Nucleophilic reactivities of tertiary alkylamines

Article abstract of DOI:10.1002/poc.1707

The kinetics of the reactions of tertiary amines, triethylamine (1a), N-methylpyrrolidine (1b), N-methylpiperidine (1c), and N-methylmorpholine (1d) with benzhydrylium ions (Ar₂CH⁺) have been studied in acetonitrile and dichlorometha

Full text of DOI:10.1002/poc.1707

Research Article
Received: 4 February 2010,
Accepted: 4 March 2010,
Published online in Wiley Online Library: 8 July 2010
(wileyonlinelibrary.com) DOI 10.1002/poc.1707
Nucleophilic reactivities of tertiary alkylaminesy
Johannes Ammera, Mahiuddin Baidyaa, Shinjiro Kobayashia
and Herbert Mayra
*
The kinetics of the reactions of tertiary amines, triethylamine (1a), N-methylpyrrolidine (1b), N-methylpiperidine (1c),
and N-methylmorpholine (1d) with benzhydrylium ions (Ar2CHR) have been studied in acetonitrile and dichlor-
omethane. The benzhydryl cations were generated by laser flash photolysis of quaternary phosphonium and
ammonium tetrafluoroborates. For most reactions, exponential decays of the absorbances of the benzhydryl cations
were observed because the carbocations were generated in the presence of a high excess of the amines (pseudo-
first-order conditions). From the linear plots of kobs versus the amine concentrations, the second-order rate constants k
were obtained, which allowed us to calculate N and s for these amines in CH3CN and CH2Cl2. The linear free energy
relationship log k ¼ s(N R E) was thus used to integrate 1a–d into our comprehensive nucleophilicity scales. Copyright
ß 2010 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper.
Keywords: amines; carbocations; kinetics; linear free energy relationships; organocatalysis
INTRODUCTION
Numerous kinetic investigations have shown that the rate
constants for the reactions of n-, p-, and s-nucleophiles with
Tertiary alkylamines are generally used as Brønsted bases in
organic synthesis.[1–2] On the other hand, many reactions are
known, where tertiary amines act as nucleophilic catalysts.[3–32]
1,4-Diazabicyclo[2.2.2]octane (DABCO, 1e) and quinuclidine (1f),
for example, are common catalysts in Baylis–Hillman reactions[7]
and in cyclopropanations of Michael acceptors.[8] N-
Methylpiperidine (1c) and N-methylmorpholine (1d) have been
reported to function as nucleophilic catalysts in Baylis–Hillman
reactions,[9,10] and N-methylmorpholine (1d) served as a catalyst
for the aziridination of a,b-unsaturated carbonyl compounds.[11–13]
Though acylations are commonly catalyzed by pyridines, in
particular 4-dimethylaminopyridine (DMAP),[14–18] triethylamine
(1a),[19–27] and the cyclic amines 1b[27] and 1c[23] have also been
employed as acylation catalysts. Analogously, the hydrolyses of
esters, imides, and amides are catalyzed by tertiary amines,
including 1d,[28] through a nucleophilic mechanism.[28–30] Nucleo-
philic substitution reactions of aromatic heterocycles have also
been catalyzed by tertiary amines, including 1a and 1c.[31,32]
Because the nucleophilic activities of amines are known
to correlate only poorly with their Brønsted basicities (pKaH),[33–35]
we now set out to include the tertiary amines 1(a–d) in our
comprehensive nucleophilicity scales[36–40] by studying the rates
of their reactions with benzhydrylium ions.[36]
carbocations can be described by Eqn (1),[36–40]
log k ¼ sðN þ EÞ
(1)
where nucleophiles are characterized by two parameters (N, s)
and electrophiles are characterized by one parameter (E). By
employing benzhydrylium ions (2, Table 1)[36] and structurally
related quinone methides[40] as reference electrophiles, it
became possible to compare reactivities of a large number of
nucleophiles in a single scale.[36–40] With this methodology, we
have previously quantified the nucleophilicities of numerous n-,
p-, and s-nucleophiles,[41] including primary and secondary
amines,[42] pyridines,[43] amidines,[44] cinchona alkaloids,[45] as
well as the tertiary alkylamines 1e,f.[46] In this work, we will report
on the nucleophilic reactivities of amines 1a–d.
RESULTS AND DISCUSSION
As the benzhydrylium ions (Ar2CHþ, 2) are colored and their
reactions with the amines 1a–d yield colorless adducts, the
progress of the reactions can be monitored by UV–Vis
spectroscopy. However, formation of quaternary ammonium
salts from 1a–d and the more stabilized benzhydrylium ions
*
Correspondence
to:
H.
Mayr,
Department
Chemie,
Ludwig-
Maximilians-Universita¨t, Butenandtstraße 5-13 (Haus F), 81377 Mu¨nchen,
Germany.
E-mail: Herbert.mayr@cup.uni-muenchen.de
a
J. Ammer, M. Baidya, S. Kobayashi, H. Mayr
Department Chemie, Ludwig-Maximilians-Universita¨t, Butenandtstraße 5-13
(Haus F), 81377 Mu¨nchen, Germany
y
This article is published in Journal of Physical Organic Chemistry as a special
issue on Twelfth European Symposium on Organic Reactivity, edited by Amnon
¸
Stanger, Zvi Rappoport, and Marie-Francoise Ruasse.
J. Phys. Org. Chem. 2010, 23 1029–1035
Copyright ß 2010 John Wiley & Sons, Ltd.

J. AMMER ET AL.
Table 1. Abbreviations and electrophilicity parameters (E) of the reference electrophiles employed in this work.
Ar2CHþ
X
Y
Ea
Ph2CHþ
H
H
CH3
H
H
CH3
CH3
OCH3
OCH3
5.90
4.59
3.63
2.11
0.00
ꢀ1.36
(Ph)(tol)CHþ
(tol)2CHþ
(Ph)(ani)CHþ
(ani)2CHþ
(fur)2CHþ
OCH3
(pfa)2CHþ
(mfa)2CHþ
(dpa)2CHþ
(mor)2CHþ
N(Ph)CH2CF3
N(CH3)CH2CF3
NPh2
N(Ph)CH2CF3
N(CH3)CH2CF3
NPh2
ꢀ3.14
ꢀ3.85
ꢀ4.72
ꢀ5.53
(mpa)2CHþ
(dma)2CHþ
(pyr)2CHþ
(thq)2CHþ
N(Ph)CH3
N(CH3)2
N(CH2)4
N(Ph)CH3
N(CH3)2
N(CH2)4
ꢀ5.89
ꢀ7.02
ꢀ7.69
ꢀ8.22
(ind)2CHþ
ꢀ8.76
[36]
a From Reference
.
(E < ꢀ9 to ꢀ4) is thermodynamically unfavorable. Similar to
previous observations for 1e,f,[46] those benzhydryl cations,
which do combine with the tertiary amines 1a–d, react very
rapidly (k > 5 ꢁ 105 Mꢀ1 sꢀ1 at 20 8C). Conventional UV–Vis
spectroscopy, even in combination with stopped-flow tech-
niques, was thus not suitable for following the rates of these
reactions because they are completed during the mixing time of
the stopped-flow instrument. For this reason, we have studied
the reactions of 1a–d with Ar2CHþ in CH3CN and CH2Cl2 by
laser-flash photolytic techniques (Scheme 1).
precursor can be generated in solution by combining Ar2CHþBF4ꢀ
with the corresponding nucleophile. We have previously applied
this approach to study the nucleophilicities of thiocyanate,[47]
halide,[48] nitrite,[49] and cyanate[50] ions, as well as the tertiary
amines 1e,f.[46] In this work, we will use it to determine the
nucleophilic reactivities of the tertiary amines 1a–d. This
procedure is simple because the quaternary ammonium salts
3-BFꢀ4 which serve as precursors for laser flash photolysis can be
prepared in solution by adding a high excess (>10 equivalents) of
the tertiary amine which is required for the kinetic experiment to
Laser-flash-photolytic generation of benzhydryl cations
In acetonitrile
In polar solvents like acetonitrile, numerous photo-leaving groups
can be employed to generate benzhydryl cations
2 by
photoheterolysis of the respective precursors.[77–79] If the
corresponding benzhydrylium ion is available as a stable
tetrafluoroborate[36] and the nucleophile to be studied can act
as a photo-leaving group, the corresponding benzhydrylium
Scheme 1. Laser-flash-induced heterolytic cleavage of suitable precur-
sors yields benzhydryl cations 2 which combine with the amines 1 to yield
ammonium ions 3
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J. Phys. Org. Chem. 2010, 23 1029–1035

NUCLEOPHILIC REACTIVITIES OF TERTIARY ALKYLAMINES
a 10ꢀ5–10ꢀ4 M solution of the benzhydrylium tetrafluoroborate
2-BFꢀ4 . Due to the low concentration of 2-BFꢀ4 , the concentration
of the tertiary amine remains virtually unchanged. This method
has the further advantage that photoheterolysis of the resulting
precursors only regenerates the benzhydrylium ion and the
tertiary amine.
The choice of photo-leaving group becomes more critical for
less stabilized benzhydryl cations because photoheterolysis gets
less favorable with decreasing cation stability. For the generation
of benzhydryl cations with E > ꢀ2, which cannot readily be
isolated as stable salts, we usually use precursors which are
known to have a high efficiency of photoheterolysis, such as
chlorides (5),[51–53] acetates (6),[54–58] and phosphonium salts
(4).[59–63] The concentrations of Clꢀ, AcOꢀ, and R3P generated by
photolysis, which can be calculated from the absorbances and
known extinction coefficients[51] of the benzhydrylium ions, are
so small that the rate of external return with the photo-leaving
group is usually negligible.
were unsuccessful because the fast combination of benzhydry-
lium ions with the amines was followed by an unknown
subsequent reaction so that the end absorptions were not
constant.
Qualitatively, the thermodynamic stabilities of the quaternary
ammonium salts in CH3CN decrease for a given benzhydrylium ion in
the order DMAP ꢂ quinuclidine > DABCO ꢃ N-methylpyrrolidine >
N-methylpiperidine > N-methylmorpholine > NEt3. In CH2Cl2, the
formation of ammonium salts from benzyhydrylium ions and tertiary
amines is thermodynamically less favorable than in CH3CN.
Kinetics of the reactions of tertiary amines with benzhydryl
cations
The benzhydryl cations were generated by laser flash photolysis
(7 ns pulse, 266 nm, 40–60 mJ/pulse) of suitable precursors (see
above and footnotes in Table 2) in the presence of a high excess
of the amines 1a–d in CH3CN or CH2Cl2 (Scheme 1). The kinetics
of the reactions of the benzhydrylium ions 2 with the tertiary
amines 1a–d were then followed by monitoring the decrease of
the absorbance of Ar2CHþ at lmax. Unlike primary and secondary
amines, tertiary amines react only very slowly with dichlor-
omethane,[69] which allowed us to study their reactivity also in
CH2Cl2 solution.
In dichloromethane
Phosphonium tetrafluoroborates (4-BFꢀ4 ) are particularly inter-
esting precursors for laser flash photolysis, because they allow us
to generate reactive carbocations efficiently in low polarity
solvents such as dichloromethane.[63] Photolyses of neutral
precursors, for example chlorides (5) or acetates (6), on the other
hand, yield only radicals in dichloromethane if the aryl rests have
p-MeO or less electron-donating substituents.[51] An important
reason for the high efficiency of phosphonium salts 4-BFꢀ4 as
precursors in apolar solvents is the fact that they already bear a
positive charge and no net charge is generated during the
separation of the carbocation and the neutral phosphine. A
similar argument could be made for quaternary ammonium salts,
and therefore we were also interested in the laser flash photolysis
of the ammonium salts 3-BFꢀ4 in dichloromethane. As far as we
are aware of, the photoheterolysis of quaternary ammonium
salts[64–66,80] has only been described in more polar solvents.
Photolysis of the quaternary ammonium bromide 3e-Brꢀ with
Ar1¼Ar2¼Ph[67] in CH2Cl2 did not give rise to any absorbance of
the benzhydryl cation (Ph2CHþ). This is not surprising because
the Brꢀ anion undergoes a diffusion-controlled reaction with
Ph2CHþ,[48] and in CH2Cl2, the Brꢀ anion would presumably form
contact ion pairs with the ammonium ions, i.e., it can intercept
the carbocation within the geminate solvent cage. We then
prepared the corresponding ammonium tetrafluoroborate
3e-BFꢀ4 (Ar1¼Ar2¼Ph) from the bromide by salt exchange with
AgBF4 in CH3CN. When we photolyzed 3e-BFꢀ4 (Ar1¼Ar2¼Ph) in
CH2Cl2, we could indeed observe the benzhydryl cation Ph2CHþ
and identify it by its spectrum.
In some cases, where the amines 1a–d form only moderately
stable adducts with the benzhydryl cations, we did not observe
the expected pseudo-first-order kinetics due to an unidentified
side or subsequent reaction on a similar timescale.
In cases, where the combination reactions of the benzhy-
drylium ions with the tertiary amines are fast, the absorbances of
the benzhydrylium ions decrease mono-exponentially (Fig. 1) and
the pseudo-first-order rate constants kobs were obtained by
fitting the decays of the absorbances to the mono-exponential
functions At ¼ A0eꢀk þ C. Plots of kobs versus [amine] are linear
t
obs
and the second-order rate constants k (Table 2) were derived
from the slopes of such plots (Fig. 1).
Figure 2 and the data in Table 2 show that the rate constants of
the reactions of the benzhydrylium ions with the amines increase
with increasing electrophilicity parameter E until the diffusion
limit is reached, i.e., (3–5) ꢁ 109 Mꢀ1 sꢀ1 for 1b–d in acetonitrile.
The fact that the diffusion-controlled rate constants for the
reactions of NEt3 (1a) are 2–3 times smaller than for the cyclic
amines 1b–d can be rationalized by the greater steric demand of
NEt3.
Typically, plots of log k versus E show linear correlations from
which the nucleophile-specific parameters N and s can be
obtained (Eqn (1)). However, Eqn (1) is only valid for rate
constants up to ꢄ2 ꢁ 108 Mꢀ1 sꢀ1 [36]
,
because then the corre-
lation lines start to flatten as the rate constants approach the
diffusion limit, which is also evident from Fig. 2. As a
consequence, the suitable reactivity range to determine N and
s parameters for 1a–d is very narrow, limited by thermodynamic
stability of the combination products on the lower end, and
limited by diffusion control on the upper end. For that reason,
only few rate constants can be used for the determination of N
and s for triethylamine (1a) and N-methylmorpholine (1d) in
acetonitrile, as well as for 1a–d in dichloromethane (Table 2).
Moreover, in acetonitrile, combination reactions of N-phenyl
substituted benzhydrylium ions, particularly (dpa)2CHþ and
(mpa)2CHþ, with nucleophiles are usually faster than one would
predict based on their E parameters.[70] Reactions of 1b–d with
these cations in CH3CN have similar or even higher rate constants
Thermodynamics of the combination reactions
As mentioned above, combinations of the tertiary amines 1a–d
with the highly stabilized benzhydryl cations are thermodyna-
mically unfavorable and their solutions remain colored even
when a high excess of the amines is added. In some cases, partial
combinations occur, and we have previously reported on
photometric determinations of equilibrium constants for the
combination reactions of benzhydrylium ions with the tertiary
amines 1e,f in acetonitrile[46] as well as for tertiary phosphines in
dichloromethane.[68] Attempts to determine equilibrium con-
stants for the combinations of 1a–d with Ar2CHþ in this work
J. Phys. Org. Chem. 2010, 23 1029–1035
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J. AMMER ET AL.
Table 2. Second-order rate constants for the reactions of 1a–d with benzhydrylium ions (Ar2CHþ, 2) in CH3CN and CH2Cl2 at 20 8Ca.
k/Mꢀ1 sꢀ1
NEt3
1a
1b
1c
1d
2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
Ph2CHþb
1.45 ꢁ 109
4.65 ꢁ 109
3.71 ꢁ 109
2.56 ꢁ 109
(Ph)(tol)CHþb
(tol)2CHþb
(Ph)(ani)CHþb
(ani)2CHþb
(fur)2CHþb
(pfa)2CHþ
(mfa)2CHþ
(dpa)2CHþ
(mor)2CHþ
(mpa)2CHþ
(dma)2CHþ
(pyr)2CHþ
(thq)2CHþ
(ind)2CHþ
3.66 ꢁ 109
3.55 ꢁ 109
1.64 ꢁ 109
7.31 ꢁ 108
4.66 ꢁ 108
1.91 ꢁ 108
4.06 ꢁ 109
2.97 ꢁ 109
2.00 ꢁ 109
2.66 ꢁ 109
3.05 ꢁ 109
1.65 ꢁ 109
6.31 ꢁ 108
4.86 ꢁ 108
1.87 ꢁ 108
6.53 ꢁ 107
5.29 ꢁ 107
1.68 ꢁ 109
8.32 ꢁ 108
1.53 ꢁ 108
4.00 ꢁ 107
4.07 ꢁ 107
5.08 ꢁ 106
6.61 ꢁ 106
(1.4 ꢁ 106)c
1.27 ꢁ 109
5.96 ꢁ 108
1.45 ꢁ 108
7.79 ꢁ 107
(3 ꢁ 107)c
8.38 ꢁ 108
2.71 ꢁ 108
1.63 ꢁ 107
4.36 ꢁ 106
5.06 ꢁ 106
1.96 ꢁ 108
2.31 ꢁ 109
9.24 ꢁ 108
3.28 ꢁ 108
3.04 ꢁ 108
6.39 ꢁ 107
8.55 ꢁ 107
1.22 ꢁ 107
7.19 ꢁ 106
7.10 ꢁ 107
(1.4 ꢁ 107)c
d
6.73 ꢁ 105
d
2.08 ꢁ 106
d
a Generated from the corresponding ammonium salts 3-BFꢀ4 , if not mentioned otherwise.
b Generated from 5, 6, or 4-BFꢀ4 in CH3CN, and from 4-BF4ꢀ in CH2Cl2; for details see Supporting Information.
c Fits of the time-dependent absorbances of the benzhydryl cations to an exponential curve are not very good, and these rate
constants have to be considered approximate.
d Reactions do occur when higher concentrations of amines are used, but the reactions are not of pseudo-first order.
than cations with somewhat higher E values (Table 2 and Fig. 2).
This deviation indicates small differential solvent effects on the
reactivities of these electrophiles with the consequence that the
E-parameters of benzhydrylium ions which were derived from
rate constants determined in dichloromethane[36] are not
applicable in CH3CN. Therefore, we did not consider rate
constants measured with (dpa)2CHþ and (mpa)2CHþ in CH3CN
for the determination of the N and s parameters.
Due to these limitations, only two series in Table 2 contain
enough data points to derive the nucleophilicity parameters from
Eqn (1), yielding N ¼ 20.59, s ¼ 0.52 for 1b and N ¼ 18.72, s ¼ 0.52
for 1c (Table 3). Assuming that the slope s ¼ 0.52 also holds for
the other reaction series, nucleophilicity parameters for 1a,d in
CH3CN and 1a–d in CH2Cl2 have been estimated from 1 to 3
reliable rate constants in the supposedly linear range of the
correlations. From the N parameters in Table 3, and from the rate
constants in Table 2, it can be seen that the tertiary amines 1a–d
have almost equal nucleophilicities in CH2Cl2 and in CH3CN. The
nucleophilicity of DMAP also differs by less than one order of
magnitude in these solvents.[43] However, due to the paucity of
data, the N and s parameters published in this work have to be
considered approximate.
We can now compare the nucleophilic reactivities of 1a–d with
those of other N- and P-nucleophiles. Because reactions of the
tertiary alkylamines 1a–f with electrophiles which would react
with second-order rate constants of k ¼ 1 Mꢀ1 sꢀ1 are thermo-
dynamically unfavorable, N values (which reflect the relative
reactivities toward such electrophiles) are less suitable for
comparing these nucleophiles than relative reactivities toward an
electrophile which does combine with these compounds.
Therefore, we have plotted log k of the combination reactions
with (dma)2CHþ in Fig. 3.
Figure 1. Exponential decay of the absorbance DA at 613 nm and linear
correlation of the pseudo-first-order rate constants kobs versus [1c] for the
reaction of (mpa)2CHþ with 1c in CH3CN at 20 8C
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NUCLEOPHILIC REACTIVITIES OF TERTIARY ALKYLAMINES
10
9
8
7
6
5
-10
-8
-6
-4
-2
0
2
4
6
E
Figure 2. Correlation of log k for the reactions of triethylamine (1a, ^), N-methylpyrrolidine (1b, ~), and N-methylpiperidine (1c, &) with
benzhydrylium ions in CH3CN at 20 8C with electrophilicity parameters E—rate constants for (mpa)2CHþ and (dpa)2CHþ (open symbols) were not
used for the determination of the N and s parameters. N-Methylmorpholine (1d) is not shown because the data points overlap with the line for 1a
As discussed previously,[46] the higher reactivity of DABCO (1e)
compared with quinuclidine (1f) is due to the fact that both rate
constants are close to diffusion control, and attack at the
diazacompound 1e is favored statistically. The monocyclic
compounds 1b and 1c are one (1b) and two orders of magnitude
less reactive. Remarkably, the five-membered ring compound 1b
is almost one order of magnitude more reactive than 1c, while
the corresponding secondary amines pyrrolidine and piperidine
show very similar reactivities toward (dma)2CHþ in acetonitrile
(Fig. 3) as well as in methanol and water.[42,71,72] The increase of
steric hindrance, which may explain the reduction of reactivity
from the bicyclic compounds 1e,f to the monocyclic compounds
1b,c may also account for the further reduction of nucleophilicity
from 1b,c to triethylamine (1a) which is so severe that the rate
constant for the reaction of NEt3 with (dma)2CHþ had to be
calculated by Eqn (1) because this reaction is highly reversible
and cannot be directly measured. An analogous effect was found
in the series of secondary amines, as shown by the comparison of
piperidine, pyrrolidine, and diethylamine on the left side of Fig. 3.
Introduction of an oxygen in N-methylpiperidine also reduces the
nucleophilicity, and N-methylmorpholine (1d) is calculated to
react one order of magnitude more slowly than 1c; again, the rate
constant for the reaction (dma)2CHþ þ 1d could not be measured
N
log k
8.26
8.07
N
1e
1f
8
7
6
5
N
H
N
7.02b
6.97b
N
1b
1c
H
N
7.09
6.15
H
N
6.39b
5.90b
N
O
DBN
5.79b
PBu3 (CH2Cl2)
5.89
HNEt2
N
5.75
DBU
(5.24)c
(5.08)c
NEt3
N
1a
1d
5.36
Table 3. Reactivity parameters N of amines 1a–d in CH3CN
and CH2Cl2 (with s ¼ 0.52)
PPh3 (CH2Cl2)
4.76
N
DMAP
O
Amines
N (CH3CN)
N (CH2Cl2)
Figure 3. log k for reactions of (dma)2CHþ (E ¼ ꢀ7.02) with different N
and P nucleophiles in CH3CNa,b,c aRate constants for 1e,f,[46] DMAP,[43]
.
1a
1b
1c
1d
17.1a
20.59
18.72
16.8a
17.3a
20.6a
18.9a
16.5a
DBU,[44] and the phosphines[68] were reported previously; rate constants
for 1b,c from this work.bRate constants of reactions of secondary amines
and DBN with (dma)2CHþ have not been measured and were calculated
from Eqn (1) using N and s parameters from References [42,44].c1a and 1d
do not react with (dma)2CHþ, and rate constants for these reactions were
calculated from Eqn (1)
a Estimated using s ¼ 0.52.
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J. AMMER ET AL.
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Figure 4. Correlation of log k for reactions of (dma)2CHþ (E ¼ ꢀ7.02) in
CH3CN with different N-nucleophiles and their pKaH values in CH3CN[73–76]
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stronger
base
than
N-methylpyrrolidine
(1b)
and
N-methylpiperidine (1c),[74] is the weakest nucleophile of the
three. In subsequent work, it will be shown how the N and s
parameters reported in this work can be used to rationalize the
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SUPPORTING INFORMATION
Detailed kinetic data for reactions of 1a–d with benzhydrylium
ions are available with the online version of the paper.
Acknowledgements
[41] For a comprehensive data base for nucleophilicity parameters, see:
www.cup.lmu.de/oc/mayr/DBintro.html
The authors thank Nathalie Hampel for technical assistance and
the Deutsche Forschungsgemeinschaft (Ma673/21-3) for financial
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