Kinetic evidence for a novel, Grob-like substitution/fragmentation mechanism for the reaction of nucleophiles with trialkylammoniomethyl halides

Article abstract of DOI:10.1039/a900218i

Kinetic evidence is presented in favor of a concerted, bimolecular mechanism for the unusual nucleophilic substitution/fragmentation reactions of iodide ion with (halomethyl)trimethylammonium salts. The relative reactivities of allyl, ethyl and methyl groups for this Grob-like reaction are also determined. Activation parameters are presented for the thermal reactions of 1-iodo-N,N,N-trimethylmethaniminium iodide (log A = 8.7. E_a = 19.0 kcal mol^-1) and 1-iodo-N-allyl-N,N-dimethylmethaniminium iodide (log A = 14.6, E_a = 25.7 kcal mol^-1) in acetonitrile, the latter reaction having an observed second order rate constant 39 times larger than the former at 70 °C. The results are compared with the classic data of Hughes, Ingold and Conant for S_N2 reactions of alkyl halides.

Full text of DOI:10.1039/a900218i

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Kinetic evidence for a novel, Grob-like substitution/fragmentation
mechanism for the reaction of nucleophiles with
trialkylammoniomethyl halides
Michelle O. Fletcher, Li Zhang, Quyen Vu and William R. Dolbier, Jr.*
Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Received (in Gainesville, FL) 4th January 1999, Accepted 29th March 1999
Kinetic evidence is presented in favor of a concerted, bimolecular mechanism for the unusual nucleophilic
substitution/fragmentation reactions of iodide ion with (halomethyl)trimethylammonium salts. The relative
reactivities of allyl, ethyl and methyl groups for this Grob-like reaction are also determined. Activation parameters
are presented for the thermal reactions of 1-iodo-N,N,N-trimethylmethaniminium iodide (log A = 8.7, Ea = 19.0
kcal molϪ1) and 1-iodo-N-allyl-N,N-dimethylmethaniminium iodide (log A = 14.6, Ea = 25.7 kcal molϪ1) in
acetonitrile, the latter reaction having an observed second order rate constant 39 times larger than the former
at 70 ЊC. The results are compared with the classic data of Hughes, Ingold and Conant for SN2 reactions of
alkyl halides.
Results from our initial studies of the reactivity of α-ammonio
distonic radical cations, 2, have been reported in two recent
papers.1,2 This work demonstrated that a trialkylammonium
substituent imparts electrophilic character and enhanced
reactivity to a methyl radical with respect to its 5- and 6-exo,trig
alkenyl cyclizations and its hydrogen abstraction processes.
Such conversions could occur by any of a number of uni-
molecular or bimolecular nucleophilic substitution mechanisms
that are given in Schemes 1 and 2.
I–
+
N
slow
Ph
I–
+
I
N
+
PhCH2I
SN2
1f
I–
I–
I–
+
fast
+
N
Ph
+
N
N
Ph
hν
PhCH2I
Ph
N
+
I
R
R
2
– I
1
3
I–
+
N
Ph
SN1
slow
+
Numerous radicals of type 2 were studied, and the preferred
precursors were always the respective iodomethyl compounds,
1. Such iodomethyl compounds were generally synthesized by
the reaction of the appropriate tertiary amine with methylene
iodide, as shown for a number of examples below.3,4
I
+
PhCH2
N
+
1f
fast
+
Ph
N
PhCH2
+
3
(or via PhCH2I)
I–
Scheme 1 Concerted mechanisms.
+
N
R
N
+
CH2I2
I
R
+
N
1
I
I
slow
Ph
Ph
+
I
PhCH2Ι
N
SN2
SN1
1a, R = CH3 ( 98%); 1b, R = CH2=CH(CH2)3 (55%)
1c, R = PhCH=CH(CH2)3 (76%); 1d, R = Ph2C=CH(CH2)3 (96%)
1e, R = PhCH=CH(CH2)2 (95%)
I–
1f
+
slow
I
N
PhCH2
+
N
However, in an attempt to prepare 1f (R = benzyl) and 1g
(R = cinnamyl) anomalous and initially puzzling results were
obtained, wherein the only products obtained were N,N-
dibenzyl-N,N-dimethylammonium iodide (3) and N,N-dicin-
namyl-N,N-dimethylammonium iodide (4) in 81 and 85% yield,
respectively.
Ph
N
+
PhCH2Ι
or
PhCH2
3
fast
I–
I
fast
N
+N
I–
26 oC, 12 h
+
N
R
R
N
+
CH2I2
R
Scheme 2 Stepwise mechanisms.
CH3CN
To our knowledge, there has been but one previously reported
example of such a nucleophilic substitution/fragmentation pro-
cess, that by Eschenmoser in his classic communication on the
preparation of what has become known as Eschenmoser’s Salt.6
Eschenmoser proposed a concerted, bimolecular mechanism
for this reaction, and consistent with his contention of a
Grob-like mechanism,7 he found that, unlike 1a, tetramethyl-
3, R = Ph (81%)
4, R = PhCH=CH (85%)
R = Ph and PhCH=CH
In hypothesizing a possible pathway for the formation of 3
and 4, we presumed that expected products 1f and g were inter-
mediates in the reactions,5 but that under the reaction condi-
tions they were converted to 3 and 4.
J. Chem. Soc., Perkin Trans. 2, 1999, 1187–1192
1187

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Table 1 Rate constants for the reaction of 1-iodo-N,N,N-trimethyl-
methanaminium iodide, 1a, in CD3CN
ammonium iodide did not produce methyl iodide at a signifi-
cant rate at 200 ЊC. To our knowledge, no subsequent efforts
have been made to further demonstrate and elucidate the
mechanism of this unusual transformation.8
Temperature/ЊC
65
70
75
Rate/10Ϫ4 MϪ1 sϪ1
2.8 ( 0.1)
4.1 ( 0.2)
6.6 ( 0.2)
Log A = 8.7 0.2, Ea = 19.0 0.3 kcal molϪ1
.
H3C
H3C
CH3
1a
+
N
150 oC, 10-15 min
sulfolane
H3C
H3C
I–
+
N
I
CH3I
+
I–
Table 2 Rate constant comparison for the reactions of 1-halo-N,N,N-
trimethylmethanaminium iodides or tetrafluoroborates, 1a, 5b and 6b,
in CD3CN at 101 ЊC
∆, 200 oC
H3C
H3C
CH3
+
N
no CH3I
Compound
X
k/MϪ1 sϪ1
krel
sulfolane
CH3
I–
6ba
5ba
1a
Cl
Br
I
4.8 ( 0.1) × 10Ϫ6
1.9 ( 0.1) × 10Ϫ5
4.3 × 10Ϫ3 b
1
40
896
In this paper we present clear kinetic evidence in favor of
the concerted, bimolecular mechanism for the nucleophilic
substitution/fragmentation reactions of (halomethyl)trimethyl-
ammonium salts.
a One equiv. of PhCH2NMe2ϩIϪ added to provide IϪ as nucleophile.
b Rate extrapolated to 101 ЊC using the Arrhenius data for 1a.
In devising a strategy to distinguish the mechanisms in
Scheme 1 and Scheme 2, it was reasoned that if the mechanism
were to proceed in a stepwise manner, as in Scheme 2, then,
regardless of whether the reaction is bimolecular or unimolecu-
lar, the kinetic influence of the halogen substituent of (CH3)3-
NϩCH2X should derive only from its influence on the leaving
group ability of the amine, (CH3)2NCH2X. That is, its influ-
ence should depend directly and simply on the electronegativity
of the halogen. In contrast, if the reaction proceeded by one of
the concerted mechanisms in Scheme 1, then the influence of the
halogen substituent should depend somewhat on its electro-
negativity, but primarily upon its leaving group ability, i.e., the
inverse of its basicity.
Such a distinction is in principle easy to test because halogen
substituents have an inverse relationship between their electro-
negativity and their leaving group ability. Thus, if a stepwise
mechanism were operational, one would expect the order of
rates for reaction of (CH3)3NϩCH2X with iodide ion to be
X = Cl > Br > I, whereas the opposite order of reactivity
should be obtained in the event of a concerted mechanism.
CH3
H3C
∆
+N
I–
CH2I
H3C
CH3I
+
+
N
CD3CN
H3C
H3C
I–
1a
CH3
H3C
H3C
∆, CD3CN
+
+N
N
CH3I
CH2X
+
H3C
+
PhCH2NMe3 I–
–
BF4
–
H3C
BF4
5b, X = Br
6b, X = Cl
that an Arrhenius correlation could be obtained and rates then
extrapolated to the higher temperatures required for the analo-
gous reactions of substrates 5b and 6b.
Rate constants for the reaction of iodide ion with the less
reactive bromomethyl and chloromethyl analogs 5b and 6b were
obtained at 101 ЊC, and those rates, along with that calculated
for the iodomethyl compound, are given in Table 2.
Consistent with these reactions being bimolecular in nature,
the second order rate constant for reaction of bromomethyl salt
5b was observed to remain relatively unchanged when one
doubled the concentration of iodide ion [k = 1.7 ( 0.1) × 10Ϫ5
MϪ1 sϪ1 at 101 ЊC]. The observed [IϪ] dependence is actually
somewhat surprising since reactions of negative nucleophiles
with positively charged substrates are notorious for exhibiting
non-uniform kinetics.9
Since the second order rate constants in Table 2 were
observed to correlate with the relative leaving group abilities
rather than the electronegativities of substituent X, we con-
clude that the mechanism of these reactions is the bimolecular,
Grob-like, concerted substitution/fragmentation mechanism
depicted in Scheme 1.
Results and discussion
The required 1-halo-N,N,N-trimethylmethanaminium salts, 1a,
5a and 6a, were readily prepared by the reactions of trimethyl-
amine with the appropriate dihalomethane in acetonitrile, using
essentially the method of Isaacs.3
CH2X2
(CH3)3N
(CH3)3N+CH2X
X–
CH3CN, 25 oC, 24 h
1a, X = I, 96%
5a, X = Br, 93%
6a, X = Cl, 44%
The kinetic studies were carried out in CD3CN as solvent,
using benzene as an internal standard. Progress of reactions
1
was monitored using H NMR to measure the loss of starting
Ethyl versus methyl group reactivities
material (CH3, δ 3.3 ppm). The rates of reaction of the iodo
system, 1a, were measured directly in the probe of the 300 MHz
NMR spectrometer, whereas the reactions of bromo and chloro
systems, 5b and 6b, were carried out in a constant temperature
oil bath. Tetrafluoroborate salts 5b and 6b, prepared in 90%
yield by treatment of 5a and 6a with AgBF4 in acetonitrile, were
used for their kinetic studies in order to ensure that the counter
ion would not compete with iodide in the displacement process.
In all cases, such as these, where iodide ion needed to be added,
benzyltrimethylammonium iodide was used as the iodide
source, because of its good solubility in acetonitrile and its
stability at the required reaction temperatures.
Because of the general lack of data related to the relative
susceptibilities of alkyl groups in tetraalkylammonium com-
pounds to undergo nucleophilic attack, and because (iodo-
methyl)trialkylammonium compounds, such as 1, have a
significantly greater reactivity and propensity to undergo
dealkylation processes than do tetraalkylammonium com-
pounds, it was decided to exploit the exceptional SN2-type
of reactivity of such substrates to further examine structure–
reactivity factors in this reaction.
With this in mind, the series of methyl- and ethyl-substituted
ammoniomethyl iodides (1a, 7, 8 and 9) was examined, with the
intent of obtaining relative rates for displacement at ethyl versus
methyl.
Rate constants were obtained at three temperatures, and are
given in Table 1, for the most reactive substrate, 1a (X = I), so
1188
J. Chem. Soc., Perkin Trans. 2, 1999, 1187–1192

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Table 3 Rate constants for the reaction of 1-iodo-N,N,N-trialkyl-
methanaminium iodides, 1a, 7, 8 and 9 at 101 ЊC in CD3CN
Table 4 Rates of the reaction of 1-iodo-N-allyl-N,N-dimethylmethan-
aminium iodide, 10a, in CD3CN
koverall (×10Ϫ3
Ϫ1 sϪ1
kMe (per
methyl)
kEt (per
ethyl)
Temperature/ЊC
k/10Ϫ5 sϪ1
40
50
70
39 ( 2)
Substrate
M
)
[MeI]/[EtI]
1.2 ( 0.1)
4.6 ( 0.3)
Log A = 14.6 1.3, Ea = 25.7 0.2 kcal molϪ1
.
1a
7
4.3
12.6 ( 0.4)
6.3 ( 0.3)
—
1.4
5.9
4.8
—
—
13.8 ( 0.7)
2.9 ( 0.4)
—
0.85
0.81
0.93
8
probably also have an impact on the observed rate constants.
The relative importance of each of these factors can not be
determined from our limited study.
9
2.79 ( 0.05)
I–
R3
R2
CH3I
and/or
CH3CH2I
∆, 101 o
CD3CN
C
+
N
+
+
(Alkyl)2N=CH2
I
Allyl system
R1
I–
Although the putative benzyl intermediate (1f) proposed in the
overall reaction process in Scheme 1 could not be isolated, pre-
sumably because of its high in situ reactivity with iodide ion,
the analogous allyl derivative (10) could be prepared, albeit in
lower yield (38%) than for other primary alkyl derivatives. The
ability to prepare 10 provided a good opportunity to obtain a
quantitative measure of allyl group reactivity in its reaction
with iodide ion.
1a, R1 = R2 = R3 = CH3
7, R1 = R2 = CH3, R3 = C2H5
8, R1 = CH3, R2 = R3 = C2H5
9, R1 = R2 = R3 = C2H5
Although there is an abundance of kinetic data available in
the literature regarding the SN2 reactivity of methyl, ethyl,
and other alkyl halide substrates with various nucleophiles
(most of the data deriving from the early work of the groups
of Hughes, Ingold and Conant),10,11 there is a relative dearth of
quantitative information on the related SN2 reactivity of tetra-
alkylammonium compounds. In those days, interest in tetra-
alkylammonium compounds was mostly related to their E2
(Hofmann) reactivity, and what little is known about the com-
petition between E2 and SN2 and the relative reactivities of alkyl
substituents in these systems derives from a short series of
papers by Hughes and Ingold.12–14
Kinetic studies of the three ethyl-containing 1-iodo-N,N,N-
trialkylmethanaminium compounds, 7–9, were carried out in
CD3CN at 101 ЊC, in the manner described above, except that
conversion of starting material was monitored by following the
disappearance of each compound’s methylene (CH2I) peak at
δ 4.9–5.1 ppm. In this manner were obtained the second order
rate constants (in Table 3), which when combined with the
ratios of CH3I:C2H5I,15 allowed calculation of the listed partial
rate factors that provide a measure of the relative reactivities of
the methyl and ethyl groups in this reaction.
Although the data in Table 3 clearly indicate that a methyl
group is more reactive than an ethyl group, it appears that the
relative Me:Et rate ratios for ammonium dealkylative SN2 pro-
cesses are not nearly as large as those that have been observed
for SN2 reactions where halide has been the leaving group.
In fact, the relevant Me vs. Et SN2 kinetic data that are in the
literature indicate a significant range in values. For example in
the classic series of papers by De La Mare, Fowden, Hughes,
Ingold and Mackie,11 the relative rates for the reaction of MeY
versus EtY with chloride ion in acetone at 25 ЊC varied from a
value of 71 for Y = Cl, to 61 for Y = Br, to 11 for Y = I, indicat-
ing a significant leaving group dependence. They also observed
relative rates, for X– ϩ CH3Br versus CH3CH2Br, of 140 for
X = I, 76 for X = Br, and 61 for X = Cl, indicating a significant
dependence of this ratio on nucleophile.
As indicated earlier, there do not appear to be any quanti-
tative data in the literature on Me:Et relative rate ratios for SN2
reactions of tetraalkylammonium compounds.11 However, our
data are consistent with the conclusion that structure–reactivity
relationships in dealkylative SN2 reactions of 1-halo-N,N,N-
trialkylmethaniminium (and indeed all tetraalkylammonium)
compounds must involve a complex interplay of a number of
factors, the most important of which is probably the reactivity
of the alkyl group undergoing substitution. However, relief of
A-strain (that is relief of ground state non-bonded interactions)
must also be playing an important role, as is reflected by the
larger partial rate factors for substitution on CH3 when the
leaving group bears at least one ethyl group. Differences in
ground state solvation of the various ammonium substrates
Me
+
10a, X = Ι
10b, X = BF4
N
CH2I
Me
X–
+
∆
Me2N=CH2
CH2=CH-CH2I
+
10a
10b
CD3CN
I–
∆
No reaction
CD3CN, 5% CD3OD
Rates for the reaction of iodide salt 10a were obtained in
CD3CN at three temperatures, as shown in Table 4. Unlike the
results for displacement of a methyl group discussed above (i.e.,
for 1a, 5b and 6b), no apparent rate dependence on [IϪ] was
observed for the reaction of 10a. Second order rate constants of
16, 6.4 and 5.0 × 10Ϫ2 MϪ1 sϪ1 were observed for 1, 2.4 and 3
equivalents of IϪ (0.024, 0.055 and 0.074 molar), respectively.
In fact, with calculated pseudo first order rate constants of 3.9,
3.5 and 3.7 × 10Ϫ4 Ϫ1, the reaction of 10a, to all extents and
s
purposes, appears to be first order. However, as was pointed out
by a referee, and as indicated by the work of Swain and Kaiser
on the behavior of trialkylsulfonium compounds towards
nucleophiles,9,16 the apparent absence of a linear dependence of
concentration of nucleophile need not indicate an SN1 mechan-
ism. Indeed, the fact that the reaction of allyl salt 10a with
iodide ion is bimolecular was clearly demonstrated by an
experiment in which tetrafluoroborate salt 10b was heated
under identical conditions [40 ЊC for 24 h and 70 ЊC for 0.5 h in
CD3CN (with 5% CD3OD added to trap any carbocations
formed)], with no reaction of the substrate being detected.
When an equivalent amount of benzyltrimethylammonium
iodide was added at 70 ЊC, disappearance of 10b was observed,
with a second order rate constant of 1.02 ( 0.02) × 10Ϫ2 MϪ1
s
Ϫ1. Therefore, in spite of the observed first order reactivity of
10a with its counter ion IϪ, the mechanism of its nucleophilic
displacement must be SN2, as is the case for other allyl sub-
strates (i.e., halides and tosylates) in their reactions with
nucleophiles.17
Although the available data are limited, the SN2 reactivities
of allyl halides are similar, perhaps somewhat greater, than
those of methyl halides, with allyl halides being 3–4 times less
reactive than benzyl halides.11 Thus, one would have expected
iodide displacement on methyl and allyl to have been competi-
tive. In fact, no methyl iodide was observed in our study of 10a.
In this study the observed second order rate constant [k =
1.6 × 10Ϫ2 MϪ1 sϪ1] of 10a was actually 39 times larger than that
of 1a [k = 4.1 × 10Ϫ4 MϪ1 sϪ1] at 70 ЊC. The remarkably different
J. Chem. Soc., Perkin Trans. 2, 1999, 1187–1192
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activation parameters for allyl and methyl displacement pro-
cesses of 10a and 1a indicate that there are significant differ-
ences in the detailed mechanisms of the two reactions. The
exact nature of these differences remains ambiguous. Neverthe-
less, an interesting artifact of the current study is the finding
that the relative reactivity of the allyl group in substrate 10a
towards SN2 displacement (compared to methyl) is much
greater than has been observed in the past for halide displace-
ment reactions.
N,N-Dibenzyl-N,N-dimethylammonium iodide (3)
3 was made using the general procedure for the synthesis of the
iodide salts.3 The salt was obtained in 80.9% yield: mp 185 ЊC
1
(decomp); H (DMSO-d6) δ 2.91 (s, 6H), 4.72 (s, 4H), 7.59 (m,
10H); 13C (DMSO-d6) δ 48.05, 66.76, 127.86, 128.85, 130.24,
133.05; HRMS (LSIMS POS) calcd for C16H20N: 226.1596;
found 226.1577.
N,N-Dicinnamyl-N,N-dimethylammonium iodide (4)
Using the general procedure for the synthesis of iodide salts,3
the title salt was obtained starting from cinnamyldimethyl-
Conclusions
1
amine20 in 84.5% yield: mp 170 ЊC (decomp); H (DMSO-d6)
In conclusion, the reactivities of a series of 1-halo-N-alkyl-
N,N-dimethylmethanaminium iodides towards nucleophilic
attack by iodide ion have been examined in order to elucidate
the mechanism of these novel reactions. On the basis of kinetic
data, where the alkyl group is methyl, ethyl and allyl, it was
determined that the mechanism of these reactions involves a
concerted, SN2, Grob-like process, such as that proposed
originally by Eschenmoser.6
δ 3.11 (s, 6H), 4.22 (d, J = 7.41 Hz, 4H), 6.58 (dt, J = 15.65 Hz,
2H), 6.98 (d, J = 15.66 Hz, 2H), 7.38 (m, 6H), 7.63 (d, J = 6.87,
2H); 13C (DMSO-d6) δ 49.09, 64.83, 116.77, 127.18, 128.62,
128.83, 135.28, 140.78; HRMS (LSIMS POS) calcd for
C20H24N, 278.1909; found, 278.1910.
1-Bromo-N,N,N-trimethylmethaniminium tetrafluoroborate
(5b)3
Experimental
General method for preparation of iodide salts3
5b was synthesized in 90.4% yield when 1.00 g (5.47 mmol) of
1-bromo-N,N,N-trimethylmethaniminium bromide (5a) was
reacted with one equivalent of silver tetrafluoroborate (1.07 g,
5.47 mmol) following the general procedure for the synthesis of
In a dry, three-necked, round-bottomed flask, equipped with a
magnetic stirrer were added 50% w/w of CH3CN and CH2I2
(4 equivalents), amine (1 equivalent) and a few crystals of
hydroquinone. Most reactions were left to stir overnight, after
which the precipitated salts were removed by filtration. The
salts were washed several times with ether, acetone or ethyl
acetate and the desired products were obtained as white solids.
1
tetrafluoroborate salts: mp 166–167 ЊC; H NMR (DMSO-d6)
δ 3.19 (s, 9H), 5.31 (s, 2H); 13C NMR (DMSO-d6) δ 51.84,
59.06; HRMS (LSIMS POS) calcd for C4H11NBr: 152.0075;
found, 152.0019.
1-Chloro-N,N,N-trimethylmethaniminium tetrafluoroborate
(6b)21
General method for preparation of tetrafluoroborate salts
6b was obtained in 89.9% yield when 1.00 g (7.00 mmol) of
1-chloro-N,N,N-trimethylmethaniminium chloride (6a) was
reacted with 1.36 g (7.00 mmol) of silver tetrafluoroborate in
10 mL of acetonitrile. The crude product was recrystallized
from 6:1 ethanol–acetonitrile solvent mixture: mp 221–224 ЊC;
1H NMR (DMSO-d6) δ 3.18 (s, 9H), 5.35 (s, 2H); 13C NMR
(DMSO-d6) δ 42.36, 47.13; HRMS (LSIMS POS) calcd for
C4H11NCl: 108.0580; found, 108.0575; CHN analysis calcd
for C4H11NClBF4: C, 24.59, H, 5.68, N, 7.17; found C, 24.55,
H, 5.57, N, 7.04%.
A stirred solution of the silver tetrafluoroborate (1 equiv.) in
MeOH was added dropwise to a suspension of the iodide salt
(1 equiv.) in MeOH. After the addition, the mixture was stirred
for 2 h at room temperature and then filtered in order to remove
the silver iodide. The filtrate was concentrated under reduced
pressure to give crude tetrafluoroborate salt. The tetrafluoro-
borate salts were washed with ether, acetone, ethyl acetate and
then recrystallized in either ethanol, ethyl acetate–ethanol or
water.
1-Iodo-N-allyl-N,N-dimethylmethaniminium iodide (10a)
1-Chloro-N,N,N-trimethylmethaniminium chloride (6a)3
10a was synthesized in 38% yield when 1.00 g (11.7 mmol) of
allyldimethylamine18,19 was reacted with 9.44 g (0.353 mol) of
diiodomethane in 6 mL of acetonitrile, using the general pro-
Into a gas sampling tube that was cooled to –78 ЊC, was
weighed 3.12 g (52.8 mmol) of trimethylamine gas. The amine
was then dissolved with 10 ml acetonitrile and the resulting
solution transferred to a 50 mL, three-necked, round-bottomed
flask fitted with a magnetic stirrer and a 25 mL pressure-
equalizing addition funnel. To the flask was added 11.9 mL
(13.5 g, 158 mmol) of dichloromethane in 7 mL acetonitrile
over 4 h. The reaction was stirred at Ϫ78 ЊC for 5 h and then
allowed to warm up to room temperature over 19 h, with stir-
ring. The white ammonium chloride salt, which was hygro-
scopic, was filtered from the reaction mixture under nitrogen
atmosphere, and then washed with three 10 mL portions of
diethyl ether. The crude product was isolated in 44.3% yield: mp
cedure for the synthesis of iodide salts:3 mp 101–104 ЊC; H
1
NMR (DMSO-d6) δ 3.11 (s, 6H), 4.05 (d, J = 7.2 Hz, 2H), 5.11
(s, 2H), 5.68 (m, 2H), 6.00 (m, 1H); 13C NMR (DMSO-d6)
δ 33.07, 50.88, 66.09, 125.40, 128.29; HRMS (LSIMS POS)
calcd for C6H13NI: 226.0093; found, 226.0095; CHN analysis
calcd for C6H13NI2: C, 20.42, H, 3.71, N, 3.97; found C, 20.58,
H, 3.69, N, 3.91%.
1-Iodo-N-allyl-N,N-dimethylmethanaminium tetrafluoroborate,
10b
Tetrafluoroborate salt 10b was obtained in the usual manner in
94.0% yield: 1H NMR (DMSO-d6/TMS) δ 3.09 (s, 6H), 4.04 (d,
2H), 5.10 (s, 2H), 5.68 (m, 2H), 6.00 (m, 1H).
1
150–153 ЊC; H NMR (DMSO-d6) δ 3.27 (s, 9H), 5.62 (s, 2H);
13C (DMSO-d6) δ 50.64, 69.63; HRMS (LSIMS POS) calcd for
C4H11N1ϩCl: 108.0580; found 108.0552.
1-Iodo-N,N,N-trimethylmethaniminium iodide (5)3
1-Bromo-N,N,N-trimethylmethaniminium bromide (5a)
5 was prepared by the general method described above. Tri-
methylamine (7.4 g, 0.125 mol) was bubbled slowly into the
solution of diiodomethane. The desired product was obtained
as a white solid in 95.9% yield: mp 235 ЊC (decomp); 1H NMR
(DMSO-d6) δ 3.22 (s, 9H), 5.24 (s, 2H); 13C NMR (DMSO-d6)
δ 34.80, 53.13.
5a was synthesized using the same methodology described
for the synthesis of the iodide salts.3 One equivalent of tri-
methylamine gas was reacted with three equivalents of
dibromomethane to give the bromide salt in 92.7% yield after
recrystallization in absolute ethanol: mp 165–166 ЊC; 1H NMR
1190
J. Chem. Soc., Perkin Trans. 2, 1999, 1187–1192

View Article Online
(DMSO-d6) δ 3.32 (s, 9H), 5.61 (s, 2H); 13C (DMSO-d6) δ 51.58,
demethylation of 1a are summarized in Table 1. Formation of
59.05.
methyl iodide was verified by adding authentic methyl iodide to
the reaction mixture and observing the growth of the corre-
sponding peak at δ 2.2 ppm. A plot of the data in Table 1
provided Arrhenius parameters for the reaction of 1a: Ea = 19.0
( 0.3) kcal molϪ1 and log A = 8.7 ( 0.2).
General procedure for determination of rates of dealkylation of
ammonium salts
A stock solution (~20 mM) of the salt in acetonitrile-d3 was
made with benzene included as an internal standard for concen-
tration. In sealed pyrex NMR tubes, 0.7 mL of the reaction
mixture were heated at the appropriate temperature. (Note: for
reactions below 80 ЊC, the tubes were heated in a Varian Gemini
300 spectrometer which was calibrated using neat ethylene gly-
col as a reference. For reactions above 100 ЊC, the tubes were
heated in a constant temperature oil bath.) The disappearance
of the starting materials with respect to time was monitored by
proton NMR, with the reactions being generally followed for
one half-life. Concomitant formation of iminium ion 3 was
Determination of the rates of demethylation of 5b and 6b
Solutions of 0.0167 mmol of 5b and 6b plus 0.0167 mmol
benzyltrimethylammonium iodide in 0.7 mL acetonitrile-d3
were heated in a constant temperature oil bath at 101 ЊC for ten
minute intervals for a total period of 60 min. The disappear-
ance of the bromide and chloride salts was monitored by
observing the decrease of their methyl peaks at δ 3.2 ppm with
respect to time. The proton signal for the methyl peak in the
iodide salt at δ 3.03 ppm was used as an internal standard.
Second order rate constants were obtained by applying the
usual rate equation for a situation where the reactants are equal
or unequal in concentration [eqn. (1)].
1
indicated by appearance of its characteristic signals in the H
NMR at δ 3.6 and 8.1 ppm. Pseudo first order rate constants
were obtained by plotting the natural logarithm of the concen-
tration (NMR intensity) of the salt with respect to time in sec-
onds, with the observed rate of dealkylation being obtained
from the slope of the plot. The observed rate constants were
converted to second order rate constants by using the equation:
kactual = kobserved[iodide salt]Ϫ1, and Arrhenius parameters were
determined by plotting the logarithms of these second order
rate constants against the reciprocals of the temperatures in K.
1/(a0 Ϫ x) = kAt ϩ 1/a0 or ln[1 ϩ a0/a] = a0kAt ϩ ln 2 (1)
The rate constants for 5b and 6b were found to be 18.7 ( 0.8)
and 4.79 ( 0.07) × 10Ϫ6 MϪ1 sϪ1, respectively (see Table 2), and
when 2 equivalents of iodide were used in a reaction of 5b, the
rate constant was 17 ( 1) × 10Ϫ6 MϪ1 sϪ1
.
1-Iodo-N,N,N-triethylmethaniminium iodide (9)
Determination of the rate of deallylation of 10a
9 was prepared by the general method described for the
trimethyl-substituted salts.3 Triethylamine (2.0 g, 0.0198 mol)
and diiodomethane (15.9 g, 0.0593 mol) were stirred together
in 20 mL of ethyl acetate at room temperature for 48 h. The
desired product 9 was filtered from the reaction mixture
through a glass frit and isolated in 47.7% yield (3.48 g) after
recrystallization from absolute ethanol: mp 178 ЊC (decomp),
1H NMR (DMSO-d6) δ 1.21 (t, J = 7.14 Hz, 9H), 3.34 (q,
J = 7.15 Hz, 6H), 5.1 (s, 2H); 13C NMR (DMSO-d6) δ 7.74,
27.86, 53.93; HRMS (LSIMS POS) calcd for C7H17NI,
242.0406; found, 242.0398.
Rate constants for the deallylation of 25 mM 10a were deter-
mined at 40, 50 and 70 ЊC, using the method described above.
Spectra were collected every 10 min for 2 h, and the disappear-
ance of the 10a was monitored by observing the decrease of its
methyl peak at δ 3.16 ppm. The data were analyzed as described
above and gave excellent first order correlation, and the
results are summarized in Table 4. Formation of allyl iodide
and methylenedimethylammonium iodide in the reaction was
verified by addition of authentic samples to the reaction mix-
tures and observing the growth of the product peaks. An
Arrhenius plot of the data in Table 4 provided the following
activation parameters for 10: Ea = 25.7 ( 0.2) kcal molϪ1 and
log A = 14.6 1.3.
1-Iodo-N,N-diethyl-N-methylmethaniminium iodide (8)
A 25 mL round-bottomed flask fitted with a magnetic stirrer
was charged with 10 mL of ethyl acetate. The flask was sealed
with a rubber septum. Via syringe, 3 mL of diethylmethylamine
(2.16 g, 0.0248 mol) were added followed by 3.03 g (0.0113 mol)
of diiodomethane with stirring. The reaction mixture was
stirred at room temperature for 18 h before adding an addi-
tional 10 mL of the amine. The stirring was allowed to continue
for an additional 24 h period. The solid product was filtered
from the reaction mixture through a glass frit and later
recrystallized from absolute ethanol. The product 8 was dried
under full vacuum and was isolated in 9.2% yield (0.37 g): mp
146–147.5 ЊC; 1H NMR (DMSO-d6) δ 1.23 (t, J = 7.15 Hz, 6H),
3.04 (s, 3H), 3.41 (m, 4H), 5.1 (s, 2H); 13C NMR (DMSO-d6)
δ 7.91, 30.15, 47.65, 57.45; HRMS (LSIMS POS) calcd for
C6H15NI, 228.0249; found, 228.0256.
Reactivity of 10b
The NMR tubes containing 0.7 ml portions of a 24.7 mM
solution of 1a in deuterated acetonitrile (with 5% deuterated
methanol) and benzene as internal standard were heated in an
oil bath. One tube was heated at 40 ЊC for 24 h, the other one
was heated at 70 ЊC for 0.5 h. The reaction was monitored by
300 MHz proton NMR spectroscopy. There was no detectable
reaction in either case.
Reaction of 10b with iodide ion
A sealed NMR tube containing 0.7 ml of 24.7 mM solution
of 10b and benzyltrimethylammonium iodide in deuterated
acetonitrile was heated at 70 ЊC. The disappearance of starting
material was monitored by observation of the decrease of the
methylene peak at 4.04 ppm. The pseudo first order rate con-
1-Iodo-N-ethyl-N,N-dimethylmethaniminium iodide (7)
stant was calculated to be 2.50 ( 0.04) × 10Ϫ4
s
Ϫ1, and the
7 was prepared in the same manner as its diethyl analog. In this
reaction, 1.02 g of dimethylethylamine (0.0139 mol) and 5.53 g
(0.0206 mol) of diiodomethane were stirred together in 8 mL of
ethyl acetate at room temperature for 25.5 h. To the reaction
mixture were added 10 mL extra of the amine and 5 mL of ethyl
acetate, after which the reaction mixture was stirred at room
temperature for an additional 24 h. The solid product was fil-
tered from the reaction mixture through a glass frit, and then
recrystallized from absolute ethanol to give the pure product 7
in 36.8% yield (2.59 g): mp 120–121.5 ЊC; 1H NMR (DMSO-d6)
second order rate constant was calculated to be 1.02 ( 0.02) ×
10Ϫ2 MϪ1 sϪ1
.
Determination of the rate of demethylation of 1a
As in the case of 10, 20 mM solutions of 1b in deuterated
acetonitrile were heated in the Varian Gemini 300 spectrometer
at 65, 70 and 75 ЊC, and the disappearance of the 1a (i.e. its
methyl peak at δ 3.3 ppm) was monitored by proton NMR
with respect to time. The second order rate constants for the
J. Chem. Soc., Perkin Trans. 2, 1999, 1187–1192
1191

View Article Online
2 L. A. Rios, M. D. Bartberger, W. R. Dolbier, Jr. and R. Paredes,
Tetrahedron Lett., 1997, 38, 7041.
3 B. Almarzoqi, A. V. George and N. S. Isaacs, Tetrahedron, 1986, 42,
601.
4 L. A. Rios and W. R. Dolbier, Jr., unpublished results.
5 Iodomethyl intermediate 1f could be detected (<10%) after 24 h of
reaction, when the reaction was carried out in a 50:50 mixture of
acetonitrile and methanol. It was observed to convert to product 3
with a longer reaction time.
6 J. Schreiber, H. Maag, N. Hashimoto and A. Eschenmoser, Angew.
Chem., Int. Ed. Engl., 1971, 10, 330.
7 C. A. Grob and P. Schiess, Angew. Chem., Int. Ed. Engl., 1967, 6, 1.
8 The synthesis of 14C-labeled Eschenmoser Salt has also been
reported: L. Kupczyk-Subotkowska and H. J. Shine, J. Labelled
Compd. Radiopharm., 1993, 33, 301.
9 C. G. Swain and L. E. Kaiser, J. Am. Chem. Soc., 1958, 80, 4089.
10 J. B. Conant, W. R. Kirner and R. E. Hussey, J. Am. Chem. Soc.,
1925, 47, 488.
11 P. B. D. De La Mare, L. Fowden, E. D. Hughes, C. K. Ingold and
J. D. H. Mackie, J. Chem. Soc., 1955, 3200; and previous papers in
series.
12 W. Hanhart and C. K. Ingold, J. Chem. Soc., 1927, 997.
13 E. D. Hughes and C. K. Ingold, J. Chem. Soc., 1933, 69.
14 E. D. Hughes, C. K. Ingold and C. S. Patel, J. Chem. Soc., 1933, 526.
15 Obtained from NMR spectra of the crude product mixtures as the
reaction proceeds. The reported CH3I:C2H5I ratios are an average
of those measured.
δ 1.25 (t, J = 7.2 Hz, 3H), 3.14 (s, 6H), 3.47 (q, J = 7.2 Hz, 2H),
5.19 (s, 2H); 13C NMR (DMSO-d6) δ 8.16, 32.61, 50.59, 60.06;
HRMS (LSIMS POS) calcd for C5H13NI, 214.0093; found,
214.0106.
Determination of the rate of deethylation of 9
A 20 mM stock solution of 9 in deuterated acetonitrile with
benzene as an internal standard was used for the kinetic study
of 9, which was carried out in the usual manner, following the
disappearance of the methylene peak of the starting material
(at δ 5.1 ppm). The pseudo first order rate constant was
obtained in the usual way, with the second order rate constant
being 2.79 ( 0.05) × 10Ϫ3 MϪ1 Ϫ1. Formation of ethyl iodide
s
was verified by adding authentic ethyl iodide to the reaction
mixture and observing the growth of the corresponding peaks
at δ 1.8 and 3.3 ppm.
Determinations of the absolute rates for dealkylation of 7 and 8
The determinations were carried out via the usual procedure.
The reactions were performed using 21 mM stock solutions.
Pseudo first order rate constants were obtained in the usual
way, and the second order rate constants were 6.3 ( 0.3) and
12.6 ( 0.4) × 10Ϫ3 MϪ1 sϪ1, respectively.
16 C. G. Swain, L. E. Kaiser and T. E. C. Knee, J. Am. Chem. Soc.,
1958, 80, 4092.
17 D. N. Kevill and T. J. Rissmann, J. Org. Chem., 1985, 50, 3062.
18 S. W. Zhang, T. Mitsudo, T. Kondo and Y. Watanabe, J. Organomet.
Chem., 1995, 195, 304.
19 Sadtler Standard C-13 NMR Spectra (spectrum # 9785) (1978),
Sadtler Research Laboratories, Inc., Philadelphia, PA.
20 F. D. Lewis, G. D. Reddy, S. Schneider and M. Gahr, J. Am. Chem.
Soc., 1991, 113, 3498.
Acknowledgements
Support of this research in part by the National Science
Foundation is acknowledged with thanks. The authors are also
grateful to the referees of this paper for their comments and
suggestions. The results of one suggested series of experiments
led to a significant enhancement of this paper.
21 A. J. Blake, E. A. V. Ebsworth, R. O. Gould and N. Robertson,
Z. Kristallogr., 1991, 58(23), 6198.
References
1 L. A. Rios, W. R. Dolbier, Jr., R. Paredes, J. Lusztyk, K. U. Ingold
and M. Jonnson, J. Am. Chem. Soc., 1996, 118, 11313.
Paper 9/00218I
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J. Chem. Soc., Perkin Trans. 2, 1999, 1187–1192