Nucleophilic reactivities of hydrazines and amines: The futile search for the α-effect in hydrazine reactivities

Article abstract of DOI:10.1021/jo301497g

The kinetics of the reactions of amines, hydrazines, hydrazides, and hydroxylamines with benzhydrylium ions and quinone methides were studied in acetonitrile and water by UV-vis spectroscopy, using conventional spectrometers and stopped-flow and laser-flash techniques. From the second-order rate constants k₂ of these reactions, the nucleophilicity parameters N and s_N were determined according to the linear free energy relationship log k₂ = s_N(N + E). While methyl groups increase the reactivities of the α-position of hydrazines, they decrease the reactivities of the β-position. Despite the 10² times lower reactivities of amines and hydrazines in water than in acetonitrile, the relative reactivities of differently substituted amines and hydrazines are almost identical in the two solvents. In both solvents hydrazine has a reactivity similar to that of methylamine. This observation implies that replacement of one hydrogen in ammonia by Me increases the nucleophilicity more than introduction of an amino group, if one takes into account that hydrazine has two reactive centers. Plots of log k₂ versus the corresponding equilibrium constants (log K) or Bronsted basicities (pKaH) do not show enhanced nucleophilicities (α-effect) for either hydrazines or hydroxylamine relative to alkylamines.

Full text of DOI:10.1021/jo301497g

Article
pubs.acs.org/joc
Nucleophilic Reactivities of Hydrazines and Amines: The Futile
Search for the α‑Effect in Hydrazine Reactivities
Tobias A. Nigst, Anna Antipova, and Herbert Mayr*
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse 5-13 (Haus F), 81377 Munchen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: The kinetics of the reactions of amines, hydrazines, hydrazides, and
hydroxylamines with benzhydrylium ions and quinone methides were studied in
acetonitrile and water by UV−vis spectroscopy, using conventional spectrometers
and stopped-flow and laser-flash techniques. From the second-order rate constants
k2 of these reactions, the nucleophilicity parameters N and sN were determined
according to the linear free energy relationship log k2 = sN(N + E). While methyl
groups increase the reactivities of the α-position of hydrazines, they decrease the
reactivities of the β-position. Despite the 102 times lower reactivities of amines and
hydrazines in water than in acetonitrile, the relative reactivities of differently
substituted amines and hydrazines are almost identical in the two solvents. In both
solvents hydrazine has a reactivity similar to that of methylamine. This observation
implies that replacement of one hydrogen in ammonia by Me increases the
nucleophilicity more than introduction of an amino group, if one takes into account that hydrazine has two reactive centers. Plots
of log k2 versus the corresponding equilibrium constants (log K) or Brønsted basicities (pKaH) do not show enhanced
nucleophilicities (α-effect) for either hydrazines or hydroxylamine relative to alkylamines.
transition state, have been claimed to be associated with large
α-effects.5,6i,l,o Fina and Edwards emphasized, however, that the
magnitude of βnuc can only be related to the α-effect when
similar substrates are compared.5c Buncel, Um, and co-workers
concluded that the magnitude of the α-effect strongly depends
on the nature of the solvent system.5a,6e,i
Several theories on the origin of the α-effect have emerged,
which include the destabilization of the ground state by
electron repulsions, the stabilization of the transition state,
thermodynamic stabilization of the products, and solvent
effects.5 In order to properly elucidate the influence of the
product stabilities, Ren and Yamataka proposed to compare the
reaction rates with the equilibrium constants for the reactions
under consideration rather than with the corresponding
Brønsted basicities.7
In recent years, a renewed interest in the topic arose with the
newly established mass-spectrometric techniques8 and the
progress in quantum chemical methods,7,9 which reveal the
intrinsic reactivities of the unsolvated α-effect nucleophiles.
However, experimental studies in the gas-phase also showed
that the α-effect depends on the system investigated. For
example, an α-effect was found for the nucleophilic substitution
reactions of the hydroperoxide anion with methyl fluoride,
anisoles, and dimethyl methylphosphonate,8a,c but not for its
reactions with methyl formate and alkyl chlorides.8b,d
INTRODUCTION
■
In 1962, Pearson and Edwards created the term α-effect to
account for the enhanced reactivity of nucleophiles, which bear
an unshared pair of electrons at the atom adjacent to the
nucleophilic center.1 This definition was adopted by the 1979
version of the IUPAC Glossary of Terms used in Physical
Organic Chemistry and exemplified by the higher nucleophil-
icity of HOO− compared to that of HO−.2a Because of the
problem in specifying a reference nucleophile with which the α-
effect nucleophile should be compared, Hoz and Buncel
defined the α-effect as the positive deviation from a Brønsted
plot.3 This definition has been accepted by the 1994 version of
the IUPAC glossary.2b Um, Im, and Buncel have later
introduced the additional criterion that the α-effect nucleo-
philes and the reference nucleophiles should react by the same
mechanisms.4 They pointed out that the classical assessment of
the α-effect fails for reactions of HOO− with substituted phenyl
methanesulfonates, because the mechanisms differ from those
of the corresponding reactions with HO−.
The α-effect, which has been investigated for various
reactions of nucleophiles including acylations, Michael
additions, SN2 reactions, and nucleophilic aromatic substitu-
tions has been the topic of several reviews,3,5 but its origin and
extent are still discussed controversially.5,6 Over the years,
several factors have been specified, which are supposed to
contribute to the magnitude of the α-effect. The α-effect was
claimed to depend on the hybridization of the reaction center
of the electrophilic reaction partner5 and to increase in the
order sp3 < sp2 < sp. Large slopes βnuc in Brønsted correlations,
which are attributed to a large extent of bond formation in the
Ren and Yamataka investigated the activation energies of SN2
reactions of alkyl halides and of E2 reactions of ethyl chloride
Received: July 19, 2012
Published: August 27, 2012
© 2012 American Chemical Society
8142
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
with a series of anionic bases in the gas phase using the G2(+)
level of theory.7,9c,d,f They found that α-effect nucleophiles
deviated significantly from plots of the activation barriers of
both reactions versus the proton affinities and claimed that α-
effect nucleophiles react with lower deformation energies.
However, the hydrazide anion H2NNH− has been calculated to
react more slowly with methyl chloride than expected from the
correlation with the proton affinities, though it has been
calculated to react faster than the more basic amide anion
9f
−
NH2 .
The relative reactivities of hydrazines and hydroxylamines
depend strongly on the electrophilic reaction partners and the
reaction conditions, and the magnitude of the α-effect is much
smaller than for other typical α-effect nucleophiles, such as
oximates and hydroperoxide anions.5 Bernasconi and Murray
found that the rates of nucleophilic attack of hydrazine,
hydroxylamine, and semicarbazide at benzylidene Meldrum’s
acid correlated well with those of normal primary amines in the
Brønsted plot.6l On the other hand, the equilibrium constants
for the formation of the zwitterionic adducts from benzylidene
Meldrum’s acid with hydrazine, semicarbazide, and methoxy-
amine were significantly larger than those with isobasic
amines.6l Dixon and Bruice reported that hydrazines add to
malachite green faster and with greater equilibrium constants
than primary amines of the same Brønsted basicities.6s The
linear correlation between the rate and equilibrium constants
with a slope of 1.0 shows that the different product stabilities
are fully reflected by the transition states.
Figure 1. Plots of the second-order rate constants log k2 or log k2′ for
the reactions of hydrazine (1) and 1,1-dimethylhydrazine (2) with
benzhydrylium ions and quinone methides in CH3CN at 20 °C versus
the E parameters of 16 (for structures of 16c−k see Table 1). Figure
modified from ref 11.
As part of our program to include the N-nucleophiles 1−15
in our comprehensive nucleophilicity scales,10 we have recently
investigated the reactions of hydrazine (1), 1,1-dimethylhy-
drazine (2), and trimethylhydrazine (3) with benzhydrylium
ions and quinone methides in acetonitrile.11 We observed that
methylation increases the nucleophilicity of the substituted
nitrogen and decreases the reactivity of the adjacent center. As
a result, the tertiary nitrogen atoms of the asymmetric
hydrazines 2 and 3 are the more reactive sites under conditions
of kinetic control, while substitutions of the less substituted
nitrogen atoms were observed under conditions of thermody-
namic product control (Scheme 1, Figure 1).
These results were in contrast to theoretical predictions
(DFT) by Hocquet and co-workers based on the principle of
maximum hardness.12 While the nucleophilic Fukui function
f−(r) predicted similar reactivities of the two centers, the “dual
descriptor” (second-order Fukui function) Δf(r)13 and the
calculated charge densities indicated a higher nucleophilicity for
the NH2 terminus in 1,1-dimethylhydrazine (2) and methyl-
hydrazine (4), respectively.
In order to clarify the influence of substituents on the
nucleophilic reactivities and regioselectivities of potential α-
effect nucleophiles, we have now studied the kinetics of the
reactions of the hydrazines 1−5, hydrazides 6−9, hydroxyl-
amines 10 and 11, ammonia (12), and methylamines 13−15
with quinone methides 16a−c and benzhydrylium ions 16d−n
as reference electrophiles (Table 1) in acetonitrile and water
and evaluated their N and sN parameters according to the linear
free energy relationship eq 1.14
Scheme 1. Ambident Reactivity of 1,1-Dimethylhydrazine
a
(2) in Reactions with Benzhydrylium Ions (16)
log k2 (20 °C) = sN(N + E)
(1)
In eq 1, electrophiles are characterized by one solvent-
independent parameter (E), and nucleophiles are characterized
by two solvent-dependent parameters, N and sN.10
RESULTS AND DISCUSSION
■
Product Characterization. Complementary to previous
studies of 1−3,11 we characterized the products of
representative combinations of the nucleophiles 4−15 with
quinone methides 16a−c and benzhydrylium ions 16d−n.
a
Scheme modified from ref 11.
8143
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
Table 1. List of the Reference Electrophiles 16 Used in this
Study
Scheme 3. Products of Reaction of 6, 8, and 9 with 16i and
1H and 13C NMR Chemical Shifts (ppm) of the Ar2CH
Group
a
1H NMR spectroscopic analysis of the crude product showed the
exclusive formation of 19 as a 2:1 mixture of (Z)- and (E)-isomers.
The regioselectivity can only be reversed when the more acidic
acylated NH group is deprotonated.18 No reaction was
observed when N′,N′-dimethylformohydrazide (7) was com-
bined with equimolar amounts of 4,4′-dimethoxybenzhydryl
chloride (16n-Cl) at 20 °C, which can be explained by the low
equilibrium constant for attack of 16n at the NMe2 group of 7
(see below).
a
b
−
Counterion of the benzhydryl cations: BF4
.
Electrophilicity
c
parameters E from refs 10c, 10d, and 10f. Revised electrophilicity
parameter from ref 15.
Combination of 16i with 5.5 equiv of hydroxylamine (10),
which was generated by treatment of its hydrochloride with 1.7
equiv of trimethylamine (15), yielded a 9:1 mixture of the
mono- and double-alkylation products 22 and 23 (Scheme 4).
On the other hand, the combination of 10 with an equimolar
amount of 16e yielded the monoalkylated hydroxylamine 25
selectively. Regioselective monoalkylation of the nitrogen to
give 24 was also found for the combination of 16i with 2.4
equiv of N-methylhydroxylamine (11), which was generated
from the corresponding hydrochloride with 1 equiv of
trimethylamine (Scheme 4). In line with these results, N-
alkylation of hydroxylamine has previously been observed.6z,19
Only derivatives of hydroxamic acid, i.e., hydroxylamines
carrying electron-withdrawing groups at nitrogen, were found
to react at oxygen in transition-metal-catalyzed allylic
substitution reactions20 and in SN2 reactions when the hydroxyl
group was deprotonated with NaH.21
Methylhydrazine (4) and 1,2-dimethylhydrazine (5) reacted
smoothly with the quinone methide tol(tBu)2QM (16b) in
acetonitrile at 20 °C to form the 1:1 addition products 17 or
18, respectively (Scheme 2), as recently described for the
Scheme 2. Products of Reactions of Hydrazines 4 and 5 with
1
16b and H and 13C NMR Chemical Shifts (ppm) of the
Ar2CH Group
When 16i was added to 18 equiv of ammonia (12) in
acetonitrile at 20 °C, we observed the exclusive formation of
the secondary amine 27 (Scheme 5). Unlike ammonia (12),
methylamine (13) and dimethylamine (14) reacted with 16i to
yield the 1:1 products 28 and 29 exclusively.
Treatment of (ani)2CHCl (16n-Cl) with an ethanolic
solution of 5 equiv of trimethylamine (15) in acetonitrile at
20 °C resulted in the formation of the quaternary ammonium
salt 30 (Scheme 6). Less reactive carbocations, such as 16i,
reacted reversibly with trimethylamine (15), and products
could not be isolated (detailed discussion below).
parent hydrazine (1) and trimethylhydrazine (3).11 While 5 has
two equivalent nucleophilic centers, 4 could, in principle, attack
the quinone methide with either the primary or the secondary
amino function. We obtained only the product from
regioselective reaction at the NHMe group in 94% yield,
which was identified by heteronuclear multiple-bond correla-
tion spectroscopy (HMBC-NMR).16
Regioselective reactions at the NH2 groups were found for
Kinetics of Reactions of 1−15 with Reference Electro-
philes 16. The rates of the reactions of the amines, hydrazines,
hydrazides, and hydroxylamines 1−15 with the reference
electrophiles 16 were determined spectrophotometrically in
acetonitrile or water at 20 °C using conventional and stopped-
flow methods as described previously.10 The nucleophiles 1−15
were used in large excess (over 8 equiv) relative to the
electrophiles 16 to ensure first-order conditions. For the fast
reactions (k2 > 106 M−1 s−1), benzhydrylium ions 16h−n were
the reactions of the benzhydrylium salt (dma)2CH+BF4 (16i)
−
with formohydrazide (6), tert-butyl hydrazinecarboxylate (8),
and benzohydrazide (9). After alkaline workup, the products
19−21 were obtained (Scheme 3). Like formohydrazide (6),
the product 19 exists as a mixture of (Z)- and (E)-isomers (2:1
in CDCl3). These results are in agreement with those of other
researchers who showed a large preference for attack at the
NH2 group of hydrazides under various reaction conditions.17
8144
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
Scheme 4. Products of the Reactions of 10 and 11 with 16i or 16e and 1H and 13C NMR Chemical Shifts (ppm) of the Ar2CH
Group
a
1
The ratio 22/23 was determined by H NMR spectroscopic analysis of the crude product.
1
Scheme 5. Products of Reactions of 12−14 with 16i and H and 13C NMR Chemical Shifts (ppm) of the Ar2CH Group
Monoexponential decays of the absorbances of the electro-
philes were observed for all reactions, and the first-order rate
constants kobs (s−1) were obtained by least-squares fitting of the
Scheme 6. Formation of Quaternary Ammonium Salt 30 by
1
Treatment of 16n-Cl with Trimethylamine (15) and H and
13C NMR Chemical Shifts (ppm) of the Ar2CH Group
obst
exponential function A = A0 e−k + C to the decays of the
absorbances; a typical example is shown in Figure 2. Plots of
kobs versus the nucleophile concentrations were linear for all
reactions of 6−15 with the reference electrophiles 16.
According to eq 2, the second-order rate constants k2 (M−1
s−1) were obtained as the slopes of these plots (Table 2).
kobs = k2[Nu] + k0
(2)
For the determination of the kinetics of the reactions of
hydroxylamine (10), N-methylhydroxylamine (11), methyl-
amine (13), and dimethylamine (14) with benzhydrylium ions
and quinone methides 16, the nucleophiles were generated by
partial deprotonation of the corresponding hydrochlorides with
0.50−0.95 equiv of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
as recently reported for analogous studies of hydrazine (1).11
generated by laser-flash photolysis (7 ns pulse, 266 nm) of
substituted benzhydryl triphenyl or tributyl phosphonium
tetrafluoroborates in acetonitrile in the presence of excess
nucleophile.11,14a
8145
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
the protonated DBU. Stock solutions of ammonia (12) were
prepared by gas injection in acetonitrile, and trimethylamine
was used as a 33% solution in ethanol. In both cases, the
concentrations of the stock solutions were determined by
titration with hydrochloric acid.
Tetramethylhydrazine was not used in our kinetic studies,
because we could not obtain this compound in sufficient purity,
and even small contaminations by trimethylhydrazine (3) are
problematic since previous work11 suggested trimethylhydra-
zine (3) to be considerably more nucleophilic than
tetramethylhydrazine.
While linear kobs versus [nucleophile] plots were also
obtained for the reactions of methylhydrazine (4) and 1,2-
dimethylhydrazine (5) with most electrophiles, the correlations
between kobs and the hydrazine concentrations showed upward
curvatures for the reactions of 4 with 16b and 5 with 16c in
acetonitrile (Figure 3).
In these cases, the attack of the hydrazines is followed by a
rate-determining proton transfer step, in which a second
hydrazine molecule acts as general base catalyst (Scheme 7). An
analogous behavior was previously observed for the reactions of
secondary amines with quinone methides,14d as well as with
thiocarbonates, thionobenzoates, and activated esters of indole-
3-acetic acid.22
Figure 2. Exponential decay of the absorbance at 616 nm during the
reaction of 16f (1.74 × 10−5 M) with methylhydrazine ([4] = 3.56 ×
10−4 M; kobs = 73.2 s−1) in acetonitrile at 20 °C. Inset: The plot of kobs
versus [4] yielded the second-order rate constant k2 = 2.15 × 105 M−1
s−1.
The kinetics of the reactions in Scheme 7 follow the rate law
of eq 3, which is derived in the Supporting Information; it can
be rewritten as eq 4.
k2kb[Nu]2
k−2 + kb[Nu]
kobs
=
(3)
k−2
k2kb[Nu]
[Nu]
kobs
1
k2
=
+
Figure 3. Plot of kobs versus [4] for the reaction of methylhydrazine
(4) with 16b in CH3CN at 20 °C. Inset: Plot of [4]/kobs versus 1/[4]
from which the second-order rate constant k2 (1/0.0894 M s = 11.2
M−1 s−1) was obtained as the reciprocal intercept.
(4)
In line with eqs 3 and 4, plots of [Nu]/kobs against 1/[Nu]
were linear for a wide range of concentrations, as illustrated in
the inset of Figure 3 for the reaction of 4 with 16b. The second-
order rate constants k2 marked with footnote g in Table 2 were
obtained from the intercepts (1/k2) of these linear correlations.
Since in all other reactions, including those of dimethylamine
(14) and methylhydrazine (4) with quinone methides in
acetonitrile, linear correlations of the observed rate constants
with the concentrations of the nucleophiles were obtained (see
Supporting Information), one can conclude that the initial
Scheme 7. Reaction of Quinone Methides 16b and 16c (E)
with the Mono- and 1,2-Dimethylhydrazines 4 and 5 (Nu)
attack of the nucleophiles is generally irreversible, i.e., k−2
kb[Nu].
≪
The reactions of hydrazine (1) and methylhydrazine (4) with
the benzhydrylium ions 16 have also been studied in water,
where competing reactions with either water or hydroxide ions
have to be considered. The observed first-order rate constants
kobs are the sum of the rate constants for the reactions of the
benzhydrylium ions 16 with the hydrazines (k2), with
hydroxide (k2,OH), and with water (kw) as described previously
(eq 5).14h,i
kobs = k2[hydrazine] + k2,OH[OH−] + kw
(5)
The concentrations of the hydrazines and of hydroxide were
calculated from the pKaH values as described in the Supporting
Information. With these concentrations and the previously
published values for k2,OH one can calculate k1,eff as defined
by eq 6.
For the reaction of methylamine (13) with 16h, KOtBu was
used as an alternative deprotonation agent. The similar rate
constants obtained with both bases confirmed the complete
deprotonation of methylamine hydrochloride by DBU and
proved that the reactivities of the amines were not affected by
hydrogen bonding of the amines to the protonated amines or
14k
k1,eff = kobs − k2,OH[OH−] = k2[hydrazine] + kw
(6)
8146
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
Table 2. Second-Order Rate Constants k2 for Reactions of Reference Electrophiles 16 with the Amines 1−15 and 26 at 20 °C
and Resulting N and sN Parameters
a
b
c
Cosolvent: 0.75 vol % CH3CN. Cosolvent: 1.0 vol % CH3CN. Rate constants for the reactions of 1−3 with 16 and resulting nucleophilicity
d
e
f
parameters for 1−3 in acetonitrile from ref 11. Reaction at the primary center of 4. Reaction at the tertiary centers of 2 or 3, respectively. Reaction
at the secondary center of 3. Second-order rate constants k2 were derived from eq 4 and are less precise. The nucleophiles were generated by
deprotonation of the corresponding hydrochloride salts with DBU. For the determination of the nucleophilicity parameters N and sN, the average of
g
h
i
the second-order rate constants obtained from reactions of 16h with 13 generated from methylamine hydrochloride (13·HCl) with KOtBu or DBU
j
was used. The nucleophiles were generated by deprotonation of the corresponding hydrochloride salts with KOtBu.
As a consequence, the second-order rate constants k2 for the
reactions of hydrazines 1 and 4 with 16 in water were obtained
from the slopes of the correlations of k1,eff with the hydrazine
concentrations (Table 2). It is observed that neither the
reactions with hydroxide nor with water contribute more than
1% to the overall observed rate constants. As described above
for the reactions in acetonitrile, the linearity of the k1,eff versus
[hydrazine] plots indicates a rate law that is first order in
8147
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
hydrazine, implying that the C−N-bond formation and not the
subsequent deprotonation is the rate-determining step.
As ammonia (12) yielded the secondary amine 27 in the
reaction with 16i (see above), we have also determined the
kinetics of the reaction of 16i with the intermediate primary
amine 26, which was synthesized by treatment of
(dma)2CHOH with phthalimide and subsequent hydrolysis
with hydrochloric acid according to the literature.23 As shown
in Table 2, 26 reacts 2.7 times faster with 16i than ammonia
(12). As more than 70 equiv of ammonia was used for the
determination of its nucleophilic reactivity toward 16i, the
measured rate constants refer to the formation of the
monosubstituted product 26, which did not react with further
16i under the conditions of the kinetic experiments. This
interpretation is confirmed by the linear dependence of the
observed rate constants on the concentration of NH3 in the
investigated concentration range, which would not be obtained
if the subsequent reaction of 26 with 16i would contribute to
the observed rate constant.
The formation of the secondary amine 27 under synthetic
conditions must, therefore, be the result of thermodynamic
control. Traces of protons may regenerate 16i from 26 and thus
lead to the thermodynamically more favored product 27. This
interpretation is in line with the results by Villiger and
Kopetschni, who showed that 26 disproportionates to ammonia
(12) and 27 under proton catalysis.24
When the logarithms of the second-order rate constants k2
were plotted against the previously reported electrophilicity
parameters E of the benzhydrylium ions and quinone methides
16, linear correlations were obtained (Figure 4), from which
the nucleophile-specific parameters N and sN (Table 2) were
determined according to eq 1.
Figure 4. Correlations of the second-order rate constants log k2 with
the E parameters of the reference electrophiles for the reactions of
selected representative nucleophiles with benzhydrylium ions and
quinone methides 16 at 20 °C in (a) H2O and (b) acetonitrile.
We can now compare the nucleophilic reactivities of the
amines and hydrazines 1−15, which cover the reactivity range
from 10 < N < 24, with each other and with those of other
amines. The sN parameters of the nucleophiles studied in this
work vary from 0.45 to 0.76, i.e., the relative reactivities of these
amines will depend on the reactivities of the reference
electrophiles. In order to avoid ambiguity, the following
discussion will focus on the rates of the reactions with
(dma)2CH+ (16i) (Figures 5 and 6). Whereas the nucleophil-
icity parameters N in Table 2 refer to the gross reactivities of
the molecules, the rate constants for the symmetrical
nucleophiles hydrazine (1) and 1,2-dimethylhydrazine (5) in
Figures 5 and 6 were corrected by the statistical factor of 2 to
reflect the relative reactivities of the individual nucleophilic
centers. Figure 5 shows a comparison of the second-order rate
constants for the reactions of 16i with differently substituted
amines, hydrazines, hydrazides, and hydroxylamines in
acetonitrile. The rows illustrate the influence of α-substitution
as well as branching (β-substitution), while the columns reflect
the effect of methylation of the reactive center, i.e., the change
from primary over secondary to tertiary centers.
Replacement of the hydrogen atoms in ammonia (12) by
alkyl groups significantly increases the nucleophilicity. While
substitution of one hydrogen by a methyl group results in a 2.6
× 102 times higher reactivity, the second and third methyl
groups increase the reactivity by factors of 20 (14/13) and 2.6
(15/14). The activation by long-chained alkyl groups is
considerably smaller: One propyl group activates by a factor
of 93 (31/12). In comparison, diethylamine (34) is 5.5 times
more reactive than 31, and the third ethyl group even lowers
the reactivity by a factor of 4.5 (35/34). We thus arrive at the
noticeable conclusion that trimethylamine (15) is 1.1 × 102
times more nucleophilic than triethylamine (35).
As shown in the first line of Figure 5, branching of the alkyl
groups in primary amines leads to a steady reduction of
reactivity, and tert-butylamine (33) is 58 times less nucleophilic
than methylamine (13).
The vertical comparison of hydrazine (1), methylhydrazine
(4), and 1,1-dimethylhydrazine (2) shows that the methyl
groups in hydrazine activate the substituted nitrogen by factors
of 11 (4/1) and 4.9 (2/4), respectively, i.e., the trend is similar
to that in the series methylamine (13), dimethylamine (14),
trimethylamine (15).
The retarding effect of methyl groups on the reactivity of the
adjacent nitrogen corresponds to the branching effect in the
series of the primary amines. This effect is more pronounced in
the series of hydrazines, however. While isopropylamine (32) is
7.6 times less reactive than methylamine (13), the NH2 group
in 1,1-dimethylhydrazine (2) is 60 times less reactive than one
NH2 group in the parent hydrazine (1). Similar retarding effects
of methyl groups at the adjacent nitrogen center can be
observed in the series of hydrazines with secondary and tertiary
nitrogen reaction centers: the NHMe group of trimethylhy-
drazine (3) is 69 times less reactive than one position in 1,2-
dimethylhydrazine (5), which in turn reacts 2.0 times slower
than the NHMe group of methylhydrazine (4); analogously the
NMe2 group of trimethylhydrazine (3) is 17 times less reactive
than the corresponding group in 1,1-dimethylhydrazine (2).
8148
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
Figure 5. Comparison of relative second-order rate constants for the reactions of (dma)2CH+ (16i) with ammonia, amines, hydrazines, hydrazides,
and hydroxylamines in CH3CN at 20 °C (centers of attack are marked in red for primary nitrogens, in green for secondary nitrogens, in blue for
tertiary nitrogens). Notes: aThe rate constants for the reactions of 16i with 1−311 and 31−3214d were reported previously. bThe rate constants were
calculated by eq 1 using the E, N, and sN parameters.11,14a,d cThe rate constants for the reactions of 16i with the symmetrical hydrazines 1 and 5 were
statistically corrected by a factor of 2. dNucleophiles 7 and 35 and the NMe2 group of 3 do not react with (dma)2CH+ (16i), and rate constants for
these reactions were calculated by eq 1 using the E, N, and sN parameters.11,14a eThe rate constant for the reaction of 7 with 16i was obtained by
extrapolation over a wide range and has to be considered approximate.
Figure 6. Comparison of relative second-order rate constants for reactions of (dma)2CH+ (16i) with amines, hydrazines, semicarbazide (37), and
hydroxylamine (10) in H2O at 20 °C (centers of attack are marked in red for primary nitrogens and in green for secondary nitrogens). Notes: aRate
constants for the reactions of 16i with 10,14k 12−14, 32−34, 36,14h and 3714k were reported previously. bThe rate constant for the reaction of 16i
with hydrazine (1) was statistically corrected by a factor of 2. The rate constants were calculated by eq 1 using the E, N, and sN parameters.14h
c
1,1-Dimethylation of formohydrazide (6→7) increases the
reactivity by a similar amount (factor 62) as 1,1-dimethylation
of hydrazine (1→2, factor 55).
(6/12, factor 0.28) and the tert-butoxycarbonylamido group
(8/12, factor 0.86), whereas the benzamido group in 9 induces
a 2.7-fold higher reactivity.
An increase of reactivity by N-methylation was also observed
in the series of hydroxylamines. With a factor of 41 (11/10) the
effect is somewhat larger than in the series of amines (14/13
factor of 20) and hydrazines (4/1 factor of 11).
We will now compare the effects of heteroatom substitution.
While replacement of one hydrogen in NH3 by methyl
increases the reactivity 2.6 × 102 fold, the NH2 group activates
by a factor of 96 (1/12) and OH by a factor of 2.8 (10/12).
Slight retarding effects are observed for the formamido group
A similar trend can be observed in the series of the secondary
reaction centers (second row of Figure 5). While methylation
of methylamine activates by a factor of 20 (14/13), amination
activates less (4/13 = 4.1) and hydroxylation even deactivates
slightly (11/13 = 0.45).
The third row of Figure 5 shows that replacement of H in
dimethylamine by methyl activates only 2.6-fold (15/14) and
that replacement of H by NH2 does not affect the
8149
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
nucleophilicity (2 ≈ 14), while the formamido group
deactivates significantly (7/14 = 1/3.0 × 102).
In summary, in all three rows discussed, hydrazines R2N-NH2
are generally less nucleophilic than the corresponding amines
R2N-Me, independent of the nature of R.
are again more reactive than ammonia (12, green circles in
Figure 7). Among the primary amines, anilines have the lowest
basicities but nevertheless are among the strongest nucleophiles
in water and react with similar rates as other primary amines in
acetonitrile.14d,h Increasing size of the alkyl groups reduces the
nucleophilic reactivities but not the Brønsted basicities as
shown by the low reactivities of isopropylamine (32) and tert-
butylamine (33) compared to other primary amines or by the
greatly reduced reactivity of triethylamine (35) in comparison
with the slightly less basic trimethylamine (15).
When the Brønsted-type correlation for the reactions in
water is restricted to structurally related α-unbranched primary
amines, a linear correlation with βNu = 0.22 is obtained, from
which hydrazine (1), hydroxylamine (10), and semicarbazide
(37) do not deviate significantly (Figure 8a). This observation
Though the absolute rate constants for the reactions of
amines and hydrazines are approximately 102 times smaller in
water than in acetonitrile, the relative reactivities of ammonia
(12), primary and secondary amines, and hydrazines are almost
identical in the two solvents (Figure 6). One, therefore, has to
conclude that the differences in reactivities of the amines and
hydrazines derived from these kinetic data reflect intrinsic
properties of these nucleophiles, which are only slightly affected
by solvation. Only hydroxylamine (10) deviates somewhat, as it
reacts 13 times faster than ammonia (12) in water, while the
reactivity ratio is only 2.8 in acetonitrile. Possibly, in water the
electrophilic attack at nitrogen is accompanied by simultaneous
deprotonation of the amino group.
Correlation of Kinetic with Thermodynamic Data. As
shown in Figure 7, the rate constants of the reactions of amines
Figure 8. Brønsted plots of the statistically corrected second-order rate
constants versus the statistically corrected basicities14,26 for the
reactions of (dma)2CH+ (16i) with (a) unbranched primary and (b)
secondary amines in H2O at 20 °C (p = number of equivalent protons
of the conjugated acids;25c,27 q = number of equivalent nucleophilic
centers25c,27).14
Figure 7. Brønsted plots of the statistically corrected second-order rate
constants versus the statistically corrected basicities14,26 for the
reactions of (dma)2CH+ (16i) with amines at 20 °C (a) in H2O
and (b) acetonitrile (p = number of equivalent protons of the
conjugated acids;25c,27 q = number of equivalent nucleophilic
centers;25c,27 filled circles: primary amines, open circles: secondary
amines, filled triangles: tertiary amines; open triangles: pyridines;
green symbols: ammonia (12); red symbols: α-nucleophiles).11,14
contrasts an earlier report that α-nucleophiles, including
hydrazine (1), methylhydrazine (4), and semicarbazide (37),
showed an upward deviation of 1.5 orders of magnitude in an
analogous Brønsted correlation for the reactions of malachite
green with primary amines (βnuc = 0.42).6s Though previous
and hydrazines with (dma)2CH+ (16i) in water (Figure 7a) and
acetonitrile (Figure 7b) are not correlated with their basicities,
in agreement with earlier reports.14d,h,25 One can see some
general trends, however, which were previously reported for
reactions with other electrophiles:6j,o,v,w Secondary amines
(open circles in Figure 7) generally react faster than primary
amines (filled circles in Figure 7) of the same basicities, which
analyses indicated that the magnitude of the α-effect increases
5,6i,l,o
with βnuc
,
the large difference in reactions with
benzhydrylium ions and malachite green is surprising.
The Brønsted correlation for the reactions of secondary
amines with the benzhydrylium ion 16i shows more scatter
8150
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
(Figure 8b) than that of the primary unbranched amines
(Figure 8a). Again, no significant deviation for the α-
nucleophile methylhydrazine (4) is observed.
Table 3. Equilibrium Constants K for the Reactions of
Benzhydrylium Ions Ar2CH+ (16) with the Hydrazines
Containing Tertiary Nitrogen Centers 2, 3, 7 and the
Tertiary Amines 15 and 39−42 in Acetonitrile at 20 °C
As previously reported, the reactions of stabilized benzhy-
drylium ions with tertiary amines proceed incompletely, in
contrast to the analogous reactions with primary or secondary
amines, where the initially formed ammonium ions are
subsequently deprotonated.14a,f We were, therefore, able to
determine equilibrium constants for the reactions of benzhy-
drylium ions with 1,4-diazabicyclo[2.2.2]octane (DABCO; 39)
and quinuclidine (40) in acetonitrile.14f
An analogous determination of equilibrium constants for the
attack of benzhydrylium ions at the NMe2 groups of the
hydrazines 2 and 3 was impossible, because the initial
formations of the quaternary hydrazinium ions were reversible
and the benzhydrylium ions were consumed completely by the
subsequent slower reactions with the adjacent NH2 or NHMe
group (Scheme 1). However, when the reactions of the
carbocations 16h,i with high concentrations of 2 were
monitored on the μs time scale using the laser-flash photolysis
setup, monoexponential decays of the absorbances of 16h,i
were found (Figure 9).11 After these decays, which correspond
a
b
From ref 11. Since trimethylamine (15) was used as a 33% ethanolic
solution, K was determined from measurements on the μs time scale,
c
d
where the reaction with ethanol did not occur. From ref 14f. The
rate constant for the reactions of 41 with 16h was calculated by eq 1
e
using the published E, N, and sN parameters.14a From ref 14a.
the hydrazine 2 were used, such that the determination of K
was again impossible.
For the same reasons, the reaction of the benzhydrylium ion
16j with trimethylhydrazine (3) was the only one for which the
equilibrium constant for the attack at the NMe2 group of 3
could be determined.
Figure 9. Exponential decays of the absorbance at λ = 605 nm on the
μs time scale during the reaction of 16i generated from 16i-PBu3 (1.41
× 10−5 M) with different concentrations of 1,1-dimethylhydrazine (2)
in acetonitrile at 20 °C.
Equilibrium constants for the reactions of 16l−n with the
NMe2 group of N′,N′-dimethylformohydrazide (7) were
similarly determined on the microsecond time scale, because
the fast initial reactions were followed by unknown subsequent
reactions on a slower time scale. As the subsequent reactions
were not considerably slower than the initial ones, the
equilibrium constants K were determined from the initial
absorbances A0 and the constant C obtained by fitting the
to the fast attack at the NMe2 group (k2′ = 3.78 × 106 M−1 s−1
for 16h and 8.05 × 106 M−1 s−1 for 16i), the benzhydrylium
absorbances reached plateaus because the subsequent reactions
at the NH2 group (k2 = 1.44 × 103 M−1 s−1 for 16h and 2.46 ×
103 M−1 s−1 for 16i) occurred on the seconds time scale.
From the initial absorbances (A0) of the benzhydrylium ions
generated by the 7 ns laser pulse and the absorbances at the
plateaus on the microsecond time scale (Aeq), the equilibrium
constants (K) as defined by eq 7 were determined as the slopes
of the linear correlations of (A0 − Aeq)/Aeq with [Nu] (Table
3).
obst
monoexponential function A = A0 e−k + C to the time-
dependent absorbances.
Due to unknown subsequent reactions it was also impossible
to determine the equilibrium constants for the formation of
quaternary ammonium ions from the benzhydrylium ions 16g−
n with N-methylpiperidine (41) and N-methylpyrrolidine (42)
using conventional UV−vis spectrometers.14a Therefore, the
corresponding equilibrium constants were determined by the
same procedure described above for the 1,1-dimethylhydra-
zines.
[Ar CHNu+]
A0 − Aeq
Aeq[Nu]
2
K =
=
[Ar CH+][Nu]
2
(7)
We were not able to determine the equilibrium constants for
the reactions of other benzhydrylium ions with 2. The better
stabilized carbocations (16d−f) gave such low concentrations
of quaternary hydrazinium ions by attack at the NMe2 group
that only the slower reactions at the NH2 group were
observable.11 With more reactive carbocations (16j−k), on
the other hand, the formation of the quaternary hydrazinium
ions was almost quantitative, even when low concentrations of
A correlation of the rate constants for the reactions of the
tertiary amines and hydrazines with (pyr)2CH+ BF4 (16h)
−
with the corresponding equilibrium constants is linear with a
slope of 0.52 (Figure 10) from which 1,1-dimethylhydrazine
(2) and trimethylhydrazine (3)28 do not deviate.
8151
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
EXPERIMENTAL SECTION
■
10c
Materials. The benzhydrylium tetrafluoroborates (16d−n)-BF4
and quinone methides 16a−c10b,29 were synthesized as described in
the literature. Hydrazine monohydrate (1·H2O), hydroxylamine
hydrochloride (10·HCl), N-methylhydroxylamine hydrochloride
(11·HCl), methylamine hydrochloride (13·HCl), dimethylamine
hydrochloride (14·HCl), and trimethylamine (15, 33% ethanolic
solution) were purchased and used without further purification.
Methylhydrazine (4), benzohydrazide (9), and 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) were purchased and purified by distillation or
recrystallization prior to use. N-Methylpiperidine (41) and N-
methylpyrrolidine (42) were distilled over LiAlH4 prior to use.
Commercially available 1,2-dimethylhydrazine hydrochloride (5·HCl)
was deprotonated with NaOH in analogy to a literature procedure.30
Solutions of ammonia (12) in acetonitrile were prepared by gas
injection.
Figure 10. Plot of the rate constants for reactions of tertiary amines
−
with (pyr)2CH+ BF4 (16h) in acetonitrile at 20 °C versus the
Formohydrazide (6),31 N′,N′-dimethylformohydrazide (7),30 tert-
butyl hydrazinecarboxylate (8),32 and (dma)2CHNH2 (26)23 were
synthesized according to literature procedures. Trimethylhydrazine (3)
has been synthesized as described previously.11
corresponding equilibrium constants (black: tertiary amines; red: 1,1-
dimethylhydrazines). Data points for 2 and 3 were not included for the
determination of the slope. The rate constant for the reactions of 3
with 16h was calculated with the published E, N, and sN parameters.11
The rate and equilibrium constants for the reaction of 16h with
DABCO (39) were statistically corrected by a factor of 2.
The phosphonium tetrafluoroborates (16h−k)-PBu3 were prepared
by adding equimolar amounts of PBu3 to solutions of the
benzhydrylium tetrafluoroborates (16h−k), which gave completely
or almost colorless solutions.33 The phosphonium tetrafluoroborates
(16l−n)-PPh3 were obtained by reactions of the benzhydrols (16l−
34
−
+
n)OH with HPPh3 BF4 .
CONCLUSION
Acetonitrile (>99.9%, extra dry) was purchased and used without
further purification. Water was distilled and passed through a water
purification system (resistivity 18 MΩ/cm).
■
As previously described for numerous classes of nucleophiles,10
including amines,14 the reactions of hydrazines and hydroxyl-
amines with benzhydrylium ions follow the linear free energy
relationship eq 1, which provides a quantitative comparison of
their nucleophilicities and allows us to include them into our
comprehensive nucleophilicity scale.10 Remarkably, alkyl effects
are almost identical in the amine and hydrazine series, i.e., in
both series methyl substitution in the α-position causes a
significant increase of nucleophilicity, whereas methyl sub-
stitution in the β-position causes a significant decrease of
nucleophilicity.
1
Analytics. In the H and 13C NMR spectra the chemical shifts in
ppm refer to tetramethylsilane (δH = 0.00) or the solvent residual
signals as internal standard: CDCl3 (δH = 7.26, δC = 77.0), CD3CN
(δH = 1.94, δC = 1.32), or d6-DMSO (δH = 2.50, δC = 39.5). The
following abbreviations were used for signal multiplicities: s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet, br = broad. NMR
signal assignments were based on additional 2D-NMR experiments
(COSY, HSQC, and HMBC). For reasons of simplicity, the 1H NMR
signals of AA′BB′-spin systems of p-substituted aromatic rings were
treated as doublets.
HRMS in EI mode (70 eV) were determined with sector field
detectors. HRMS-ESI spectra were obtained on an Fourier transform
ion cyclotron resonance mass spectrometer (IonMax ion source, 4
kV).
Product Characterization. 2,6-Di-tert-butyl-4-((1-
methylhydrazinyl)(p-tolyl)methyl)-phenol (17). Methylhydrazine (4,
25 μL, 0.48 mmol) was added to a solution of tol(t-Bu)2QM (16b, 50
mg, 0.16 mmol) in acetonitrile (10 mL) over 5 min at rt. After 30 min
of stirring, the volatile compounds were evaporated under reduced
pressure: 17 (54 mg, 0.15 mmol, 94%), colorless crystals; mp 94−96
°C (hexane). 1H NMR (400 MHz, CD3CN): δ 1.38 (s, 18 H,
C(CH3)3), 2.27 (s, 3 H, CH3), 2.31 (s, 3 H, NCH3), 4.08 (s, 1 H,
Ar2CH), 5.34 (br s, 1 H, OH), 7.10 (d, J = 7.8 Hz, 2 H, Har), 7.24 (s, 2
H, Har), 7.32 (d, J = 8.1 Hz, 2 H, Har). 13C NMR (100 MHz,
CD3CN): δ 21.1 (q), 30.6 (q), 35.2 (s), 47.1 (q), 82.3 (d, Ar2CH),
124.9 (d), 128.3 (d), 130.1 (d), 135.7 (s), 137.3 (s), 138.3 (s), 142.4
(s), 153.5 (s). HRMS (ESI, positive) m/z calcd for C23H35N2O+:
355.2744, found 355.2744.
2,6-Di-tert-butyl-4-((1,2-dimethylhydrazinyl)(p-tolyl)methyl)-
phenol (18). 1,2-Dimethylhydrazine (5, 60 μL, 0.83 mmol) was added
to a solution of tol(t-Bu)2QM (16b, 100 mg, 0.324 mmol) in
acetonitrile (15 mL) over 15 min at rt. After 30 min of stirring, the
volatile compounds were evaporated under reduced pressure: 18 (117
mg, 0.317 mmol, 98%), colorless oil. 1H NMR (400 MHz, CD3CN): δ
1.40 (s, 18 H, C(CH3)3), 2.23 (s br, 1 H, NH), 2.27 (s, 3 H, CH3),
2.30 (s, 3 H, NCH3), 2.45 (s, 3 H, NHCH3), 4.35 (s, 1 H, Ar2CH),
5.29 (br s, 1 H, OH), 7.08 (d, J = 8.2 Hz, 2 H, Har), 7.24 (s, 2 H, Har),
7.30 (d, J = 8.1 Hz, 2 H, Har). 13C NMR (100 MHz, CD3CN): δ 21.1
(q), 30.7 (q), 35.2 (q), 35.5 (s), 42.3 (q), 78.1 (d, Ar2CH), 124.9 (d),
128.4 (d), 129.8 (d), 136.4 (s), 136.9 (s), 137.9 (s), 142.7 (s), 153.2
If the enhanced nucleophilicity of hydrazine (factor of 102)
and hydroxylamine (factor of 3) relative to ammonia is assigned
to an α-effect, one has to realize that this α-effect is smaller than
the activating effect of the α-methyl group in methylamine,
whatever its origin is. The problem of the reference system
remains, when we follow the current, more generally accepted
definition for the α-effect, that α-nucleophiles show positive
deviations in Brønsted plots.
Though we feel unable to interpret the contrasting results
obtained with malachite green, our investigations clearly show
that neither hydrazines nor hydroxylamine deviate from log k2
versus pKaH correlations for the reactions of primary alkyl-
amines with benzhydrylium ions. If alkylamines are considered
as references, the common log k2 versus pKaH correlation
implies that neither hydrazines nor hydroxylamines show an α-
effect. However, one might also argue that alkyl groups, like
NH2 and OH, show an α-effect, because NH3 is considerably
below their common correlation line. Whatever definition is
employed, as anilines are more reactive than ammonia and are
considerably more nucleophilic than isobasic hydrazines and
hydroxylamines, they should be considered as α-effect amines
par excellence.
In order to elucidate the significance of the α-effect in
reactions with other electrophiles we are presently investigating
the kinetics of the reactions of amines, hydrazines, and
hydroxylamines with acyl derivatives and alkyl halides.
8152
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
(s). HRMS (ESI, positive) m/z calcd for C24H37N2O+: 369.2900,
found 369.2898.
Hz, 8 H, Har). 13C NMR (75 MHz, CDCl3): δ 40.9 (q), 70.2 (d,
Ar2CH), 112.6 (d), 129.6 (d), 130.6 (s), 149.6 (s).
N′-(Bis(4-(dimethylamino)phenyl)methyl)-formohydrazide (19).
A solution of (dma)2CH+BF4− (16i, 50 mg, 0.15 mmol) in acetonitrile
(5 mL) was added to a solution of formohydrazide (6, 9.0 mg, 0.15
mmol) in acetonitrile (5 mL) at rt. Then trimethylamine (0.1 mL, 33%
in ethanol) was added, and volatile compounds were evaporated under
reduced pressure after 5 min stirring at rt. The residue was dissolved in
N-(Bis(4-(dimethylamino)phenyl)methyl)-N-methylhydroxyl-
amine (24). Trimethylamine (15, 0.3 mL 33% in ethanol, 0.08 g, 1
mmol) was added to N-methylhydroxylamine hydrochloride (11·HCl,
60 mg, 0.72 mmol) at rt. A solution of (dma)2CH+BF4− (16i, 100 mg,
0.294 mmol) in acetonitrile (5 mL) was added dropwise over 5 min.
The 2 M NaOH (10 mL) was added, and the solution was extracted
with diethyl ether (15 mL). The ethereal phase was dried (Na2SO4)
and filtered, and the volatile compounds were evaporated under
reduced pressure: 24 (67 mg, 0.22 mmol, 76%), colorless oil. 1H NMR
(400 MHz, CDCl3): δ 2.56 (s, 3 H, N(OH)(CH3)), 2.87 (s, 12 H,
N(CH3)2), 4.43 (s, 1 H, Ar2CH), 5.16 (s br, 1 H, OH), 6.65 (d, J = 8.8
Hz, 4 H, Har), 7.28 (d, J = 8.7 Hz, 4 H, Har). 13C NMR (100 MHz,
CDCl3): δ 40.8 (q), 46.2 (q), 79.0 (d, Ar2CH), 112.8 (d), 128.5 (d),
130.8 (s), 149.8 (s). HRMS (EI, positive) m/z calcd for C18H25N3O+:
299.1998, found 299.2006.
1
CDCl3 and filtered. According to the H NMR, the product 19 was
formed exclusively as a 2:1 mixture of the (Z)- and (E)-isomers.35 1H
NMR (400 MHz, CDCl3): δ 2.91 (s, 12 H, CH3 Z), 2.92 (s, 12 H,
CH3 E), 4.14 (d, J = 5.6 Hz, 1 H, NHCH E), 4.81 (d, J = 5.0 Hz, 1 H,
Ar2CH E), 5.09 (s, 1 H, Ar2CH Z), 6.67−6.69 (m, 9 H, 4 × Har, Z, 4 ×
Har E, NHCHO E superimposed), 6.97 (s, 1 H, NHCHO Z), 7.17 (d,
J = 8.8 Hz, 4 H, Har E), 7.28 (d, J = 8.6 Hz, 4 H, Har Z), 8.00 (s, 1 H,
CHO Z), 8.26 (d, J = 10.9 Hz, 1 H, CHO E). 13C NMR (100 MHz,
CDCl3): δ 40.7 (q, N(CH3)2 E), 40.8 (q, N(CH3)2 Z), 67.6 (d, Ar2CH
E), 69.1 (d, Ar2CH Z), 112.8 (d, ArH Z and E superimposed), 128.1
(s, qAr E), 128.5 (d, ArH Z), 128.5 (d, ArH Z), 129.5 (s, qAr E), 150.1
(s, qAr Z), 150.2 (s, qAr E), 160.0 (d, CHO Z), 166.9 (d, CHO E).
HRMS (ESI, negative) m/z calcd for C18H23N4O−: 311.1877, found
311.1881.
N-(Bis(1,2,3,5,6,7-hexahydropyrido(3,2,1-ij)quinolin-9-yl)methyl)-
hydroxylamine (25). Trimethylamine (15, 0.5 mL 33% in ethanol, 0.1
mg, 2 mmol) was added to hydroxylamine hydrochloride (10·HCl, 7.8
mg, 0.11 mmol) at rt. A solution of (jul)2CH+BF4− (16e, 50 mg, 0.11
mmol) in acetonitrile (5 mL) was added dropwise at rt. The solution
was concentrated under reduced pressure, diethyl ether (5 mL) was
added, the precipitate was filtered off, and volatile compounds were
evaporated under reduced pressure: 25 (41 mg, 0.11 mmol, quant.),
colorless oil. 1H NMR (400 MHz, d6-DMSO): δ 1.24 (s br, 1 H, NH),
1.80−1.86 (m, 8 H, CH2CH2CH2), 2.61 (t, J = 6.5 Hz, 8 H,
CH2CH2CH2N), 3.02 (t, J = 5.5 Hz, 8 H, CH2CH2CH2N), 4.57 (s, 1
H, Ar2CH), 6.64 (s, 4 H, HAr), 7.15 (s br, OH). 13C NMR (100 MHz,
d6-DMSO): δ 21.8 (t), 27.2 (t), 49.4 (t), 69.4 (d, Ar2CH), 120.4 (s),
125.8 (d), 130.0 (s), 141.4 (s). HR-MS (ESI, positive) m/z calcd for
tert-Butyl 2-(bis(4-(dimethylamino)phenyl)methyl)-hydrazinecar-
boxylate (20). tert-Butyl hydrazinecarboxylate (8, 39 mg, 0.30 mmol)
−
was added to a solution of (dma)2CH+BF4 (16i, 100 mg, 0.294
mmol) in acetonitrile (5 mL) and stirred for 5 min at rt. Then 2 M
NaOH (10 mL) was added, and the solution was extracted with
diethyl ether (15 mL). The ethereal phase was dried (Na2SO4) and
filtered, and the volatile compounds were evaporated under reduced
1
pressure: 20 (113 mg, 0.294 mmol, quantitative), colorless oil. H
NMR (400 MHz, CDCl3): δ 1.42 (s, 9 H, C(CH3)3), 2.88 (s, 12 H,
N(CH3)2), 4.30 (s br, 1 H, NH), 5.11 (s, 1 H, Ar2CH), 6.09 (s br, 1 H,
+
C25H29N2 [M − NHOH]+: 357.2325, found 357.2325.
NH), 6.66 (d, J = 8.9 Hz, 4 H, Har), 7.25 (d, J = 8.7 Hz, 4 H, Har). 13
C
Bis(bis(4-(dimethylamino)phenyl)methyl)-amine (27). A solution
−
of (dma)2CH+BF4 (16i, 100 mg, 0.294 mmol) in acetonitrile (10
NMR (100 MHz, CDCl3): δ 28.5 (q), 40.8 (q), 67.2 (d, Ar2CH), 80.2
mL) was added to a solution of ammonia (12, 10 mL, 0.54 M, 5.4
mmol) in acetonitrile over 30 min at rt. After diethyl ether (20 mL)
was added, the solution was washed with 2 M NaOH (25 mL), dried
(Na2SO4), and filtered, and the solvent was evaporated under reduced
pressure: 27 (75 mg, 0.14 mmol, 98%), colorless crystals; mp 191−
192 °C (pentane), lit.24 mp 188 °C (benzene, ethanol). 1H NMR (300
MHz, CDCl3): δ 1.62 (s br, 1 H, NH), 2.91 (s, 24 H, N(CH3)2), 4.61
(s, 2 H, Ar2CH), 6.68 (d, J = 8.8 Hz, 8 H, Har), 7.22 (d, J = 8.7 Hz, 8
H, Har). 13C NMR (75 MHz, CDCl3): δ 41.0 (q), 62.2 (d, Ar2CH),
112.8 (d), 128.4 (d), 133.5 (s), 149.6 (s). HRMS (EI, positive) m/z
(s), 112.7 (d), 128.6 (d), 130.2 (s), 149.9 (s), 156.7 (s). HRMS (EI,
positive) m/z calcd for C22H32N4O2 : 384.2520, found 384.2512.
+
N′-(Bis(4-(dimethylamino)phenyl)methyl)-benzohydrazide (21).
Benzohydrazide (9, 60 mg, 0.44 mmol) was added to a solution of
−
(dma)2CH+BF4 (16i, 150 mg, 0.441 mmol) in acetonitrile (5 mL)
over 5 min at rt. Then 2 M NaOH (5 mL) was added, the solution was
extracted with diethyl ether (15 mL), and the ethereal phase was dried
(Na2SO4) and filtered. The solvent was partially evaporated under
reduced pressure, and the residue was cooled to −60 °C to crystallize
the product: 21 (161 mg, 0.41 mmol, 93%), colorless crystals; mp
143−144 °C (Et2O). 1H NMR (300 MHz, CD3CN): δ 2.88 (s, 12 H,
CH3), 5.10 (s br, 2 H, Ar2CH, NH), 6.71 (d, J = 8.9 Hz, 4 H, Har),
7.28 (d, J = 8.8 Hz, 4 H, Har), 7.38−7.42 (m, 2 H, Har), 7.46−7.53 (m,
1 H, Har), 7.61−7.66 (m, 2 H, Har), 8.36 (d br, J = 6.4 Hz, 1 H, NH).
13C NMR (75 MHz, CD3CN): δ 40.9 (q), 68.3 (d, Ar2CH), 113.5 (d),
+
calcd for C34H43N5 : 521.3518, found 521.3513.
(Bis(4-(dimethylamino)phenyl)methyl)-methylamine (28). Meth-
ylamine (13, 1 mL, 33% in ethanol, 0.2 g, 8 mmol) was added to a
solution of (dma)2CH+BF4− (16i, 100 mg, 0.294 mmol) in acetonitrile
(10 mL) and stirred for 5 min at rt. Then 2 M NaOH (10 mL) was
added, and the solution was extracted with diethyl ether (15 mL). The
ethereal phase was dried (MgSO4) and filtered, and the volatile
compounds were evaporated under reduced pressure: 28 (82 mg, 0.29
128.0 (d), 129.3 (d), 129.5 (d), 131.6 (s), 132.5 (d), 134.5 (s), 151.2
(s), 167.9 (s). HRMS (ESI, negative) m/z calcd for C24H27N4O−:
387.2190, found 387.2190.
1
mmol, 98%), colorless crystals; mp 125−126 °C (pentane). H NMR
N′-(Bis(4-(dimethylamino)phenyl)methyl)-hydroxylamine (22)
and N,N-(Bis-(bis(4-(dimethylamino)phenyl)methyl))-hydroxyl-
amine (23). Trimethylamine (15, 0.5 mL 33% in ethanol, 0.1 mg, 2
mmol) was added to hydroxylamine hydrochloride (10·HCl, 85 mg,
1.2 mmol) at rt, and acetonitrile (10 mL) was added. A solution of
(dma)2CH+BF4− (16i, 75 mg, 0.22 mmol) in acetonitrile (10 mL) was
added dropwise at rt. The solution was concentrated under reduced
pressure, diethyl ether (5 mL) was added, the precipitate was filtered
off, and volatile compounds were evaporated under reduced pressure.
According to the 1H NMR spectrum of the crude product, a 9:1
mixture of 22 and 23 was obtained. 22: 1H NMR (300 MHz, CDCl3):
δ 2.89 (s, 12 H, CH3), 5.05 (s, 1 H, Ar2CH), 5.53 (br s, 2 H, NH and
OH superimposed), 6.68 (d, J = 8.7 Hz, 4 H, Har), 7.22 (d, J = 8.8 Hz,
4 H, Har). 13C NMR (75 MHz, CDCl3): δ 40.8 (q), 69.6 (d, Ar2CH),
112.8 (d), 128.6 (d), 129 (s), 150.0 (s). HRMS (EI, positive) m/z
(300 MHz, CDCl3): δ 2.39 (s, 3 H, NH(CH3)), 2.90 (s, 12 H,
N(CH3)2), 4.54 (s, 1 H, Ar2CH), 6.68 (d, J = 8.8 Hz, 4 H, Har), 7.23
(d, J = 8.7 Hz, 4 H, Har). 13C NMR (75 MHz, CDCl3): δ 35.2 (q),
40.9 (q), 68.4 (d, Ar2CH), 112.9 (d), 128.0 (d), 132.9 (s), 149.7 (s).
+
HRMS (EI, positive) m/z calcd for C18H25N3 : 283.2048, found
283.2038.
(Bis(4-(dimethylamino)phenyl)methyl)-dimethylamine (29). Di-
methylamine (14, 0.5 mL 40% in water, 0.2 g, 4 mmol) was added to a
solution of (dma)2CH+BF4− (16i, 100 mg, 0.294 mmol) in acetonitrile
(10 mL) and stirred for 5 min at rt. Then 2 M NaOH (10 mL) was
added, and the solution was extracted with diethyl ether (15 mL). The
ethereal phase was dried (Na2SO4) and filtered, and the volatile
compounds were evaporated under reduced pressure: 29 (89 mg, 0.30
mmol, quantitative), pale yellow crystals; mp 92−93 °C (hexane), lit.36
mp 94 °C. 1H NMR (300 MHz, CDCl3): δ 2.19 (s, 6 H,
Ar2CHN(CH3)2), 2.88 (s, 12 H, N(CH3)2), 3.91 (s, 1 H, Ar2CH),
6.65 (d, J = 8.8 Hz, 4 H, Har), 7.25 (d, J = 8.9 Hz, 4 H, Har). 13C NMR
1
calcd (C17H24N3O+) 286.1914, found 286.1914. 23: H NMR (300
MHz, CDCl3): δ 2.89 (s, 24 H, CH3), 4.81 (s, 2 H, Ar2CH), 5.53 (br s,
1 H, OH superimposed by 22), 6.68 (d, 8.7, 8 H, Har), 7.29 (d, J = 8.7
8153
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
(75 MHz, CDCl3): δ 40.9 (q), 44.9 (q), 76.8 (d, Ar2CH), 112.8 (d);
128.5 (d), 132.2 (s), 149.6 (s). HRMS (EI, positive) m/z calcd for
C19H27N3 : 297.2205, found 297.2201.
(Bis(4-(methoxy)phenyl)methyl)-trimethylammonium chloride
(30). A solution of (ani)2CHCl (16n-Cl, 50 mg, 0.19 mmol) in
acetonitrile (5 mL) was added to trimethylamine (15, 0.2 mL 33% in
ethanol, 0.05 g, 0.8 mmol) at rt. Volatile compounds were evaporated
under reduced pressure: 30 (60.5 mg, 0.188 mmol, 99%) colorless oil.
1H NMR (400 MHz, CD3CN): δ 3.16 (s, 9 H, N(CH3)3), 3.77 (s, 6
ACKNOWLEDGMENTS
■
+
We acknowledge financial support by the Deutsche For-
schungsgemeinschaft (SFB 749) and the Fonds der Chem-
ischen Industrie. We also thank Dr. Armin R. Ofial and
Johannes Ammer for their help during preparation of this
manuscript and for assistance in using the laser flash apparatus.
REFERENCES
H, OCH3), 6.86 (s, 1 H, Ar2CH), 6.98 (d, J = 9.0 Hz, 4 H, Har), 7.91
(d, J = 8.9 Hz, 4 H, Har). 13C NMR (100 MHz, CD3CN): δ 52.2 (q),
56.2 (q), 79.5 (d, Ar2CH), 115.5 (d), 126.3 (s), 133.8 (d), 161.7 (s).
■
(1) Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84, 16−24.
(2) (a) Gold, V. Pure Appl. Chem. 1979, 51, 1725−1801. (b) Muller,
P. Pure Appl. Chem. 1994, 66, 1077−1184.
(3) Hoz, S.; Buncel, E. Isr. J. Chem. 1985, 26, 313−319.
(4) Um, I.-H.; Im, L.-R.; Buncel, E. J. Org. Chem. 2010, 75, 8571−
8577.
−
HRMS (ESI, negative) m/z calcd forC18H24Cl2NO2 : 356.1190, found
356.1196.
Kinetic Experiments. The kinetics of the reactions of 1−15 and
26 with the benzhydrylium ions and quinone methides 16 were
followed by UV−vis spectroscopy in acetonitrile or water at 20 °C.
For slow reactions (τ1/2 > 10 s), the spectra were collected at
different times by using a diode array spectrophotometer that was
connected to a quartz immersion probe (5 mm light path) by fiber
optic cables with standard SMA connectors. All kinetic measurements
in CH3CN were carried out in Schlenk glassware under exclusion of
moisture. The temperature of the solutions during the kinetic studies
was maintained at 20 0.1 °C and monitored with a thermocouple
probe that was inserted into the reaction mixture.
(5) (a) Buncel, E.; Um, I.-H. Tetrahedron 2004, 60, 7801−7825.
(b) Grekov, A. P.; Veselov, V. Y. Russ. Chem. Rev. 1978, 47, 631−648.
(c) Fina, N. J.; Edwards, J. O. Int. J. Chem. Kinet. 1973, V, 1−26.
(d) Jencks, W. P. Catalysis in Chemistry and Enzymology; McGraw-Hill:
New York, 1969; pp 107−110.
(6) Selected examples: (a) Kirby, A. J.; Manfredi, A. M.; Souza, B. S.;
Medeiros, M.; Priebe, J. P.; Brandao, T. A. S.; Nome, F. ARKIVOC
̃
2009, iii, 28−38. (b) Han, X.; Balakrishnan, V. K.; vanLoon, G. W.;
Buncel, E. Langmuir 2006, 22, 9009−9017. (c) Terrier, F.; Rodriguez-
Stopped-flow spectrophotometer systems were used for the
investigation of faster reactions (10 ms < τ1/2 < 10 s). The kinetic
runs were initiated by mixing equal volumes of the solutions of the
amines and the electrophiles 16.
́
Dafonte, P.; Le Guevel, E.; Moutiers, G. Org. Biomol. Chem. 2006, 4,
4352−4363. (d) Yanchuk, N. I. Russ. J. Gen. Chem. 2006, 1240−1242.
(e) Um, I.-H.; Hwang, S.-J.; Buncel, E. J. Org. Chem. 2006, 71, 915−
920. (f) Um, I.-H.; Lee, E.-J.; Seok, J.-A.; Kim, K.-H. J. Org. Chem.
Reactions with τ1/2 < 10 ms were analyzed by laser-flash photolytic
generation of 16h−n from phosphonium ions in presence of excess
nucleophile. Solutions of the carbocation precursors were irradiated
with a 7 ns pulse from a quadrupled Nd:YAG laser (266 nm, 40−60
mJ/pulse), and a xenon lamp was used as probe light for UV−vis
detection. The system was equipped with a fluorescence flow cell and a
synchronized pump system, which allows complete exchange of the
sample volume between subsequent laser pulses. For each
concentration, ≥ 50 individual measurements were averaged.37
The nucleophiles 1−15 and 26 were used in large excess (>8 equiv)
relative to the electrophiles 16 to ensure first-order conditions with
kobs = k2[Nu]0 + k0. From the exponential decays of the absorbances at
λmax of 16, the first-order rate constants kobs (s−1) were obtained by
́
2005, 70, 7530−7536. (g) Moutiers, G.; Le Guevel, E.; Cannes, C.;
Terrier, F.; Buncel, E. Eur. J. Org. Chem. 2001, 3279−3284. (h) Um, I.-
H.; Hong, J.-Y.; Buncel, E. Chem. Commun. 2001, 27−28. (i) Um, I.-
H.; Buncel, E. J. Org. Chem. 2000, 65, 577−582. (j) Oae, S.; Kadoma,
Y. Phosphorus, Sulfur Silicon 1997, 123, 293−300. (k) Oae, S.; Kadoma,
Y. Can. J. Chem. 1986, 64, 1184−1188. (l) Bernasconi, C. F.; Murray,
C. J. J. Am. Chem. Soc. 1986, 108, 5251−5257. (m) Palling, D. J.;
Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 4869−4876. (n) Morris, J.
J.; Page, M. I. J. Chem. Soc., Perkin Trans. 2 1980, 220−224.
(o) Ritchie, C. D.; Minasz, R. J.; Kamego, A. A.; Sawada, M. J. Am.
Chem. Soc. 1977, 99, 3747−3753. (p) Ritchie, C. D.; Virtanen, P. O. I.
J. Am. Chem. Soc. 1973, 95, 1882−1889. (q) Dixon, J. E.; Bruice, T. C.
J. Am. Chem. Soc. 1972, 94, 2052−2056. (r) Dixon, J. E.; Bruice, T. C.
J. Am. Chem. Soc. 1971, 93, 6592−6597. (s) Dixon, J. E.; Bruice, T. C.
J. Am. Chem. Soc. 1971, 93, 3248−3254. (t) Klopman, G.; Tsuda, K.;
Louis, J. B.; Davis, R. E. Tetrahedron 1970, 26, 4549−4554.
(u) Blackburn, G. M.; Jencks, W. P. J. Am. Chem. Soc. 1968, 90,
2638−2645. (v) Gregory, M. J.; Bruice, T. C. J. Am. Chem. Soc. 1967,
89, 4400−4402. (w) Gregory, M. J.; Bruice, T. C. J. Am. Chem. Soc.
1967, 89, 2327−2330. (x) Bruice, T. C.; Donzel, A.; Huffman, R. W.;
Butler, A. R. J. Am. Chem. Soc. 1967, 89, 2106−2121. (y) Jencks, W. P.;
Carriuolo, J. J. Am. Chem. Soc. 1960, 82, 675−681. (z) Jencks, W. P.;
Carriulo, J. J. Am. Chem. Soc. 1960, 82, 1778−1786.
obst
least-squares fitting to the single-exponential curve At = A0 e−k + C.
The slopes of plots of kobs versus the concentrations of the
nucleophiles yielded the second-order rate constants k2 (M−1 s−1).
Stock solutions of hydroxylamine (10), N-methylhydroxylamine
(11), methylamine (13), and dimethylamine (14) were generated for
the kinetic measurements by partial deprotonation of the correspond-
ing hydrochloride salts with 0.50−0.95 equiv of DBU. For the
reactions of 13 with 16 h−i and of 14 with 16d, KOtBu has been used
as alternative deprotonation agent. Stock solutions of ammonia (12)
were prepared by gas injection in acetonitrile, and trimethylamine was
used as a 33% solution in ethanol. In both cases, the concentrations of
the stock solutions were determined by titration with hydrochloric
acid.
(7) Ren, Y.; Yamataka, H. J. Org. Chem. 2007, 72, 5660−5667.
(8) (a) Garver, J. M.; Gronert, S.; Bierbaum, V. M. J. Am. Chem. Soc.
2011, 133, 13894−13897. (b) Villano, S. M.; Eyet, N.; Lineberger, W.
C.; Bierbaum, V. M. J. Am. Chem. Soc. 2009, 131, 8227−8233.
(c) McAnoy, A. M.; Paine, M. R. L.; Blanksby, S. J. Org. Biomol. Chem.
2008, 6, 2316−2326. (d) DePuy, C. H.; Della, E. W.; Filley, J.;
Grabowski, J. J.; Bierbaum, V. M. J. Am. Chem. Soc. 1983, 105, 2481−
2482.
(9) (a) Mazera, D. J.; Pliego, J. R., Jr.; Almerindo, G. I.; Gesser, J. C. J.
Braz. Chem. Soc. 2011, 22, 2165−2170. (b) Wei, X.-G.; Sun, X.-M.;
Wu, X.-P.; Ren, Y.; Wong, N.-B.; Li, W.-K. J. Org. Chem. 2010, 75,
4212−4217. (c) Ren, Y.; Yamataka, H. J. Comput. Chem. 2008, 30,
358−365. (d) Ren, Y.; Yamataka, H. Chem.Eur. J. 2007, 13, 677−
682. (e) Patterson, E. V.; Fountain, K. R. J. Org. Chem. 2006, 71,
8121−8125. (f) Ren, Y.; Yamataka, H. Org. Lett. 2006, 8, 119−121.
(g) Hudson, R. F.; Hansell, D. P.; Wolfe, S.; Mitchell, D. J. J. Chem.
Soc., Chem. Commun. 1985, 1406−1407. (h) Wolfe, S.; Mitchell, D. J.;
ASSOCIATED CONTENT
■
S
* Supporting Information
Details of kinetic experiments and NMR spectra of all
compounds characterized. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: herbert.mayr@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
8154
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155

The Journal of Organic Chemistry
Article
Schlegel, H. B.; Minot, C.; Eisenstein, O. Tetrahedron Lett. 1982, 23,
615−618.
(19) Selected examples: (a) Ovakimyan, M. Zh.; Barsegyan, S. K.;
Kikoyan, N. M.; Indzhikyan, M. G. Russ. J. Gen. Chem. 2005, 75,
1069−1073; Zh. Obshch. Khim. 2005, 75, 1132−1136. (b) Goundry,
W. R. F.; Baldwin, J. E.; Lee, V. Tetrahedron 2003, 59, 1719−1729.
(c) Ovakimyan, M. Zh.; Barsegyan, S. K.; Karapetyan, A. A.; Panosyan,
G. A.; Indzhikyan, M. G. Russ. Chem. Bull. 2002, 51, 1744−1747.
(d) O’Neil, I. A.; Southern, J. M. Tetrahedron Lett. 1998, 39, 9089−
9092. (e) Strasser, M.; Cooper, P.; Dewald, B.; Payne, T. Helv. Chim.
Acta 1988, 71, 1156−1176. (f) Miller, A. O.; Furin, G. G. J. Fluorine
Chem. 1987, 36, 247−272. (g) Kliegel, W. Chem. Ber. 1969, 102,
1776−1777.
(10) (a) Mayr, H.; Ofial, A. R. Pure Appl. Chem. 2005, 77, 1807−
1821. (b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36,
66−77. (c) Lucius, R.; Loos, R.; Mayr, H. Angew. Chem. 2002, 114,
97−102; Angew. Chem., Int. Ed. 2002, 41, 91−95. (d) Mayr, H.; Bug,
T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos,
R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001,
123, 9500−9512. (e) Mayr, H.; Patz, M. Angew. Chem. 1994, 106,
990−1010; Angew. Chem., Int. Ed. Engl. 1994, 33, 938−957. (f) For a
comprehensive listing of nucleophilicity parameters N and sN and
electrophilicity parameters E see http://www.cup.uni-muenchen.de/
oc/mayr/DBintro.html.
(20) Miyabe, H.; Yoshida, K.; Yamauchi, M.; Takemoto, Y. J. Org.
Chem. 2005, 70, 2148−2153.
(21) Olberg, D. E.; Hjelstuen, O. K.; Solbakken, M.; Arukwe, J.;
Karlsen, H.; Cuthbertson, A. Bioconjugate Chem. 2008, 19, 1301−1308.
(22) (a) Castro, E. A. Pure Appl. Chem. 2009, 81, 685−696. (b) Um,
I.-H.; Yoon, S.; Park, H.-R.; Han, H.-J. Org. Biomol. Chem. 2008, 6,
1618−1624. (c) Um, I.-H.; Seok, J.-A; Kim, H.-T.; Bae, S.-K. J. Org.
Chem. 2003, 68, 7742−7746. (d) Pfeiffer, M. J.; Hanna, S. B. J. Org.
Chem. 1993, 58, 735−740.
(11) Nigst, T. A.; Ammer, J.; Mayr, H. Angew. Chem. 2012, 124,
1381−1385; Angew. Chem., Int. Ed. 2012, 51, 1353−1356.
́
(12) Morell, C.; Hocquet, A.; Grand, A.; Jamart-Gregoire, B. J. Mol.
Struct. THEOCHEM 2008, 849, 46−51.
(13) Ayers, P. W.; Morell, C.; De Poft, F.; Gerlings, P. Chem.Eur. J.
2007, 13, 8240−8247.
(14) Earlier investigations of amine reactivities towards benzhy-
drylium ions: (a) Ammer, J.; Baidya, M.; Kobayashi, S.; Mayr, H. J.
Phys. Org. Chem. 2010, 23, 1029−1035. (b) Baidya, M.; Brotzel, F.;
Mayr, H. Org. Biomol. Chem. 2010, 8, 1929−1935. (c) Phan, T. B.;
Nolte, C.; Kobayashi, S.; Ofial, A. R.; Mayr, H. J. Am. Chem. Soc. 2009,
131, 11392−11401. (d) Kanzian, T.; Nigst, T. A.; Maier, A.; Pichl, S.;
Mayr, H. Eur. J. Org. Chem. 2009, 6379−6385. (e) Baidya, M.; Mayr,
H. Chem. Commun. 2008, 1792−1794. (f) Baidya, M.; Kobayashi, S.;
Brotzel, F.; Schmidhammer, U.; Riedle, E.; Mayr, H. Angew. Chem.
2007, 119, 6288−6292; Angew. Chem., Int. Ed. 2007, 46, 6176−6179.
(g) Brotzel, F.; Kempf, B.; Singer, T.; Zipse, H.; Mayr, H. Chem.Eur.
J. 2007, 13, 336−345. (h) Brotzel, F.; Chu, Y. C.; Mayr, H. J. Org.
Chem. 2007, 72, 3679−3688. (i) Brotzel, F.; Mayr, H. Org. Biomol.
Chem. 2007, 5, 3814−3820. (j) Phan, T. B.; Breugst, M.; Mayr, H.
Angew. Chem. 2006, 118, 3954−3959; Angew. Chem., Int. Ed. 2006, 45,
3869−3874. (k) Minegishi, S.; Mayr, H. J. Am. Chem. Soc. 2003, 125,
286−295.
(23) Bogert, M. T.; Ruderman, A. J. Am. Chem. Soc. 1922, 44, 2612−
2621.
(24) Villiger, V.; Kopetschni, E. Ber. Dtsch. Chem. Ges. 1912, 45,
2910−2922.
(25) Selected examples: (a) Hall, H. K., Jr.; Bates, R. B. Tetrahedron
Lett. 2012, 53, 1830−1832. (b) Jaramillo, P.; Perez, P.; Fuentealba, P.
J. Phys. Org. Chem. 2007, 20, 1050−1057. (c) Heo, C. K. M.; Bunting,
J. W. J. Chem. Soc., Perkin Trans. 2 1994, 2279−2290.
(26) (a) Kaljurand, I.; Kutt, A.; Soovali, L.; Rodima, T.; Maemets, V.;
̈
̈
̈
Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019−1028.
(b) Kolodyazhnyi, Y. V.; Drapkina, N. E.; Chikina, N. L.; Baturina,
L. S.; Gol’din, G. S.; Osipov, O. A. Russ. J. Gen. Chem. 1980, 50, 845−
850. (c) Condon, F. E.; Reece, R. T.; Shapiro, D. G.; Thakkar, D. C.;
Goldstein, T. B. J. Chem. Soc., Perkin Trans. 2 1974, 1112−1121.
(d) Coetzee, J. F.; Padmanabhan, G. R. J. Am. Chem. Soc. 1965, 87,
5005−5010.
(27) (a) Bunting, J. W.; Mason, J. M.; Heo, C. K. M. J. Chem. Soc.,
Perkin Trans. 2 1994, 2291−2300. (b) Bell, R. P. The Proton in
Chemistry; Methuen: London, 1959; p 159.
(15) Ammer, J.; Nolte, C.; Mayr, H. J. Am. Chem. Soc. 2012, 134,
13902−13911.
(16) Preferred attack at the methylated nitrogen of methylhydrazine
(4) has previously been reported: (a) Too, K.; Brown, D. M.;
Bongard, E.; Yarley, V.; Vivas, L.; Loakes, D. Bioorg. Med. Chem. 2007,
15, 5551−5562. (b) Banert, K.; Hagedorn, M.; Schlott, J. Chem. Lett.
2003, 32, 360−361. (c) Gibson, C.; Goodman, S. L.; Hahn, D.;
(28) Since the equilibrium constant for the reaction of 16h with the
dimethylamino group of trimethylhydrazine (3) could not be
measured, we divided the equilibrium constant for the reaction of 3
(NMe2 group) with 16j by 3600, the ratio of equilibrium constants
[K(16j)/K(16h)] for the reactions of these two benzhydrylium ions
with several pyridines and phosphines: Maji, B.; Mayr, H.,
unpublished.
(29) (a) Lucius, R.; Mayr, H. Angew. Chem. 2000, 112, 2086−2089;
Angew. Chem., Int. Ed. 2000, 39, 1995−1997. (b) Evans, S.; Nesvadba,
P.; Allenbach, S. (Ciba-Geigy AG) Patent EP-B744392, 1996; Chem.
Abstr. 1997, 126, 46968v.
Holzemann, G.; Kessler, H. J. Org. Chem. 1999, 64, 7388−7394.
̈
(d) Ryckmans, T.; Viehe, H.-G.; Feneau-Dupont, J.; Tinant, B.;
Declercq, J.-P. Tetrahedron 1997, 53, 1729−1734. (e) Branch, C. L.;
Guest, A. W.; Finch, S. C. (Beecham Group p.l.c.) Patent US5275816,
1994. (f) Guest, A. W.; Adams, R. G.; Basker, M. J.; Brain, E. G.;
Branch, C. L.; Harrington, F. P.; Neale, J. E.; Pearson, M. J.; Zomaya, I.
I. J. Antibiot. 1993, 46, 1279−1288. (g) Hilpert, H.; Dreiding, A. S.
Helv. Chim. Acta 1984, 67, 1547−1561. (h) Trepanier, D. L.; Shriver,
K. L.; Eble, J. N. J. Med. Chem. 1969, 12, 257−260. (i) Busch, M.;
Opfermann, E.; Walther, H. H. Ber. Dtsch. Chem. Ges. 1904, 37, 2318−
2333.
(30) Beltrami, R. T.; Bissell, E. R. J. Am. Chem. Soc. 1956, 78, 2467−
2468.
(31) Boland, Y.; Hertsens, P.; Marchand-Brynaert, J.; Garcia, Y.
Synthesis 2006, 1504−1512.
(32) Bredihhin, A.; Maeorg, U. Tetrahedron 2008, 64, 6788−6793.
̈
(33) Kempf, B.; Mayr, H. Chem.Eur. J. 2005, 11, 917−927.
(34) Ammer, J.; Nolte, C.; Karaghiosoff, K.; Mayr, H. Manuscript in
preparation.
(17) (a) Bergstrom, C. P.; Bender, J. A.; Gentles, R. G.; Hewawasam,
P.; Hudyma, T. W.; Kadow, J. F.; Martin, S. W.; Regueiro-Ren, A.;
Yeung, K.-S.; Tu, Y.; Grant-Young, K. A.; Zheng, X. (Bristol-Myers
(35) Assignment of the (E)- and (Z)-isomers has been based on the
magnitude of the coupling constants according to the literature:
Walter, W.; Reubke, K.-J. Chem. Ber. 1970, 103, 2197−2207.
(36) Kranz, F. H. (Allied Chemical Corporation) Patent US2983756,
1958.
(37) Ammer, J.; Sailer, C. F.; Riedle, E.; Mayr, H. J. Am. Chem. Soc.
2012, 134, 11481−11494.
Squibb Company) Patent US2007/78122, 2007. (b) Tsu
̌
brik, O.;
Maeorg, U.; Sillard, R.; Ragnarsson, U. Tetrahedron 2004, 60, 8363−
̈
8373. (c) Yavolovskii, A. A.; Ivanov, E. I.; Ianova, R. Y. Russ. J. Gen.
Chem. 2003, 73, 1326−1327; Zh. Obshch. Khim. 2003, 73, 1402−1403.
(d) Ragnarsson, U. Chem. Soc. Rev. 2001, 30, 205−213. (e) Chan-
trapromma, K.; Ollis, W. D.; Sutherland, I. O. J. Chem. Soc., Perkin
Trans. 1 1983, 1029−1039. (f) Wawzonek, S.; Yeakey, E. J. Am. Chem.
Soc. 1960, 82, 5718−5721.
(18) (a) Hisler, K.; Commeureuc, A. G. J.; Zhou, S.-z.; Murphy, J. A.
Tetrahedron Lett. 2009, 50, 3290−3293. (b) Turner, S. (Reckitt and
Colman Products Ltd) Patent US4147794, 1979.
8155
dx.doi.org/10.1021/jo301497g | J. Org. Chem. 2012, 77, 8142−8155