Nucleophilic reactivities of pyrroles

Article abstract of DOI:10.1002/ejoc.200800092

The second-order rate constants of the reactions of alkyl-substituted pyrroles with a series of benzhydrylium ions were determined in acetonitrile, and the reaction products were fully characterized by NMR spectroscopy and mass spectrometry. The formation of the σ adducts is the rate-limiting step of these reactions. Because the second-order rate constants correlate linearly with the electrophilicity parameters of the benzhydrylium ions, the determination of the nucleophilicity parameters N and s according to the linear free energy relationship log k₂ (20 °C) = s(N + E) was achieved. With these findings, a direct comparison of the nucleophilic reactivities of these π-excessive heterocycles with other nucleophiles became possible, and the pyrroles were integrated into the comprehensive scale of nucleophilicity, covering a range of 8-9 orders of magnitude from N-(triisopropylsilyl)-pyrrole (N = 3.12), the weakest nucleophile of this series, to kryptopyrrole (3-ethyl-2,4-dimethylpyrrole, N = 11.63). Thus, highly reactive pyrroles show similar nucleophilic reactivities as enamines, whereas those of less-reactive pyrroles are comparable to allylsilanes or indoles. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800092

FULL PAPER
DOI: 10.1002/ejoc.200800092
Nucleophilic Reactivities of Pyrroles
Tobias A. Nigst,[a] Martin Westermaier,[a] Armin R. Ofial,[a] and Herbert Mayr*[a]
Dedicated to Professor Gernot Boche on the occasion of his 70th birthday
Keywords: Nitrogen heterocycles / Carbocations / Kinetics / Electrophilic substitution / Linear free energy relationships
The second-order rate constants of the reactions of alkyl-sub-
stituted pyrroles with a series of benzhydrylium ions were
determined in acetonitrile, and the reaction products were
fully characterized by NMR spectroscopy and mass spec-
trometry. The formation of the σ adducts is the rate-limiting
tivities of these π-excessive heterocycles with other nucleo-
philes became possible, and the pyrroles were integrated
into the comprehensive scale of nucleophilicity, covering a
range of 8–9 orders of magnitude from N-(triisopropylsilyl)-
pyrrole (N = 3.12), the weakest nucleophile of this series, to
step of these reactions. Because the second-order rate con- kryptopyrrole (3-ethyl-2,4-dimethylpyrrole, N = 11.63). Thus,
stants correlate linearly with the electrophilicity parameters
of the benzhydrylium ions, the determination of the nucleo-
philicity parameters N and s according to the linear free en-
ergy relationship log k2 (20 °C) = s(N + E) was achieved. With
these findings, a direct comparison of the nucleophilic reac-
highly reactive pyrroles show similar nucleophilic reactivities
as enamines, whereas those of less-reactive pyrroles are
comparable to allylsilanes or indoles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
of SN1 reactions of the side chain of the corresponding ar-
enes.[4]
Introduction
Pyrrole and its derivatives are biochemically important
compounds and can be found as substructures in many nat-
ural products, for example, heme, chlorophyll, and the pyr-
role alkaloids.[1] Electrophilic substitution of pyrroles,
which comprise electron-rich π-systems, have been investi-
gated intensively.[2] In 1957, Treibs and Fritz derived a qual-
itative reactivity scale for alkyl-substituted pyrroles from
their reactivities towards diazonium salts of variable elec-
trophilicity.[3] The most comprehensive quantitative com-
parison of the reactivities of arenes and heteroarenes has
However, σ+
parameters have only been determined
arene
for the parent pyrrole and N-methylpyrrole. As knowledge
of the nucleophilic reactivities of pyrroles is crucial for their
well-directed use in synthesis,[5] particularly as nucleophiles
in organocatalysis cycles (iminium catalysis),[6] we set out
to obtain quantitative information on the nucleophilicities
of alkyl-substituted pyrroles (Figure 1).
been based on the σ+
constants, which are defined by
arene
the Hammett–Brown relationship [Equation (1)].[2e,4]
log k/k0 = ρσ+
(1)
arene
The σ+arene constants (equivalent to σp+ or σm in the case
of monosubstituted benzenes) are a measure for the relative
reactivities of one position of an arene or heteroarene in
relation to one position of benzene. They were typically de-
rived by competition experiments, where an electrophile was
allowed to select between a pair of arenes or from the rates
Figure 1. Structures of pyrroles 1–7.
We previously reported that the reactions of carbocations
with π systems follow Equation (2) where electrophiles are
characterized by one parameter (electrophilicity E) and nu-
cleophiles are characterized by two parameters (nucleophi-
licity N and slope s).[7] Recently, it was demonstrated that
Equation (2) can also be employed for SN2 reactions if an
additional, electrophile-specific parameter sE is included.[8]
[a] Department Chemie und Biochemie, Ludwig-Maximilians-Uni-
versität München
Butenandtstrasse 5-13 (Haus F), 81377 München, Germany
Fax: +49-89-218077717
E-mail: herbert.mayr@cup.uni-muenchen.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 2369–2374
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T. A. Nigst, M. Westermaier, A. R. Ofial, H. Mayr
FULL PAPER
log k2 (20 °C) = s(N + E)
(2)
–7.02] because it is readily available and reacts fast with
–
most of the pyrroles 3–6. When (dma)2CH+BF4 (8e-BF4)
The reactivity parameters N and s of N-methylpyrrole (2, was combined with pyrroles 3–6 in acetonitrile at room
N = 5.85, s = 1.03)[7b,9] and N-(triisopropylsilyl)pyrrole (7, temperature, the resulting NMR spectra indicated the for-
N = 3.12, s = 0.93)[10] were already determined in dichloro- mation of complex product mixtures. Reactions proceeded
methane solution, and the N parameter of the parent pyr- smoothly, however, with selective formation of 9–11, when
role (1, N = 4.63) was estimated.[10] We have now studied solutions of 8e-BF4 in acetonitrile were added dropwise to
the reactions of four alkyl-substituted pyrroles 3–6 with a vigorously stirred solutions of the corresponding pyrroles
series of benzhydrylium ions 8 (for structures see Table 1) (2 equiv.) in acetonitrile at –15 °C. Compound 12 was syn-
in acetonitrile solution and used the kinetic data to deter- thesized by dropping a solution of kryptopyrrole (6) into a
mine the N and s parameters of these pyrroles.
cooled solution (–15 °C) of 8e-BF4 until the blue color of
carbocation 8e vanished (Scheme 1).
Table 1. List of benzhydrylium ions Ar2CH+ (8) used in this study
as reference electrophiles.
Scheme 1. Products of the reactions of pyrroles 3–6 with 8e-BF4 in
CH3CN at –15 °C.
Reaction products 9–12 are highly sensitive towards oxi-
dants, light, and heating; they usually turned into pink oils
within several minutes. The NMR spectra of these oils,
however, only show trace amounts of impurities and indi-
cate the structures of 9–12 (for details see the Supporting
Information). The products of the reactions of pyrroles 1,
2, and 7 with benzhydrylium ions 8 were characterized pre-
viously.[9,10]
Whereas pyrroles 3, 4, and 6 have only one site for elec-
trophilic attack, pyrrole 5 may, in principle, be attacked at
C-3 and C-5. From the NMR spectra we can derive that
regioselective substitution of 5-H took place. The proton of
the -CHAr2 moiety absorbs as a singlet at δ = 5.13–
5.16 ppm when it is attached to the 3-position of pyrrole
(in compounds 9 and 10) and at δ = 5.33–5.36 ppm when
it is located in the 2-position of the pyrrole ring (in com-
pounds 11 and 12). In the 13C NMR spectra, the benzhy-
dryl -CHAr2 carbon atom of 9–12 absorbs at δ = 45.1–
46.5 ppm (Table 2).
–
[a] Counterion: BF4 . [b] Electrophilicity parameters E are from
ref.[7b]
Table 2. NMR chemical shifts of the CHAr2 group of 9–12 (in
CDCl3).
Compound
δH / ppm
δC / ppm
Results and Discussion
9
5.13
5.16
5.33
5.36
45.1
45.3
46.5
45.2
Product Characterization
10
11
12
Product studies were performed with the 4,4Ј-bis(di-
methylamino)benzhydrylium ion [(dma)2CH+, 8e, E =
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Nucleophilic Reactivities of Pyrroles
Kinetics of the Reactions of Pyrroles with Benzhydrylium
Ions
Table 3. Second-order rate constants k2 for the reactions of pyrroles
3–6 with benzhydrylium ions 8 in CH3CN at 20 °C and resulting
N and s parameters.
The kinetics of the reactions of pyrroles 3–6 with benzhy-
drylium ions 8 were monitored by UV/Vis spectroscopy at
20 °C by using the previously described methods.[11] Pyr-
roles 3–6 were used in high excess (usually Ͼ10 equiv.) to
keep their concentrations almost constant throughout the
reactions. Exponential decay of the absorbances of benzhy-
drylium ions 8 was observed for all reactions and linear
correlations between the observed first-order rate constants
and the pyrrole concentrations were obtained as demon-
strated in Figure 2 for the combination of 1,2,5-trimethyl-
pyrrole (4) with 8c.
Pyrrole
N
s
Ar2CH+
k2 / –1 s–1
3
8.01
0.96
(pyr)2CH+ (8d)
(mpa)2CH+ (8f)
(mor)2CH+ (8g)
(dpa)2CH+ (8h)
(mfa)2CH+ (8i)
(ind)2CH+ (8c)
(pyr)2CH+ (8d)
(mpa)2CH+ (8f)
(mor)2CH+ (8g)
(dpa)2CH+ (8h)
(lil)2CH+ (8a)
1.40
2.19ϫ102
2.52ϫ102
3.87ϫ104[a]
7.32ϫ103
1.05
4
5
8.69
1.07
0.91
7.74
1.59ϫ103
1.72ϫ103
1.15ϫ105[a]
4.29
10.67
(jul)2CH+ (8b)
(ind)2CH+ (8c)
(pyr)2CH+ (8d)
(mpa)2CH+ (8f)
(mor)2CH+ (8g)
(lil)2CH+ (8a)
1.26ϫ101
4.97ϫ101
4.45ϫ102
2.47ϫ104
4.65ϫ104
4.00ϫ101
4.51ϫ102
3.83ϫ103
4.74ϫ105
4.48ϫ105
6
11.63
0.95
(ind)2CH+ (8c)
(pyr)2CH+ (8d)
(mpa)2CH+ (8f)
(mor)2CH+ (8g)
[a] The k2 values for 8h deviates significantly from the linear corre-
lations of log k2 with E and were not used for the determination
of N and s.
the weak base N-methylmorpholine,[13] kinetics were ob-
served that deviated from a first-order behavior. The evalu-
ation of the first half life of these reactions resulted in k2 =
1ϫ102 –1 s–1. When the same reactions were performed in
acetonitrile solution, perfect first-order kinetics were ob-
tained and the resulting k2 value is approximately 20 times
larger than that in dichloromethane (see Table 3). For the
analogous reactions of indoles with benzhydrylium ions, the
Figure 2. Exponential decay of the absorbance at 625 nm during
the reaction of 4 (6.48ϫ10–4 ) with 8c (1.05ϫ10–5 ). The corre-
lation of the first-order rate constants kobs with the concentrations
of 4 (in the insert) is linear with a slope corresponding to the sec-
ond-order rate constant k2.
The second-order rate constants of the reactions of pyr- reactivity increases only by a factor of 3 to 5 when changing
roles 3–6 with benzhydrylium ions 8 in CH3CN are listed from dichloromethane to acetonitrile solution.[14]
in Table 3.
When the logarithms of the second-order rate constants
When the reaction of 2,4-dimethylpyrrole (5) with (lil)2- k2 (as listed in Table 3) and the previously reported rate
CH+ (8a) was carried out in the presence of variable con- constants for the analogous reactions of N-methylpyrrole
centrations of 1,4-diazabicyclooctane (DABCO), the con- (2) are plotted against the electrophilicity parameters E of
sumption of 8a remained almost unaffected, which indi- benzhydrylium ions 8, linear correlations are obtained (Fig-
cates that the formation of the σ complex is rate limiting. ure 3) that allow us to evaluate the N and s parameters ac-
It was previously shown that the equilibrium constant for cording to Equation (2).
adduct formation from DABCO and (lil)2CH+ (8a) is so
small that at low concentrations coordination of these two relative reactivities of the pyrroles are almost independent
substrates does not occur.[12]
of the nature of the reaction partners. If a slope of 1.0 is
All correlation lines have slopes close to 1, that is, the
For the reaction of 2,5-dimethylpyrrole (3) with (dpa)2- also assumed for the parent pyrrole (1), one can calculate N
CH+ (8h), a pseudo-first-order rate law was observed when = 4.63 for the unsubstituted pyrrole (1) from the previously
more than 80 equiv. of 3 was employed. With less than published rate constant (k2 = 31.2 –1 s–1) for its reaction
80 equiv. of 3, a pseudo-first-order behavior was only with (pfa)2CH+ (8j) in dichloromethane.[10] With s = 1.0,
obeyed during the first half life of the reaction with 8h. the range from N = 4.63 (1) to N = 11.63 (6) corresponds
Similar deviations from an ideal first-order rate law were to an increase in reactivity by a factor of 10 million by the
observed when less than 40 equiv. of 1,2,5-trimethylpyrrole three alkyl groups in 6, which corresponds to relative reac-
(4) was combined with (pyr)CH+ (8d).
tion times of 1 min to 20 years!
When 1,2,5-trimethylpyrrole (4) was treated with (mpa)2-
When we plot the N values of pyrroles 3–6 against the
CH+ (8f) in dichloromethane, we obtained complex kinet- corresponding pKaH values, a linear correlation is observed
ics, and even after the addition of an equimolar amount of (Figure 4).
Eur. J. Org. Chem. 2008, 2369–2374
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T. A. Nigst, M. Westermaier, A. R. Ofial, H. Mayr
FULL PAPER
Reactions of Pyrroles with Other Electrophiles
In 1977, Butler, Pogorzelec, and Shepherd reported rate
constants for the reactions of pyrroles 1–6 with a variety
of p-substituted arenediazonium ions 13 in acidic aqueous
solution (Scheme 2).[2g]
Scheme 2. Reactions of pyrroles 1–6 with differently substituted ar-
enediazonium salts 13.
We previously derived electrophilicity parameters E of
arenediazonium ions from the rates of their reactions with
various nucleophiles in acetonitrile.[16] Because Zollinger[17]
and Matsui[18] found azo couplings to be only 2–3 times
faster in water than in acetonitrile, Equation (2) allows us
to calculate rate constants for the reactions of pyrroles with
13a (X = OMe), 13b (X = H), and 13c (X = NO2), which
are directly comparable to the rate constants reported by
Butler (Table 4).
Figure 3. Correlation of the rate constants [log k2 (20 °C) in
CH3CN] for the reactions of 2–6 with benzhydrylium ions 8 in
relation to their electrophilicity parameters E; for N-methylpyrrole
(2), the k2 values refer to reactions in CH2Cl2 from ref.[7b]
Although calculated and experimental data for the azo
couplings with pyrroles 3–6 agree remarkably well (within
a factor of 2–60), the reported rate constants for the reac-
tions with pyrrole (1) and N-methylpyrrole (2) are 170–
16000 times larger than the calculated values. In view of the
approximate nature of Equation (2) we do not want to draw
definite conclusions from these deviations. However, it is at
least surprising that the decrease in basicity (Table 4) from
3 and 4 to 1 and 2, which results in a reduced reactivity
towards benzhydrylium ions, is not accompanied by a lower
reactivity towards diazonium salts. One may speculate
whether in these cases an initial Diels–Alder reaction with
subsequent ring-opening (Scheme 3) is responsible for the
unexpected high reactivity.[19,20]
Figure 4. Correlation of the nucleophilicity parameters N of pyr-
roles 3–6 with the corresponding pKaH values in water (taken from
ref.[15]).
The slope of the line in Figure 4 is equivalent to the
Brønsted parameter as the average s parameter of pyrroles
equals 1. We can thus conclude that 71% of the changes of
basicities of pyrroles are found as changes of nucleophilic-
ity.
Scheme 3. Possible Diels–Alder reaction between diazonium ions
and pyrrole.
Table 4. Comparison of the rate constants for the reactions of pyrroles 1–6 with arenediazonium salts 13a–c determined by Butler[2g] and
calculated by log k = s (N + E) [Equation (2)].
[a]
Pyrrole
N (s)
pKaH
13a (X = OMe, E = –8.4)[b]
13b (X = H, E = –7.2)[b]
k / –1 s–1[c] kcalcd. / –1 s–1[d]
13c (X = NO2, E = –5.1)[b]
k / –1 s–1[c]
kcalcd. / –1 s–1[d]
k / –1 s–1[c]
kcalcd. / –1 s–1[d]
1
2
3
4
5
6
4.63 (1.00)
5.85 (1.03)
8.01 (0.96)
8.69 (1.07)
10.67 (0.91)
11.63 (0.95)
–3.80
–2.90
–1.07
–0.49
2.55
2.8
10.9
9.8
1.7ϫ10–4
2.4ϫ10–3
4.2ϫ10–1
2.0
6.8
25.2
32.5
2.7ϫ10–3
220
3.4ϫ10–1
5.9
4.1ϫ10–2
6.0
1.00ϫ103
[e]
–
6.2ϫ102
6.9ϫ103
1.2ϫ105
1.6ϫ106
11.8
24.4
3.9ϫ101
1.4ϫ103
1.6ϫ104
1.60ϫ103
6.80ϫ103
3.05ϫ104
1.2ϫ102
1.2ϫ103
1.34ϫ104
1.77ϫ105
–
[e]
[e]
3.75
–
[a] pKaH values in water from ref.[15] [b] Electrophilicity parameters E from ref.[16] [c] Second-order rate constants at 25 °C from ref.[2g]
[d] Calculated rate constants by using Equation (2) refer to 20 °C. [e] Not determined.
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Nucleophilic Reactivities of Pyrroles
For details and characterization of the products see the Supporting
Information.
Conclusions
Alkyl groups were found to have an enormous activating
effect on the nucleophilicities of pyrroles. Whereas parent
compound 1 has a nucleophilicity comparable to that of
silylated enol ethers, allylsilanes, and indoles, 2,3,4-trialkyl-
ated pyrrole 6 is 107 times more reactive and possesses a
nucleophilicity comparable to enamines, ketene acetals, and
pyridines (Figure 5). With the N and s parameters deter-
mined in this work, it becomes possible to make predictions
of absolute rate constants for reactions of pyrroles with
Kinetics: The kinetics of the reactions of the benzhydrylium ions
with the pyrroles were followed by UV/Vis spectroscopy by using
work stations similar to that described previously.[11]
For slow reactions (τ1/2 Ͼ 10 s), the UV/Vis spectra were collected
at different times by a J&M TIDAS diode array spectrophotometer
that was connected to a Hellma 661.060-UV quartz Suprasil im-
mersion probe (5 mm light path) through fiber optic cables with
standard SMA connectors. All kinetic measurements were made in
Schlenk glassware under exclusion of moisture. The temperature of
electrophiles of known E parameters. Strong deviations be- the solutions during the kinetic studies was maintained to within
Ϯ0.2 °C by using circulating bath cryostats and monitored with
thermocouple probes that were inserted into the reaction mixture.
tween observed and calculated rate constants are discussed
as indicators for a change in mechanism.
A stopped-flow spectrophotometer system (Applied Photophysics
SX.18MV-R) was used for the investigation of rapid reactions of
benzhydrylium ions with nucleophiles (τ1/2 Ͻ 10 s). The kinetic runs
were initiated by mixing equal volumes of acetonitrile solutions of
the pyrroles and the benzhydrylium salts. Concentrations and rate
constants for the individual kinetic experiments for the reactions
of pyrroles with benzhydryl cations are given in the Supporting
Information.
Supporting Information (see footnote on the first page of this arti-
cle): Preparative procedures, product characterization, and details
of the individual runs of the kinetic experiments are available.
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft (Ma
673/21-2) and the Fonds der Chemischen Industrie is gratefully ac-
knowledged.
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Figure 5. Comparison of the nucleophilicities of pyrroles with those
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Experimental Section
General Section: Benzhydrylium tetrafluoroborates 8-BF4 (see
Table 1) were synthesized by literature procedures.[7b] 2,5-Di-
methylpyrrole (3), 1,2,5-trimethylpyrrole (4), 2,4-dimethylpyrrole
(5), 3-ethyl-2,4-dimethylpyrrole (6), 1,4-diazabicyclo[2.2.2]octane
(DABCO), and N-methylmorpholine were purchased and purified
1
by distillation or recrystallization prior to use. H (300 MHz) and
13C NMR (75.5 MHz) spectra were measured with a Bruker ARX
300 instrument. Mass spectra were recorded with a MAT 95 Q
instrument.
Reactions of Pyrroles 3–5 with Benzhydrylium Salt 8e-BF4: A solu-
tion of the benzhydrylium salt (0.14 g, 0.40 mmol) in acetonitrile
(100 mL) was added dropwise to a stirred solution of the appropri-
ate freshly distilled pyrrole (0.80 mmol) in acetonitrile (20 mL) at
–15 °C. The solution was washed with ice water, dried, filtered, and
the solvents evaporated in vacuo.
[3] A. Treibs, G. Fritz, Justus Liebigs Ann. Chem. 1958, 611, 162–
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Substituted pyrrole 12 was obtained by adding an acetonitrile solu-
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BF4 (0.14 g, 0.40 mmol) in acetonitrile (50 mL) at –15 °C. After
fading of the blue color, the solution was washed with ice water,
dried, filtered, and the solvents evaporated in vacuo.
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Analysis of Chemical Data, Plenum, New York, 1988; e) R.
Eur. J. Org. Chem. 2008, 2369–2374
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T. A. Nigst, M. Westermaier, A. R. Ofial, H. Mayr
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Received: January 25, 2008
Published Online: March 5, 2008
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