for
helpful discussions and the Deutsche Forschungsgemeinschaft
(Ma 673/21–3) for generous support.
c
1868 Chem. Commun., 2011, 47, 1866–1868
This journal is The Royal Society of Chemistry 2011