Basicities and Nucleophilicities of Pyrrolidines and Imidazolidinones Used as Organocatalysts

Article abstract of DOI:10.1021/jacs.9b11877

The Br?nsted basicities pK_aH (i.e., pK_a of the conjugate acids) of 32 pyrrolidines and imidazolidinones, commonly used in organocatalytic reactions, have been determined photometrically in acetonitrile solution using CH acids as indicators. Most investigated pyrrolidines have basicities in the range 16 < pK_aH < 20, while imidazolidinones are significantly less basic (10 < pK_aH < 12). 2-(Trifluoromethyl)pyrrolidine (A14, pK_aH 12.6) and the 2-imidazoliummethyl-substituted pyrrolidine A21 (pK_aH 11.1) are outside the typical range for pyrrolidines with basicities comparable to those of imidazolidinones. Kinetics of the reactions of these 32 organocatalysts with benzhydrylium ions (Ar₂CH⁺) and structurally related quinone methides, common reference electrophiles for quantifying nucleophilic reactivities, have been measured photometrically. Most reactions followed second-order kinetics, first order in amine and first order in electrophile. More complex kinetics were observed for the reactions of imidazolidinones and several pyrrolidines carrying bulky 2-substituents, due to reversibility of the initial attack of the amines at the electrophiles followed by rate-determining deprotonation of the intermediate ammonium ions. In the presence of 2,4,6-collidine or 2,6-di-tert-butyl-4-methyl-pyridine, the deprotonation of the initial adducts became faster, which allowed the rate of the attack of the amines at the electrophiles to be determined. The resulting second-order rate constants k₂ followed the correlation log?k₂(20 °C) = s_N(N + E), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the two solvent-dependent parameters N and s_N. In this way, the organocatalysts A1-A32 were integrated in our comprehensive nucleophilicity scale, which compares n-, -, and σ-nucleophiles. The nucleophilic reactivities of the title compounds correlate only poorly with their Br?nsted basicities.

Full text of DOI:10.1021/jacs.9b11877

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Basicities and Nucleophilicities of Pyrrolidines and Imidazolidinones
Used as Organocatalysts
Feng An, Biplab Maji,† Elizabeth Min,‡ Armin R. Ofial,* and Herbert Mayr*
̈
̈
̈
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstraße 5-13, 81377 Munchen, Germany
S
* Supporting Information
ABSTRACT: The Brønsted basicities pKaH (i.e., pKa of the conjugate
acids) of 32 pyrrolidines and imidazolidinones, commonly used in
organocatalytic reactions, have been determined photometrically in
acetonitrile solution using CH acids as indicators. Most investigated
pyrrolidines have basicities in the range 16 < pKaH < 20, while
imidazolidinones are significantly less basic (10 < pKaH < 12). 2-
(Trifluoromethyl)pyrrolidine (A14, pKaH 12.6) and the 2-imidazo-
liummethyl-substituted pyrrolidine A21 (pKaH 11.1) are outside the
typical range for pyrrolidines with basicities comparable to those of
imidazolidinones. Kinetics of the reactions of these 32 organocatalysts
with benzhydrylium ions (Ar2CH+) and structurally related quinone
methides, common reference electrophiles for quantifying nucleo-
philic reactivities, have been measured photometrically. Most
reactions followed second-order kinetics, first order in amine and first order in electrophile. More complex kinetics were
observed for the reactions of imidazolidinones and several pyrrolidines carrying bulky 2-substituents, due to reversibility of the
initial attack of the amines at the electrophiles followed by rate-determining deprotonation of the intermediate ammonium ions.
In the presence of 2,4,6-collidine or 2,6-di-tert-butyl-4-methyl-pyridine, the deprotonation of the initial adducts became faster,
which allowed the rate of the attack of the amines at the electrophiles to be determined. The resulting second-order rate
constants k2 followed the correlation log k2(20 °C) = sN(N + E), where electrophiles are characterized by one parameter (E)
and nucleophiles are characterized by the two solvent-dependent parameters N and sN. In this way, the organocatalysts A1−A32
were integrated in our comprehensive nucleophilicity scale, which compares n-, π-, and σ-nucleophiles. The nucleophilic
reactivities of the title compounds correlate only poorly with their Brønsted basicities.
enantiopure compounds, and others were synthesized as
racemates, generally following literature procedures. Major
variations were the cyclization step in the synthesis of 2-
isopropylpyrrolidine (A4) and the synthesis of potassium
prolinate (K-A1). Since the purification of the amines has
been modified in several cases, full experimental details of all
syntheses are given in the Supporting Information.
INTRODUCTION
■
Chiral pyrrolidines and imidazolidinones play a key role as
organocatalysts in modern organic synthesis.1−3 Numerous
mechanistic investigations on organocatalytic transformations
via intermediate enamines4 and iminium ions5 have been
performed, mostly in water, DMSO, and acetonitrile. The rate
of the initial step, commonly the nucleophilic attack of the
secondary amine at the carbonyl group, depends on the nature
of the carbonyl group as well as on the basicity and
nucleophilicity of the amine. Whereas Brønsted basicities of
several pyrrolidines and imidazolidinones have been reported
in aqueous solution,6 investigations of protonation equilibria
in aprotic solvents are rare,7 and we are not aware of any
systematic determinations of their nucleophilic reactivities.
Since knowledge of these thermodynamic and kinetic data is
crucial for the systematic optimization of organocatalytic
transformations, we have now determined the Brønsted
basicities of the amines A1−A32 (Chart 1) in acetonitrile
and the kinetics of their reactions with reference electrophiles.
Brønsted Basicities in Acetonitrile. In order to avoid
confusion, basicities of the amines are always expressed by
their pKaH values, which equal the pKa values of the conjugate
ammonium ions. Since acetonitrile proved to be a suitable
solvent for our kinetic investigations, we also used acetonitrile
as the solvent for comparing the Brønsted basicities of A1−
A32. Extensive previous work by Leito and associates on
acidities in acetonitrile included the determination of pKa
values for the CH acids C1H−C6H (Chart 2), which were
suitable as indicators for our studies, since their deprotonation
yields the colored carbanions C1−−C6−.8
As illustrated in Figure 1 for the deprotonation of C4H with
A24, spectrophotometric titrations were performed by record-
RESULTS
■
Syntheses for Amines A1−A32. Compounds synthe-
sized from L-proline or L-phenylalanine were obtained as
Received: November 4, 2019
© XXXX American Chemical Society
A
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Article
the indicator acids CH). Since we wanted to compare the
equilibrium constants with kinetic data at 20 °C, also the
titrations were carried out at 20 °C.
Chart 1. Pyrrolidines and Imidazolidinones Investigated in
This Work
For each step of the titration, the equilibrium constant K for
the reaction in eq 1 can be calculated by eq 2.
K
A + CH F AH+ + C−
(1)
[AH+][C−]
[A][CH]
K =
(2)
According to the Lambert−Beer law, the equilibrium
concentrations [C−], [A], and [CH] required to calculate K
in eq 2 were obtained by applying eqs 3−5, in which V0 and
Vf are the initial and final volumes of the acetonitrile solutions,
respectively, and [A]0,i is the initial concentration of the added
amine A at a certain step i of the titration. Furthermore, the
experimentally measured absorbance after each step i of the
titration (A) and the final absorbance (Af) reached after
quantitative deprotonation of the indicator acids CH by
adding the strong Brønsted bases 1,5,7-triazabicyclo[4.4.0]-
dec-5-ene (TBD, pKaH 26.027c) or 1,8-diazabicyclo(5.4.0)-
undec-7-ene (DBU, pKaH 24.317c) in the final step of the
titration are used in eq 3.
[C−] = [AH+] = [CH]0(A/Af )(V /V )
[A] = [A]0,i − [C−]
(3)
(4)
(5)
0
f
[CH] = [CH]0(V /V) − [C−]
0
According to eq 2 and because [AH+] = [C−], the individual
equilibrium constants log K were then determined from the
slopes of a linear plot of [C−]2 vs [A][CH]. The basicity of
amine A (pKaH) is then given by eq 6:
Chart 2. Indicator Acids and Their pKa Values in
Acetonitrile (25 °C)8
pKaH(A) = pKa(CH) + log K
(6)
Since the free amines A18 and A23 are only stable in highly
dilute solutions, their basicities were determined by adding
stock solutions of the stable ammonium salts A18H+ and
A23H+ to solutions of the colored indicator anions C−.
As shown in Chart 2, the indicator acids C1H−C6H cover
an acidity range from 11.6 < pKa < 23.5, which allowed us to
compare amines of widely differing basicity. In several cases
(A7, A11, A15−A20, A22−A29), basicities were determined
with two different indicators, and the agreement was typically
within 0.03 pKaH units. Deviations of pKaH determined by
using different indicators never exceeded 0.1 pKaH units.
ing the UV−vis spectra in the range from 250 to 600 nm
(stock solutions of the amines A were added to solutions of
Figure 1. Determination of the pKaH of A24 by portionwise (steps 1−9) addition of A24 (2.27 × 10−3 M) to the solution of C4H (8.13 × 10−5
M) in acetonitrile at 20 °C. DBU was added in the final step to achieve quantitative deprotonation of C4H.
B
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Individual and averaged Brønsted basicities pKaH of all
investigated cyclic secondary amines A1−A32 are listed in
Table 1.
As illustrated in Figure 2, the basicity constants in
acetonitrile cover the range 10 < pKaH < 24; while most
pyrrolidines are in the range 16 < pKaH < 20, the
imidazolidinones are in the range 10 < pKaH < 12. Thus,
steric and electronic effects of the 2-substituents generally
reduce the basicity of the parent pyrrolidine A2 (pKaH 19.89)
by less than 4 pK units. If one disregards the slightly higher
basicity of the diamine A10, 2-(trifluoromethyl)pyrrolidine
A14 is the only neutral pyrrolidine outside this range with a
basicity constant pKaH of 12.63, that is, 7 pKa units smaller
than that of the parent pyrrolidine. On the other hand,
charged substituents have a large effect on the basicity. Thus,
the negative charge of the carboxylate group in prolinate (A1)
increases the basicity of the pyrrolidine by 4 orders of
magnitude, while the positive charge of the imidazolium group
in A21 (pKaH 11.14) reduces the pyrrolidine basicity by
almost 9 pKaH units.
Kinetic Investigations. It is obvious that a single
reference electrophile is not sufficient for comparing
nucleophiles of widely varying reactivities. Hence, we have
used a set of previously characterized p- and m-substituted
benzhydrylium ions and structurally related quinone methides
(Chart 3) as reference electrophiles, which differ widely in
reactivity while the steric surroundings of the reaction center
are kept constant.
All kinetic investigations were performed photometrically at
20 °C by following the disappearance of the colored
electrophiles (346 nm ≤ λmax ≤ 646 nm). A sufficient excess
of the amines A (≥10 equiv) over the electrophiles E was
used in all reactions to achieve pseudo-first-order kinetics. As
a consequence, in most cases a monoexponential decay of the
absorbances of the electrophiles was observed, from which the
first-order rate constants kobs (s−1) were derived by least-
squares fitting of the function At = A0 exp(−kobst) + C to the
observed time-dependent absorbances. Since the first-order
rate constants kobs did not always increase linearly with the
concentration of the amines, let us first consider the
mechanism of these reactions (Scheme 1): The reaction of
a secondary amine A with a benzhydrylium ion E generates
the ammonium ion F, which will generally be deprotonated by
A, because A and G can be assumed to have similar basicities
but A is present in high excess under the conditions of the
kinetic experiments. If A is a strong Lewis base and E is a
strong Lewis acid, the combination of A with E to give F is
irreversible, and the reactions follow second-order kinetics,
first order in E and first order in A. Second-order kinetics will
also be encountered, if the formation of F is endergonic, but
deprotonation of F is much faster than the reverse reaction
(kT[A] ≫ k−2). If the retroaddition of F is faster than its
deprotonation, the second step of Scheme 1 is rate-
determining, and in the case of kT[A] ≪ k−2, third-order
kinetics will result, first order in E and second order in A.
Since all reactions of the reference electrophiles E from
Chart 3 with pyrrolidines A give rise to analogous products,
we studied a few of the possible combinations to confirm this
assumption. As exemplified in Scheme 2 for the reactions of
the benzhydrylium tetrafluoroborate E13 with the 2-methyl-,
2-trifluoromethyl-, 2-trityl-, and 2-triphenylsilyl-substituted
pyrrolidines A3, A14, A24, and A28, respectively, in
acetonitrile at 20 °C, N-benzhydrylated pyrrolidines were
isolated and characterized by spectroscopic methods.
Recrystallization of 4,4′-((2-tritylpyrrolidin-1-yl)methylene)-
bis(N,N-dimethylaniline) delivered crystals, which were
Table 1. Basicities (pKaH) of Proline (A1), the Pyrrolidines
A2−A28, and the Imidazolidinones A29−A32 (in MeCN)
a
amine
indicator
K
individual pKaH averaged pKaH
A1
A2
A3
A4
A5
A6
A7
C1H
C2H
C2H
C2H
C2H
C2H
C2H
C3H
C2H
C2H
C6H
C2H
C3H
C4H
C2H
C2H
C5H
C3H
C4H
C2H
C3H
C3H
C4H
C3−
3.07
24.02
19.89
19.57
19.31
19.47
18.67
18.11
18.14
19.86
19.81
8.15
24.02
19.89
19.57
19.31
19.47
18.67
18.13
b
3.35 × 10−2
1.62 × 10−2
8.92 × 10−3
1.30 × 10−2
2.04 × 10−3
5.59 × 10−4
2.47
A8
A9
A9H+
A10
A11
3.19 × 10−2
2.82 × 10−2
3.46 × 10−4
4.81 × 10−2
7.65 × 10−1
1.93
4.28 × 10−3
3.28 × 10−3
4.21 × 10−1
7.56 × 10−2
1.72 × 10−1
1.14 × 10−3
6.11
19.86
19.81
8.15
20.04
17.66
20.04
17.63
17.68
18.99
18.88
12.63
16.63
16.63
18.42
18.34
17.18
17.18
18.11
18.13
16.99
16.89
16.74
16.75
11.14
17.35
17.27
25.16
19.08
19.18
16.80
16.78
17.61
17.62
17.39
17.38
15.81
15.78
17.82
17.80
11.84
11.83
10.63
10.54
10.70
A12
A13
A14
A15
18.99
18.88
12.63
16.63
A16
A17
A18
A19
A20
18.38
17.18
18.12
16.94
16.74
2.72 × 10−1
6.19 × 10−1
c
2.28
c
C4−
5.53
C3H
C4H
C3H
C4H
C6H
C3H
C4H
d
1.72 × 10−1
3.13 × 10−1
9.78 × 10−2
2.26 × 10−1
3.38 × 10−1
3.97 × 10−1
7.64 × 10−1
7.04
2.14 × 101
6.12 × 101
1.12 × 10−1
2.47 × 10−1
7.21 × 10−1
1.68
A21
A22
11.14
17.31
A22−
A23
25.16
19.13
c
C3−
C4−
c
A24
A25
A26
A27
A28
A29
C3H
C4H
C3H
C4H
C3H
C4H
C3H
C4H
C3H
C4H
C5H
C6H
C6H
C6H
C6H
16.79
17.61
17.39
15.79
17.81
11.83
4.36 × 10−1
9.82 × 10−1
1.14 × 10−2
2.46 × 10−2
1.17
2.57
6.72 × 10−2
1.64
A30
A31
A32
1.06 × 10−1
8.61 × 10−2
1.22 × 10−1
10.63
10.54
10.70
a
b
K as defined in eq 2. Leito and co-workers reported pKaH(A2)
c
19.62 in MeCN (ref 7c). Obtained by titrating AH+ into solutions of
d
deprotonated indicators C− (see text). By following the absorbance
of A22− in the titration with DBU (pKaH 24.31).
C
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Figure 2. Basicity scale (pKaH in MeCN) for the cyclic secondary amines A1−A32.
investigated by single crystal X-ray analysis,10 showing that
even the installation of the bulky trityl group in the 2-position
leaves enough space at the adjacent nucleophilic nitrogen of
the pyrrolidine to allow the attack of the benzhydrylium ions
used as reference electrophiles in this study.
As explicitly described in section 2.3 of the Supporting
Information, our initial attempts to follow the reactions of
amines A with the benzhydrylium ions E in dichloromethane
were hampered by the fact that deprotonation of the initially
formed ammonium ions F was often found to be rate-
determining. Hence, in many cases, rate constants for the
initial attack of amines A at benzhydrylium ions E could not
be derived from these measurements. Fortunately, the
reactions in acetonitrile generally followed second-order
kinetics even for combinations of pyrrolidines with weak
electrophiles, as illustrated for the reaction of A13 with E9 in
Figure 3. Therefore, acetonitrile was selected as the standard
solvent for the further investigations.11,12
D
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−
Chart 3. Electrophilicity Parameters of Benzhydrylium Ions (Counterions: BF4 ) and Quinone Methides Used as Reference
Electrophiles in This Study9
graph of Figure 4 shows, for example, that the benzhydrylium
ion E13 was consumed by less than 10% when combined with
10 equiv of the sterically shielded pyrrolidine A27. Attempts
to shift this equilibrium toward the product side by adding
more basic aliphatic tertiary amines (trimethylamine,
dimethylethylamine, diisopropylethylamine) were unsuccess-
ful, because these amines reacted with E13 (probably via
hydride transfer)13 with similar rates as A27. The 2,4,6-
trialkylated pyridines D1 and D2, however, did not react with
E13, and Figure 4 illustrates that the reaction of A27 with
E13 can be shifted more and more to the product side when
increasing quantities of 2,4,6-collidine (D2) were added.
Accordingly, a higher order of A27 was observed for the
reaction of A27 with E13 in the absence of an additive, in line
with a reversible nucleophilic attack of A27 at E13 (left graph
of Figure 5). On the other hand, clear-cut second-order
reactions, first order with respect to E13 and first order with
respect to A27, were found when sufficient amounts of
collidine (D2) or 2,6-di-tert-butyl-4-methyl-pyridine (D1)
were present (Figure 5, middle and right). Since the same
rate constants within experimental error were obtained when
D2 or D1 were used as additives, one can conclude that these
reactions proceed with rate-determining formation of an
ammonium ion F (Scheme 1), which is rapidly deprotonated
by the pyridines D1 or D2.
Scheme 1. Mechanism for the Reactions of Amines A with
Benzhydrylium Ions E8−E19
Scheme 2. Reactions of Pyrrolidines with E13
Deviations from second-order kinetics were also observed in
reactions with the CF3-substituted pyrrolidine A14. While the
reaction of A14 with the highly electrophilic and Lewis acidic
However, pyrrolidines with bulky substituents deviated
from this behavior also in acetonitrile solution. The upper
E
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Figure 3. (a) Determination of the pseudo-first-order rate constant for the reaction of A13 (c0 = 8.99 × 10−5 M) with E9 (c0 = 4.28 × 10−6 M) in
MeCN at 20 °C. (b) Determination of the second-order rate constant for the reaction of A13 with E9.
Figure 4. Reaction of E13 (c0 = 7.06 × 10−6 M) with an excess of A27 (c0 = 7.67 × 10−5 M) in the presence of increasing concentrations of D2
(in MeCN, 20 °C).
benzhydrylium ion E18 followed second-order kinetics in the
absence of any additive, the less electrophilic (and less Lewis
acidic) benzhydrylium ions E17 and E15 only reacted by
second-order kinetics when an additional base was present
(e.g., 1.23 mM D1 in the case of E17 and 2.46 mM D1 in the
case of E15). For the reaction of the even further stabilized
benzhydrylium ion E13 with excess A14, Figure 6a shows that
the pseudo-first-order rate constant kobs did not increase
linearly with the concentration of A14 even when D1 was
present in a concentration of 4.92 mM. For this reaction, also
a concentration of 2.25 mM of D2 was insufficient to achieve
a linear correlation between kobs and [A14] (Figure 6b). A
linear correlation of kobs with [A14] was eventually observed
in the presence of 4.49 mM D2 (Figure 6c). With pKaH
15.00,7c collidine (D2) is a stronger base than A14 (pKaH
12.63, Table 1), which explains the observation that second-
order kinetics for the reaction of E13 with A14 were obtained
in the presence of D2 at a concentration of 4.45 mM. Since
pyridine D1 (pKaH 12.8)14 is only slightly more basic than
A14 in acetonitrile, one can explain why D1 is ineffective to
achieve second-order kinetics.
According to the previous discussion, both steric and
electron-withdrawing effects reduce the Lewis basicities of the
pyrrolidines and lead to kinetics, in which deprotonation of
F
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Figure 5. Comparison of (a) the reactions of A27 with E13 (c0 = 2.35 × 10−6 M) without additive and (b) with added D2 (c0(E13) = 5.1 × 10−6
M) or (c) with added D1 (c0(E13) = 5.3 × 10−6 M).
Figure 6. Effect of base additives on the kinetics of the reactions between A14 and E13 (4.85 × 10−6 M).
the initially formed ammonium ions F is rate determining.
Imidazolidinones A29−A32 have a reaction center, which is
sterically shielded by the vicinal substituents, and they are less
basic than all pyrrolidines of this study (exception: cationic
base A21, Figure 2). As a consequence, even the initial attack
of imidazolidinones at the highly reactive benzhydrylium ions
E17 and E18 is reversible.
Figure 7 shows time-dependent absorption traces for three
runs of the reaction of A29 with E18 performed under exactly
the same conditions (concentrations, etc.), indicating that the
kinetics of this reaction was not reproducible in the absence of
a base. In the presence of 0.99 mM D1, the kinetics of the
reaction of A29 with E18 became reproducible and a linear
correlation between kobs and [A29] afforded the second-order
rate constant k2 (Table S186, Supporting Information).
Figure 8a illustrates that the less Lewis acidic benzhy-
drylium ion E17 was consumed to only a small extent when
combined with 11 equiv of A29. Different from the
observations in the reaction of A29 with E18, kobs for the
reaction of A29 with E17 did not increase linearly with the
concentration of A29 in the presence of pyridine D1 (0.97
mM, Figure 8b). A concentration of 1.18 mM D2 was also not
sufficient to achieve a linear correlation between kobs and
[A29] (Figure 8c). Clear-cut second-order kinetics were
observed for the reaction of A29 with E17, however, when the
concentration of collidine D2 was further increased (Figure
8d).
The quinone methides E1−E7 are weaker electrophiles
than the benzhydrylium ions E8−E19 and are, therefore,
suitable for characterizing strong nucleophiles. They have
been used as reference electrophiles for determining the
nucleophilic reactivities of A1, A2, A8, and A9. Due to the
low Lewis acidities of the quinone methides, the formation of
the zwitterions F in Scheme 3 will usually be endergonic.
Since the proton transfer, which transforms F into the
thermodynamically more stable tautomer G, cannot proceed
intramolecularly for geometrical reasons, base catalysis will be
needed. Though both A and G may catalyze the
tautomerization, the amines A are the most likely catalysts
because of their high concentration. In line with this
interpretation, the concave curvature of the kobs vs [A2]
Figure 7. Kinetics of the reactions of A29 (1.78 × 10−4 M) with E18
(1.36 × 10−5 M) were not reproducible in the absence of additional
base.
G
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Figure 8. Kinetics of the reaction of A29 with E17 ((1.01−1.33) × 10−5 M) (a) without additive and (b−d) in the presence of the pyridines D1
or D2.
second-order rate constants to be derived for its reactions with
the less electrophilic quinone methides E1 and E2 (Table 2
and ref 11a).
Scheme 3. Mechanism for the Reactions of Amines A with
Quinone Methides E1−E7
Table 2 summarizes that most reactions of the secondary
amines with benzhydrylium ions followed second-order
kinetics in acetonitrile in the absence of any additive.
Footnotes b and c in Table 2 identify those reactions, in
which D2 or D1 were added in order to get second-order
kinetics with rate-determining attack of the amine at the
electrophile.
plot in Figure 9 indicates a reaction order greater than 1 in
amine concentration. Table 2, therefore, does not report
second-order rate constants for the reactions of A2 with the
quinone methides E3 and E4. Earlier investigations using
much higher concentrations of pyrrolidine (A2) allowed
DISCUSSION
■
Correlation Analysis. In previous work, we have
demonstrated that the linear free energy relationship (eq 7)
can be used to describe the rate constants for the reactions of
carbocations and Michael acceptors with π-, σ-, and n-
nucleophiles.1o,15
log k2(20 °C) = sN(N + E)
(7)
Figure 10 shows that the second-order rate constants (log k2)
for the attack of the amines A at the electrophiles E7−E13
correlate linearly with the corresponding E parameters
according to eq 7, whereby the slopes correspond to the
nucleophile-specific parameter sN and the intercepts on the
abscissa (log k2 = 0, that is, N = −E) represent the
nucleophilicity parameters N of the amines A, which are
also listed in Table 2.
The almost parallel correlation lines in Figure 10 (numeri-
cally expressed by similar sN values) illustrate that the relative
nucleophilicities of these pyrrolidines are nearly independent
of the electrophilicity of the reaction partners. Figure 11
shows, however, that the slopes (sN) for the pyrrolidines with
bulky substituents in 2-position are larger (sN = 1.39 for A24;
sN = 0.98 for A25; sN = 1.22 for A27); that is, their reactivities
are more affected by variation of the reaction partner than
Figure 9. Plot of pseudo-first-order rate constants kobs versus the
concentration of pyrrolidine A2 for the reaction of A2 with E4 (2.06
× 10−5 M).
H
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Table 2. Second-Order Rate Constants k2 for the Reactions of the Pyrrolidines and Imidazolidinones A1−A32 with Reference
Electrophiles in Acetonitrile at 20 °C
a
b
c
d
From ref 11a. In the presence of 2,4,6-collidine (D2). In the presence of 2,6-di-tert-butyl-4-methylpyridine (D1). Second-order rate constants
k2 for the reactions of A21 with E14 and E16 were not used for the determination of the N and sN parameters.
those of ordinary pyrrolidines. All imidazolidinones A29−A32
are less nucleophilic than the investigated pyrrolidines and
have sN values around 1, that is, in between ordinary
pyrrolidines and pyrrolidines with bulky substituents.
Comparable to the pKaH scale in Figure 2, Figure 12 shows
that, with the exception of a few pyrrolidines with bulky or
electron-withdrawing substituents, most pyrrolidines are in a
I
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Figure 10. Plot of log k2 versus E of the reactions of pyrrolidines A with reference electrophiles E in acetonitrile at 20 °C.
Figure 11. Plot of log k2 versus E of the reactions of pyrrolidines carrying bulky substituents in the 2-position and of imidazolidinones with
reference electrophiles E in acetonitrile at 20 °C.
narrow range of nucleophilicity, 13 < N < 18, significantly
more nucleophilic than the imidazolidinones (5 < N < 9).
Correlations between nucleophilic reactivities and Brønsted
basicities (so-called Brønsted correlations) have been a main
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Figure 12. Nucleophilicity scale for pyrrolidines and imidazolidinones in acetonitrile (20 °C) ordered from the bottom to the top according to
increasing nucleophilicity parameters N with nucleophile-specific parameters sN given in parentheses; N and sN are defined in eq 7.
topic of Physical Organic Chemistry since the 1930s. It is
well-known that separate log k vs pKaH correlations are
obtained when the nature of the central atom of the
nucleophiles is varied.16 However, in recent work, we reported
K
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Figure 13. Plot of the rate constants (log k2) for the reactions of the amines A1−A32 with the benzhydrylium ion E11 versus the corresponding
Brønsted basicities (pKaH) in acetonitrile. The drawn correlation line is based on the reactivities of pyrrolidines identified by circles (i.e.,
pyrrolidines with bulky substituents and imidazolidinones not included). Rate constants characterized by open symbols were calculated by
applying eq 7 because their direct measurement is not possible due to the lacking thermodynamic driving force for reaction with E11 or their
extremely high rate (A1).
that log k vs pKaH correlations may also be poor when a
variety of structurally diverse N-centered nucleophiles are
considered.11,17
implies that 44% of the differences in basicity are reflected
in the transition states of their reactions with E11.
Figure 13 furthermore shows that the trityl- and
azidodiphenylmethyl-substituted pyrrolidines A24 and A27,
respectively, react 2−3 orders of magnitude more slowly than
ordinary pyrrolidines of comparable basicity. The steric
retardation is much smaller for the Hayashi−Jørgensen
catalyst A25, which is located only by a factor of 33 below
the correlation line. Eventually, the nucleophilicities of
diphenylprolinol (A26) and 2-(triphenylsilyl)pyrrolidine
(A28) are only marginally smaller than expected from their
Brønsted basicities.
The imidazolidinones A29−A32 (represented by open
triangles) react much more slowly than all pyrrolidines studied
in this work. This can only partially be due to their lower
basicity, since they also react more slowly than pyrrolidine
A21, which has a similar basicity. As the basicities of A29−
A32 are similar, their differences in nucleophilicity are
interpreted as steric effects. Obviously, steric retardation is
strongest in the reactions of MacMillan generation 2 catalyst
A30, followed by MacMillan generation 1 catalyst A29. Steric
effects also retard the reactions of the 2-furyl-substituted
imidazolidinones A31 and A32, among which the trans-isomer
is 20 times less reactive because it carries a shielding
substituent on both faces of the five-membered ring.
Because of the wide reactivity range covered by the
pyrrolidines A1−A28 and imidazolidinones A29−A32, there
is not a single reference electrophile for which experimental
rate constants with all amines A1−A32 are available, which
hampers the construction of a Brønsted log k vs pKaH plot.
However, for 25 of the 32 amines, experimental rate constants
for their reactions with E11 have been measured (Table 2).
Therefore, rate constants for the reactions of this electrophile
with the missing seven amines were calculated by applying the
correlation equation (eq 7). The accuracy of the calculated
rate constants is certified by the high quality of the
correlations in Figures 10 and 11.
A very poor correlation between the rate constants for the
reactions of the amines A1−A32 with the electrophiles E11
and their Brønsted basicities is observed when the whole data
set is considered (Figure 13). On the other hand, the drawn
correlation line shows a fair correlation (R2 = 0.92) between
the rate constants of the reactions of the benzhydrylium ion
E11 with the 2-substituted pyrrolidines marked by circles, i.e.,
when pyrrolidines with bulky substituents and imidazolidi-
nones (represented by triangles) are excluded from the
correlation. The Brønsted coefficient of this correlation
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The direct comparison of 2-alkyl effects in Scheme 4 shows
that the Brønsted basicities KaH differ by less than a factor of
units), A21 reacts 4 times faster with E11 than the more basic
CF3-substituted pyrrolidine A14. The relative nucleophilic
reactivities interconvert, however, due to the difference in sN,
and A21 reacts 4 times more slowly than A14 with
electrophile E18 (Table 2).
Figure 17 illustrates that an increasing number of phenyl
substituents in the side chain of 2-methyl-pyrrolidine (A3)
leads to a continuous decrease of basicity (pKaH) with the
largest effect between the benzhydryl (A7) and trityl groups
(A24). In contrast, nucleophilicity (log k) stays constant when
the first phenyl group is introduced (A3 → A6), drops only
slightly with entry of the second phenyl (A6 → A7), but
experiences a dramatic decrease on placement of the third
phenyl group (A7 → A24).
Scheme 4. Comparison of the Brønsted Basicities (pKaH)
and Nucleophilic Reactivities (krel) toward E11 in
Acetonitrile at 20 °C
In previous work, we have demonstrated that enamines,
derived from the trityl-substituted pyrrolidine A24 and the
Hayashi−Jørgensen catalyst A25, are less nucleophilic than
the corresponding enamines derived from the parent
pyrrolidine A2. Since, on the other hand, iminium ions
derived from A24 and A25 were even more electrophilic than
those derived from A2, we concluded that steric effects cannot
explain this behavior and deduced an electron-withdrawing
effect of the trityl and CPh2(OSiMe3) groups through negative
hyperconjugation.2k We now find the same trend in the
pyrrolidines and conclude that the low basicity of the trityl-
substituted pyrrolidine A24 (pKaH 16.79) is predominantly
due to negative hyperconjugation of the trityl group. The
exceptionally high sN value of A24 (sN = 1.39) accounts for
the fact that the reactivity ratio of 2 × 104 for the benzhydryl-
(A7) and the trityl-substituted (A24) pyrrolidines toward E11
increases to 4 × 105 toward the less electrophilic
benzhydrylium ion E8.
The prolinate anion A1 is the strongest Brønsted base as
well as the strongest nucleophile of this series. Though
carboxylate anions are stronger bases than pyrrolidines in
acetonitrile solution (Scheme 6), we assume that the prolinate
anion in acetonitrile is preferentially protonated at nitrogen to
yield a zwitterion in analogy to the situation in DMSO, where
amino acids also exist as zwitterions, though ammonium ions
are generally stronger acids in DMSO than carboxylic
acids.7g,19,20 The energy difference between the zwitterion
and the tautomer without charge separation is smaller in
DMSO than in aqueous solution, however.21 The preference
of the zwitterionic structure of proline in dipolar aprotic
solvent may be due to an intramolecular hydrogen bond, as
4. While a single alkyl group also reduces nucleophilic
reactivity only slightly (A2−A4), introduction of methyl
groups on both faces of the pyrrolidine ring (A5) reduces
nucleophilicity by 2 orders of magnitude (Scheme 4).
Figures 14 and 15 show moderate correlations between the
basicities (pKaH) and nucleophilicities (log k2 vs E11) of these
pyrrolidines with Hammett’s σm and Taft’s σ* parameters.18
While the reason is presently not understood, there is a
good correlation between the basicities of the substituted
pyrrolidines and Taft’s steric parameters Es (Figure 16).
As shown in Scheme 5a, the amino-substituted pyrrolidines
A8−A10 are slightly stronger Brønsted bases than 2-methyl-
pyrrolidine (A3), whereas the hydroxy- and methoxy-
substituted pyrrolidines A12 and A13 are slightly less basic.
Their reactivities toward electrophile E11 differ only slightly,
with the aminomethyl-substituted pyrrolidines somewhat
more nucleophilic than their oxy analogues (Scheme 5a).
Scheme 5b shows that the urea-substituted pyrrolidine A23
has a slightly lower Brønsted basicity and nucleophilic
reactivity than 2-methyl-pyrrolidine (A3), whereas the change
from the urea (A23) to the thiourea derivative A22 reduces
the Brønsted basicity by 2 orders of magnitude and the
nucleophilic reactivity by a factor of 20. While introduction of
the imidazole group in 2-methylpyrrolidine (A3 → A20)
reduces the basicity by three pK units, the nucleophilic
reactivity decreases by only 1 order of magnitude. N-
Butylation of imidazole A20 to give the positively charged
A21 reduces the Brønsted basicity by 5.6 pK units, while the
nucleophilic reactivity decreases only by a factor of 200.
Though the imidazolium derivative A21 is a 31 times weaker
base than the 2-(trifluoromethyl)pyrrolidine A14 (1.5 pK
Figure 14. Hammett plots between (a) pKaH and (b) the rate constants for the reactions of A with E11 and σm of substituents R at the
pyrrolidin-2-ylmethyl position (σm from ref 18).
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Figure 15. Taft plots between (a) pKaH and (b) the rate constants for the reactions of A with E11 and σ* of substituents at the pyrrolidin-2-
ylmethyl position (σ* from ref 18).
Figure 17. Effect of phenyl groups in the side chain of 2-
methylpyrrolidines on Brønsted basicities (black line) and rate
constants (green line) of the reactions of the corresponding
pyrrolidines with E11 (in MeCN, 20 °C).
to a hydrogen bond from the carboxylate group to the
developing ammonium hydrogen during electrophilic attack
(Scheme 6).
Figure 16. Correlation between Brønsted basicities (pKaH) and Taft’s
steric parameters Es of the 2-substituents of pyrrolidines (Es from ref
The imidazolidinones A29−A32 can be regarded as
intramolecular variants of 2-carboxamido-substituted pyrroli-
dines (Scheme 7). Two reasons may account for the fact that
the endocyclic carboxamido group in the imidazolidinones
A29−A32 reduces basicity by 7−8 pK units and nucleophilic
reactivity by 6−9 orders of magnitude more than the exocyclic
18).
suggested by the X-ray structure of 4-hydroxyproline22 (Figure
18). Accordingly, the 79-times higher nucleophilic reactivity of
prolinate A1 relative to 2-methyl-pyrrolidine (A3) may be due
Scheme 5. Comparison of Brønsted Basicities and Relative Rate Constants for the Reactions of 2-Substituted Pyrrolidines
with E11 (MeCN, 20 °C)
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derived from 2-trityl-pyrrolidine are even more reactive than
iminium ions derived from the unsubstituted pyrrolidine, we
concluded that the trityl group reduces the basicity of
pyrrolidine more through an electronic effect than through a
steric effect.2k
Scheme 6. Comparison of the Brønsted Basicity and
Nucleophilicity (krel vs E11) of the Prolinate Anion and Its
Fragments (MeCN, 20 °C)7g,23,24
Figure 13 shows that Brønsted basicities are not a useful
guide for estimating nucleophilic reactivities. Since the steric
demand of a proton is much smaller than that of the reference
electrophiles E1−E19, one can rationalize why pyrrolidines
with bulky substituents in 2-position are much less
nucleophilic than pyrrolidines of similar basicity but smaller
2-substituents. Imidazolidinones are much weaker nucleo-
philes than the acceptor-substituted pyrrolidines with similar
basicity (A14, A21). It is presently not clear whether this
difference is entirely due to steric effects, because all
investigated imidazolidinones have substituents on both
carbons attached to the nucleophilic reaction center, or
whether also electronic effects are involved which only affect
the transition states, but not the products, which electronically
resemble the protonated amines.
Using the newly determined nucleophilicities of pyrrolidines
and imidazolidinones, we now can directly compare their
reactivities with those of the corresponding enamines
generated during the catalytic cycles. Figure 19 shows, for
Figure 18. Single crystal structure of 4-hydroxyproline (CCDC
1101829).22a Crystal structures of the parent proline always include
an additional HCl molecule (CCDC 775988).22b
Scheme 7. Comparison of Brønsted Basicities and
Nucleophilic Reactivities of Proline Amide A16 and the
Imidazolidinones A29−A32 (MeCN, 20 °C)
carboxamido group in A16. The planar arrangement of the
carboxamido group in the imidazolidinones leads to a stronger
hyperconjugative interaction of the nitrogen lone pair of the
NH group with the π*-orbital of the carbonyl group. In
addition, the two nitrogen atoms in A29−A32 are in a
geminal position, and the stabilizing anomeric interactions
between these two nitrogen atoms25 will be weakened by
protonation.
Figure 19. Correlation of the reactivities of enamines PhCHCH
NR2 toward E11 (for A2, A29, and A30 in MeCN and for A24, A25,
and A28 in CH2Cl2, 20 °C)2k,3k,27a vs the corresponding reactivities
of the amines HNR2 (in MeCN, 20 °C).
CONCLUSION
■
In our efforts to pave the way to a rational design of
organocatalytic reactions with secondary amines, we have now
taken a further step. After quantifying the electrophilicities of
common iminium intermediates1l,o,3d,e,j,o,26 and the nucleo-
philicities of typical enamine intermediates,2k,3k,27 we have
now determined the basicities and nucleophilicities of a large
variety of pyrrolidines and imidazolidinones in acetonitrile.
Their pKaH values are significantly higher in acetonitrile
than in aqueous solution, and we have found (Table 1, Figure
2) that the basicities of most pyrrolidines are in the range 16
< pKaH < 20, while the imidazolidinones are significantly less
basic (10 < pKaH < 12). Whereas the pKaH values of 2-alkyl-
and 2-aminoalkyl-substituted pyrrolidines differ by less than
one pK unit from that of the parent pyrrolidine A2, ester
groups as well as the trityl group reduce the basicity by 3 pK
units. Since we had previously reported that iminium ions
example, that the nucleophilicities of the enamines derived
from 2-phenylacetaldehyde and pyrrolidines or imidazolidi-
nones correlate linearly with the nucleophilicities of the
corresponding amine precursors; i.e., substituent variation
affects amine and enamine reactivities in the same way. From
the slope of the correlation in Figure 19, one can see that 66%
of the substituent effects on amine reactivities is reflected by
the enamine reactivities. While pyrrolidines react approx-
imately 2 orders of magnitude faster than the corresponding
enamines derived from 2-phenylacetaldehyde, imidazolidi-
nones have similar nucleophilic reactivities as the correspond-
ing imidazolidinone-derived enamines (Figure 19).
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How was it then possible that MacMillan catalysts were
successfully used for asymmetric alkylations of aldehydes by
preformed carbocations and by SN1-type reactions with
alcohols?28 The reversibility of the attack of imidazolidinones
at carbocations with E < −3 observed in this work (cf. Figures
7 and 8) indicates the underlying reason: Even if the
imidazolidinone catalyst is partially consumed by the addition
to the SN1 substrate, this reaction is reversible, and
retroaddition takes the catalyst and the electrophile back to
the productive organocatalytic cycle, in which the correspond-
ing enamine undergoes an irreversible reaction with the
electrophilic substrate.
(trifluoromethyl)pyrrolidine (A14) and trifluoroacetic acid
than in the analogous reaction with the MacMillan catalyst
A29. A systematic investigation of the catalytic activities of 2-
acceptor-substituted pyrrolidines, therefore, appears promis-
ing.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b11877.
■
S
Procedures for the preparation of A1−A32 and C1H−
C6H, details of the product studies, NMR and IR
spectra of characterized compounds, details of kinetic
experiments, and determinations of equilibrium con-
stants (PDF)
The kinetic and thermodynamic data determined in this
investigation can now be used for optimizing the conditions
for reactions catalyzed by secondary amines. Fine-tuning
requires consideration of the nucleophilicities of the secondary
amines and the electrophilicities of the carbonyl substrates as
well as adjusting the pKa values of the cocatalyzing Brønsted
acids to the pKaH values of the corresponding amines. The low
nucleophilicities of the imidazolidinones (Figure 12) explain,
for example, why they generally do not react with non-
activated carbonyl groups and require the presence of
Brønsted acids, most commonly trifluoroacetic acid, which is
slightly less acidic (pKa 12.7)29 than the protonated
imidazolidinones and, therefore, does not deactivate the
imidazolidinones. On the other hand, most pyrrolidines are
much more nucleophilic than the imidazolidinones and may
react with carbonyl compounds without Brønsted acid
activation.2m,4ay,5h,m,ag,ao In some cases, strong Brønsted
acids30 may even be detrimental because they can deactivate
pyrrolidines by protonation. We did not observe any reaction
when cinnamaldehyde was combined with equimolar amounts
of pyrrolidine and trifluoroacetic acid in acetonitrile at
ambient temperature, for example. The exact role of Brønsted
acid additives depends on the particular combination of
substrates and catalyst, however, because organocatalytic
enamine- or iminium-activated reactions involve several
protonation/deprotonation steps in the catalytic cycle, which
can be rate determining also at later stages of the cycle.2n For
example, so-called “parasitic equilibria”, that is, cyclobutane or
oxazolidine formation in reactions catalyzed by prolinols,
prolinol ethers, or other pyrrolidines, are more easily
overcome or avoided in the presence of appropriate Brønsted
acids.2e,4n As the performance of organocatalytic reactions also
depends on the absolute concentrations of reactants and
additives, NMR spectroscopic methods have recently been
developed to link the rate of amine-catalyzed reactions with
the distribution of the relevant catalytic species. This analytical
approach helps to identify whether acidic or basic additives
lead to maximum catalytic efficiency for a given combination
of reactants and solvents.2r
Crystal structure for 4,4′-((2-tritylpyrrolidin-1-yl)-
methylene)bis(N,N-dimethylaniline) (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
*ofial@lmu.de
*herbert.mayr@cup.lmu.de
ORCID
Biplab Maji: 0000-0001-5034-423X
Armin R. Ofial: 0000-0002-9600-2793
Herbert Mayr: 0000-0003-0768-5199
Present Addresses
†B.M.: Department of Chemical Sciences, Indian Institute of
Science Education and Research Kolkata, Mohanpur-741246,
India.
‡E.M.: Department of Earth and Environmental Sciences,
Columbia University, Palisades, NY 10964, USA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̈
Dedicated to Dr. Klaus Romer on the occasion of his 80th
birthday. We thank Nathalie Hampel for preparing the
reference electrophiles, Dr. Sami Lakhdar for suggestions,
and Dr. Peter Mayer for the X-ray crystal structure analyses.
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