Diazonium ion chemistry: Replacement of H by alkyl at the central carbon accelerates an SN2 substitution reaction

Article abstract of DOI:10.1002/poc.768

The rate constants for hydrolysis of diazomethane, diazoethane and 1-diazopropane in aqueous 5% acetonitrile at 25°C and ionic strength 1 M (NaClO₄) were measured by stopped-flow spectrophotometry. The pH-rate profile for diazomethane hydrolysis exhibits a pH-independent section in the lower pH range, 8-10, with a downward break at higher pH, as has been reported for slightly different reaction conditions. In the case of diazoethane and 1-diazopropane, the reaction remains pH independent up to pH > 13. General acid catalysis of the hydrolysis reactions of diazomethane and diazoethane were examined in the pH-independent regions. For a limited number of catalysts, the value of Bronsted α was 0.58 for both diazoalkanes. The downward break in the pH rate profile for diazomethane hydrolysis is consistent with what was previously concluded, rate-limiting protonation by H₂O in the pH-independent region changing to rate-limiting attack of water on the diazonium ion in the pH-dependent region, the decrease in rate constant with increasing pH being attributed to deprotonation of the diazonium ion by hydroxide ion. The lack of a downward break in the pH-rate profiles for hydrolysis of the diazoethane and 1-diazopropane is attributed specifically to the increase, relative to the methyldiazonium ion, in the rate constant for water attack on the ethyl- and 1-propyldiazonium ions, perhaps by as much as >10 ³-fold. Copyright

Full text of DOI:10.1002/poc.768

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2004; 17: 483–488
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.768
Diazonium ion chemistry: replacement of H by
alkyl at the central carbon accelerates an SN2
,
substitution reactiony z
Tara E. Agnew, Hyun-Joong Kim and James C. Fishbein*
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA
Received 26 November 2003; revised 12 December 2003; accepted 12 December 2003
ABSTRACT: The rate constants for hydrolysis of diazomethane, diazoethane and 1-diazopropane in aqueous 5%
acetonitrile at 25 ꢀC and ionic strength 1 M (NaClO4) were measured by stopped-flow spectrophotometry. The pH-rate
profile for diazomethane hydrolysis exhibits a pH-independent section in the lower pH range, 8–10, with a downward
break at higher pH, as has been reported for slightly different reaction conditions. In the case of diazoethane and 1-
diazopropane, the reaction remains pH independent up to pH > 13. General acid catalysis of the hydrolysis reactions
of diazomethane and diazoethane were examined in the pH-independent regions. For a limited number of catalysts,
the value of Brønsted ꢀ was 0.58 for both diazoalkanes. The downward break in the pH rate profile for diazomethane
hydrolysis is consistent with what was previously concluded, rate-limiting protonation by H2O in the pH-independent
region changing to rate-limiting attack of water on the diazonium ion in the pH-dependent region, the decrease in
rate constant with increasing pH being attributed to deprotonation of the diazonium ion by hydroxide ion. The lack of a
downward break in the pH–rate profiles for hydrolysis of the diazoethane and 1-diazopropane is attributed specifically
to the increase, relative to the methyldiazonium ion, in the rate constant for water attack on the ethyl- and 1-
propyldiazonium ions, perhaps by as much as >103-fold. Copyright # 2004 John Wiley & Sons, Ltd.
KEYWORDS: diazonium ion; hydrolysis; alkyl substitution; SN2 reaction; rate acceleration
INTRODUCTION
methylating and ethylating nitrosamines, exocyclic
oxygen atom alkylation of guanine, cytosine and thymine
appear to be especially promutagenic lesions.1–4
The chemistry of diazonium ions is of fundamental
importance in understanding the basis of the carcinogeni-
city and mutagenicity of nitrosamines.1–3 In general,
nitrosamines exert their biological effects as a result of
metabolic activation by P450 enzymes to unstable ꢀ-
hydroxynitrosamines. These decompose with the genera-
tion of diazoic acids, the precursors to diazonium ions
that mediate the alkylation of DNA bases, as in Eqn (1):
In 1991, Brosch and Kirmse reported that chiral 1-
butylamine undergoes nitrous acid-catalyzed deamina-
tion in acetic acid or water with >98% inversion.5 This
result, combined with the detectable nucleophilic selec-
tivities measured for methyl- and ethyldiazonium ion
substitutions observed in DNA nucleoside alkylation
and with other nucleophiles, s ¼ 0.42 and 0.26, respec-
tively,6 requires the conclusion that the substitution reac-
tions on simple primary alkyl diazonium ions occur by a
concerted SN2 process. This reaction is in competition
with concurrent concerted hydride migration and prob-
ably elimination reaction as indicated by process a, b and
c, respectively, in the mechanism of Eqn (2).5 These latter
reactions account for the balance of the products ob-
served in diazonium ion decompositions. The report of
Brosch and Kirmse rectified an erroneous, and widely
cited, report which posited the involvement of primary
carbocations in nucleophilic media and disoriented a
generation of thinking about diazonium ion substitution
mechanisms.7 The selectivity of nucleophilic substi-
tution at primary diazonium ions stands in contrast to
that observed in the substitution of secondary and sub-
stituted-benzyl diazonium ions which are manifestly
unselective, in the absence of powerful resonance
ð1Þ
Mechanisms and selectivity in diazonium ion substitu-
tions are of importance because, at least for simple
*Correspondence to: J. C. Fishbein, Department of Chemistry and
Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop
Circle, Baltimore, Maryland 21250, USA.
E-mail: jfishbei@umbc.edu
Contract/grant sponsor: National Cancer Institute (NIH); Contract/
grant number: RO1 CA52881.
yThis paper is dedicated to Dr William P. Jencks, indisputably among
the most insightful thinkers concerning organic reaction chemistry of
the last century. He has been an outstanding mentor, both exacting and
tireless, and remains a powerful inspiration to all who have worked
with him or encountered his prolific contributions.
zSelected paper part of a special issue entitled ‘Biological Applications
of Physical Organic Chemistry’.
Copyright # 2004 John Wiley & Sons, Ltd.
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484
T. E. AGNEW, H.-J. KIM AND J. C. FISHBEIN
electron donating substituents attached to the reactive
center. Such reactions occur through preassociation
mechanisms in which the carbocation intermediates react
with even weak nucleophiles in the cation’s primary
solvation sphere, faster than diffusion.8–13
ð2Þ
Still, some uncertainties about structure and reactivity of
diazonium ions remain. Reports investigating DNA alkyla-
tion by methyldiazonium ion and its higher normal homo-
logues indicate that the latter give lower yields of alkyated
DNA bases.14,15 At least part of the explanation lies in the
lower nucleophilic selectivity of the latter compounds
compared to the methyldiazonium ions (see above). An
alternative explanation, invoking the formation of primary
carbocations,14 is inconsistent with the facts outlined above,
and has otherwise been discounted.16 The nature of the
differences in selectivity and the intrinsic differences in
reactivity of simple diazonium ions are uncertain. The rate
constant for nucleophilic displacement by solvent,
k¼ 2.6 sꢁ1, has been reported for the methyldiazonium
ion in 60% aqueous tetrahydrofuran,17 but there are no
other experimental data bearing on the reactivity of the
simple higher homologues. Glaser’s group has carried out
an ab initio investigation on the structure and stability of
methyl- and ethyldiazonium ions and the energetics of their
nitrogen dissociation reactions.18 These results suggest the
ethyl compound might be intrinsically less stable, but the
implications for the energetics of SN2 substitution in polar
media are unclear. Reported here is a study of the hydrolysis
of diazomethane, diazoethane and 1-diazopropane in aqu-
eous media. The differing pH dependence of these reactions
leads us to the conclusion summarized in the title of this
paper.
Figure 1. Plot of log k0, the buffer-independent rate con-
stant for diazolkane hydrolysis at 25 ꢀC, in aqueous 5%
acetonitrile, against pH for diazomethane (*), 0.2 M ionic
strength (NaClO4),17 and diazomethane (*), diazoethane
(^) and 1-diazopropane (~), 1 M ionic strength (NaClO4)
tration. The constant kb is the observed second-order rate
constant for the contribution from buffer components,
and is taken as the slopes of such buffer dilution plots.
The values of k0 in some cases varied as a function of
pH. It was possible to determine the value of k0 in the
range of pH from ꢃ8 to 13 for diazomethane and
diazoethane, and a more limited range was examined for
1-diazopropane. At values of pH below ꢃ7.7, the buffer
catalysis was so strong that accurate extrapolation to the
y-intercept was not feasible. Values of log k0 as a function
of pH are presented in Fig. 1 for diazomethane (filled
circles), diazoethane (diamonds) and 1-diazopropane
(triangles) along with data previously published for
diazomethane at 25 ꢀC and ionic strength 0.2 M (NaClO4)
in aqueous 5% acetonitrile (open circles).
Further analysis of the buffer stimulated reaction
indicates that the dominant component is the buffer
acid, as has been previously reported in the case of
diazomethane.17,19,20 Plots of kb as a function of the
percentage of buffer acid in the buffer are presented in
Fig. 2 in the reaction of diazomethane catalyzed by Tris
RESULTS
The kinetics of hydrolysis of diazoalkanes were moni-
tored at 235 or 240 nm by stopped-flow spectrophotome-
try at 25 ꢀC and ionic strength 1 M (NaClO4) in aqueous
5% acetonitrile. The decay of absorbance obeyed excel-
lent first-order kinetics over the 4–7 half-lives during
which it was monitored. Experiments were carried out in
media buffered (up to a buffer concentration of 0.1 M)
with various alkylammonium ion buffers or without
buffer in sodium hydroxide solutions. Under these con-
ditions the value of kobsd varied according to the equation
kobsd ¼ k0 þ kb½Bufferꢂtotal
ð2Þ
Figure 2. Plot of kb, the apparent second-order rate constant
for buffer catalysis of the hydrolysis of diazomethane by Tris
buffer (*) and diazoethane by ethanolamine buffer (&),
against percentage of buffer acid at 25 ꢀC, in aqueous 5%
acetonitrile, ionic strength 1 M (NaClO4)
The constant k0 represents the first-order rate constant
for the buffer-independent reaction, derived from the
y-intercepts of plots of kobsd against total buffer concen-
Copyright # 2004 John Wiley & Sons, Ltd.
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DIAZONIUM ION CHEMISTRY
485
Table 1. Second-order rate constants for protonation of
diazoalkanes by ammonium ion buffer acids at 25 ꢀC
(ꢁ ¼ 1 M, NaClO4, aqueous 5% by volume acetonitrile)
Table 2. Rate constants and rate constant ratios derived for
the kinetics, at 25 ꢀC (ꢁ ¼ 1 M, NaClO4, aqueous 5% by
volume acetonitrile), of diazoalkane hydrolysis according to
the mechanism of Eqn (3)
kHA for diazomethane kHA for diazoethane
)
Buffer acid
(Mꢁ1 sꢁ1
)
(Mꢁ1 sꢁ1
Constant
k1 (sꢁ1
Diazomethane Diazoethane Diazopropane
Glycine ethyl
ester-Hþ
30 000
16 300
)
28
950
22
<0.6
29
<0.1
ꢁ1
k
ꢁ1/k2 (M
)
Tris-Hþ
14 300
2090
7400
1480
320
Ethanolamine-Hþ
Butylamine-Hþ
As might be expected, a similar mechanism is opera-
tive for diazomethane under the slightly different condi-
tions of increased ionic strength in the present study (1 M,
NaClO4) as is indicated by the pH dependence for the
filled circles in Fig. 1. As with the original study,19 there
is some scatter in the values of k0, particularly in the low
range of pH, because the values of k0 are obtained from
extrapolation of buffer dilution plots and the reaction is
strongly buffer catalyzed in this pH region. However, the
number of experiments is sufficient to exhibit a good fit to
Eqn (4), the solid line through the filled circles, and to so
derive accurate values for the parameters k1, and kꢁ1/k2.
These are included in Table 2. The value of k1 under the
present conditions is ꢃ30% larger than observed pre-
viously at the lower ionic strength of 0.2 M (NaClO4). The
value of the ratio kꢁ1/k2 is ꢃ20% smaller than what was
observed in the earlier study from this laboratory.
In contrast to diazomethane, the pH dependences of k0
for the hydrolysis of diazoethane and diazopropane give
no indication of a change in rate-limiting step with
increasing pH. Figure 1 illustrates that the decomposition
of these compounds occurs with rate constants that are
similar to diazomethane in the lower pH range, but there
is no indication of a downward break with increasing pH
up to pH 13.3.
buffer and diazoethane catalyzed by ethanolamine buffer.
Within experimental error, the y-intercept value is not
significantly different from zero, consistent with the
buffer acid being the only active component at all com-
positions. The value of kb at 100% buffer acid was taken
as the value of kHA, the specific second-order rate constant
for ammonium ion-catalyzed decomposition. Values of
the kHA for the reactions of diazomethane and diazoethane
with a few ammonium ions are summarized in Table 1.
DISCUSSION
The mechanism of hydrolysis of diazomethane has been
previously analyzed in this laboratory, following, and in
agreement with, the work of other groups under a variety
of experimental conditions.17,19–21 In mainly aqueous
media from pH 7 to 12, the reaction exhibits a pH
dependence, being independent of pH below pH 10 and
exhibiting a downward break to a unit dependence on pH
in the higher pH region, as exhibited by the open circles
in Fig. 1 from a previous study. This dependence, in
combination with solvent deuterium kinetic isotope ef-
fects on the buffer-independent reaction, analysis of
solvent deuterium isotope incorporation into products
and the observation of general acid catalysis that occurs
with large solvent deuterium kinetic isotope effects was
rationalized in terms of the mechanism of Eqn (3).19
The general acid catalysis of the rate-limiting proto-
nation reaction that was investigated in the case of
diazomethane is similar in the case of diazoethane. The
catalytic constants, summarized in Table 1, are within a
factor of two of one another, the constant for the reaction
of diazoethane being the smaller. Figure 3 illustrates the
ð3Þ
The pH-independent reaction entails the rate-limiting
protonation of diazomethane by water, k1 (and general
acids, kHA, not pictured), while the rate-limiting step
changes to k2, attack of water on the diazonium ion,
with increasing pH as the hydroxide ion-dependent k
ꢁ1
step becomes increasingly competitive with, and ulti-
mately faster than, k2. The data previously published
exhibit an excellent fit to the kinetic expression
kobsd ¼ k1=fðkꢁ1½OHꢁꢂ=k2Þ þ 1g
ð4Þ
Figure 3. Brnsted plot for the general acid-catalyzed hydro-
lysis of diazomethane (&) and diazoethane (*) by ammo-
nium ions at 25 ꢀC, in aqueous 5% acetonitrile, ionic
strength 1 M (NaClO4)
for the mechanism of Eqn (3), seen in Eqn (4), as indi-
cated by the dashed line through the open circles in Fig. 1.
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 483–488

486
T. E. AGNEW, H.-J. KIM AND J. C. FISHBEIN
dependence of the catalytic constants upon the acid
ammonium ion pKas. The Brønsted ꢀ values for these
two reactions are both 0.58, suggesting a similar transi-
tion-state structure with respect to the degree of N—H
bond cleavage.
The upper limits for kꢁ1/k2, and the much more certain
values for k1, are summarized in Table 2. The value of
kꢁ1/k2 is more than 1500 times and 9500 times smaller
than for diazomethane in the cases of diazoethane and
diazopropane, respectively. An alternative explanation to
the differences in the pH–rate profiles, that hydroxide ion
attack on primary alkyl- (but not methyl-) diazonium ions
is faster than both kꢁ1 and k2 (water attack) so that k1 is
always rate limiting, is excluded by the pH-dependent
deuterium incorporation into the 1-butyldiazonium ion in
reactions in MeOD and D2O, alluded to earlier.
The conclusion above that, in contrast to diazo-
methane, protonation remains the rate-limiting step in
substantially more basic media in the case of the higher
normal homologues of diazomethane might have been
anticipated from earlier studies, foremost in the metha-
nolysis of diazobutane studied by Kirmse and Rinkler.21
It was shown that in methanol containing ꢄ0.49 M
sodium methoxide, the rate of methanolysis was roughly
inversely proportional to methoxide ion concentration.
This observation is consistent, as was pointed out, with a
mechanism like that in Eqn (3), with MeOH and MeOꢁ
replacing HOH and HOꢁ, in which k2 is the rate-limiting
step. The onset of a change to rate-limiting protonation
by methanol in the least basic media in that study is
indicated by experiments analyzing deuterium incorpora-
tion from solvent into product. At 0.49 M sodium meth-
oxide, one-third of the 1-butyl methyl ether contains a
single deuterium atom at the butyl carbon atom adjacent
to oxygen and the balance of the product contained two
atoms of deuterium. This observation suggests that at this
methoxide ion concentration, methanol attack on the
diazonium ion is just slightly slower than methoxide
ion-catalyzed proton abstraction. Hence a further de-
crease in methoxide ion concentration, or a shift to less
basic conditions such as those in the present study, would
presumably result in a complete shift to rate-limiting
protonation and the absence of a change in rate-limiting
step for the higher homologues, as observed in the pH–
rate profiles in Fig. 1. Similarly, it was later reported that
the incorporation of deuterium, from D2O, into C-1 of
product 1-butanol during the decomposition of (E)-1-
butanediazotate was pH dependent.16 The intermediacy
of diazonium ions in this reaction is well established. At
pD ¼ 10.50, 94% of the 1-butanol contains two H atoms
and 6% contains one D atom. In 1 M NaOD, only 75% of
the 1-butanol contains two H atoms, whereas 24% con-
tains one D atom and 1% contains two D atoms. This
clearly indicates that for 1-butyldiazonium ion in aqueous
solutions, only at 1 M lyoxide ion does k2 begin to become
It seems highly unlikely that much of the decrease in
kꢁ1/k2 can be ascribed merely to a decrease in the value of
the rate constant kꢁ1. Methyl or ethyl group substitution
for hydrogen, on changing from methyl- to ethyl- or 1-
propyldiazonium ion, might be expected to be acidifying
since the alkyl groups, relative to H, probably stabilize
the carbon nitrogen double bonds in the diazoalkane
bases. While it might therefore generally be expected
that acidifying effects would increase, and not decrease,
kꢁ1, a decrease in kꢁ1 might be observed if these proton
transfer reactions exhibit the same ‘anomaly’ as in the case
of nitroalkanes.22 Indeed, nitroethane and 2-nitropropane
are more acidic than nitromethane by ꢃ1.6 and ꢃ2.4
units, respectively,23,24 whereas the rate constants for
proton abstraction by hydroxide ion, analogous to the
k
ꢁ1 process of Eqn (4), are in fact larger.25,26 In the case
of nitroethane, the second-order rate constant for reaction
with hydroxide is smaller than for nitromethane, but only
by a factor of 5.2.
The larger rate constant for the less acidic nitro-
methane arises as a result of the ‘nitroalkane anomaly’
in which there is a lag in the development of resonance
and hyperconjugative stabilization in the transition state
for proton abstraction so that the electropositive polar
effects of the alkyl groups have more pronounced impact
on the transition-state energy than in the ground
states.22,27 The analogy of nitroalkanes might be parti-
cularly appropriate here because the NO2 group and the
Nþ2 group are similarly acidifying, in spite of the much
larger resonance electron-accepting ability of Nþ2 com-
pared with NO2 (ꢂꢁ ¼ 1.27 for NO2 and 3.43 for Nþ2 ).28
For nitromethane, the aqueous pKa ¼ 10.2,23,24 whereas
pKa ¼ 10 ꢅ 0.3 in aqueous 60% tetrahydrofuran has been
determined.17
However, there are factors that militate against pre-
suming that proton transfer reactions of diazonium ions
should be characterized by the strong imbalance that
applies in the case of nitroalkanes. First, unlike nitroalk-
anes, alkyl for hydrogen substitution on the methyldia-
zonium ion will have significant intrinsic stabilization of
the acid, the diazonium ion, in addition to the base,
diazoalkane. This stabilization arises from the consider-
able positive charge on the carbon atom proximal to N2 in
the diazonium ion, as has been demonstrated by high-
level ab initio calculations of Glaser’s group.18 This
stabilization will tend to mitigate imbalance by making
partly rate limiting, as k becomes competitive with
ꢁ1
increasing lyoxide ion concentration.
The absence of a change in rate-limiting step with
increasing pH in the hydrolysis of diazoethane and
diazopropane indicates that the ratios kꢁ1/k2 [Eqns (3)
and (4)] are more than 1000 times smaller for these
compounds compared with the case of diazomethane.
Upper limits were estimated by allowing the data for
diazoethane and diazopropane to be fit to Eqn (4),
although there is no compelling evidence for a downward
break in the plots of Fig. 1 for these compounds. The
results of the fits are indicated by the dashed lines through
the diamonds (diazoethane) and triangles (diazopropane).
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 483–488

DIAZONIUM ION CHEMISTRY
487
the transition state for proton transfer more product-like
with resonance delocalization more advanced. Second,
there is evidence that enhanced resonance electron-ac-
cepting ability of a carbanion stabilizing substituent, as iþn
the substitution of Nþ2 for NO2 in comparing CH3N2
with CH3NO2, can alleviate transition state imbalance
and result in a reversal of the ‘nitroalkane anomaly’.
Keefe and co-workers showed that in the loss of tropy-
lium cation to form nitronic acids:
substitutions to decelerate, through steric occlusion, the
rates of more classical SN2 substitutions.
EXPERIMENTAL
Inorganic and organic materials were obtained from
commercial suppliers. Unless indicated otherwise, these
were used as received. Amines, used for buffers, that
were liquids at room temperature were purified by dis-
tillation under a nitrogen or an argon stream. Acetonitrile
was distilled from, after reflux over, CaH. Water was
distilled in glass.
ð5Þ
Diazoalkanes were generated, from alkaline decomposi-
tion of the corresponding N-alkyl-N0-nitro-N0-nitrosoguani-
dines, as stock acetonitrile solutions for use within a single
day. The nitrosoguanidines were decomposed in a commer-
cially available (Sigma-Aldrich Fine Chemicals) ‘diazo-
methane generator’ by reaction of 50–100 mg of
nitrosoguanidine with 40% by weight aqueous sodium
hydroxide introduced to the solid dropwise by means of a
syringe. The gaseous diazoalkanes were collected by diffu-
sion into a 3–5 ml volume of stirred, initially dry, acetoni-
trile maintained at ꢁ30 ꢀC by an ethanol–water–CO2(s)
bath. After complete addition (over ꢃ10 min) of the sodium
hydroxide solution to the solid, an additional 30 min were
allowed for gaseous diffusion to proceed. The acetonitrile
solution containing the diazoalkane was then diluted by
addition of ꢃ20 ml of dry acetonitrile. This solution was
subsequently directly introduced into the stopped-flow
spectophotometer by means of a syringe.
Kinetics of decay of the diazoalkanes were initiated by
mixing 1 part of diazoalkane stock solution with 25 parts
aqueous solutions that were of 1.05 M ionic strength
(NaClO4). The decay of diazoalkane absorbance was
monitored at various wavelengths between 230 and
250 nm. The decay of absorbance exhibited good first-
order kinetics when monitored from between four and
seven half-lives of reaction. Values of the first-order rate
constant kobsd were determined from fits of data in this
time range. Checks were carried out at multiple wave-
lengths where appropriate for a given set of reaction
conditions that indicated that the values of kobsd were
independent of the wavelength monitored. Under other
conditions, data from single wavelengths were used
because background absorbance obviated monitoring at
wavelengths around 230 nm where the diazo group ab-
sorbs most strongly. Plots of kobsd against total buffer
concentration were linear for amine buffers employed,
and the slopes of these plots were taken as the second-
order rate constant kb. Extrapolation to zero buffer con-
centration gave the buffer independent rate constant k0.
the substrate giving rise to the most stable nitronic acid
(R1 ¼ R2 ¼ CH3) is indeed the most reactive—the oppo-
site what is observed in the proton loss to hydroxide of the
corresponding nitroalkanes.29 Hence the superior reso-
nance accepting ability of the Nþ2 group compared with
the NO2 group (see above) diminishes the expectation
that k will decrease upon alkyl for hydrogen substitu-
ꢁ1
tion on the diazonium ion in the reaction of Eqn (3).
To summarize the preceding discussion, both of the
above considerations suggest that there may be relatively
little imbalance in the proton transfer reactions of diazo-
nium ions. This carries the implication that a decrease in
the value of kꢁ1 on changing from methyl- to ethyl- or 1-
propyldiazonium ions might be slight to nil. In any case,
the change will not be of a direction or magnitude
sufficient to account for the more than 103-fold decrease
in kꢁ1/k2 indicated by the data in Fig. 1.
It is therefore concluded that much of the decrease in
kꢁ1/k2 in the change from the methyl- to the ethyl- and 1-
propyldiazonium ions must be ascribed to an increase in
the rate constant k2, the reaction rate constant for SN2
attack of water on the diazonium ions. This is opposite
the tendency of the ‘textbook’ SN2 substitution reaction,
which is generally decelerated by alkyl-for-hydrogen
substitution. An increase in k2 upon alkyl-for-hydrogen
substitutions may be anticipated for SN2 substitution on
alkyldiazonium ions on the basis of the aforementioned
calculations of Glaser’s group.18 They ascribed the re-
lative weakness of the C—N bond in the ethyl-compared
with methyldiazonium ion to the dissipation, by the
terminal methyl group in CH3CH2Nþ2 , of positive charge
on the central carbon that weakens the electrostatic
attraction of the negatively charged internal nitrogen in
the diazonium ion. An additional factor contributing to
the relative instability of the ethyl- and 1-propyldiazo-
nium ions may be the large amount of positive charge on
the central carbon in the exploded transition states that
typify SN2 substitution reactions of diazonium ions. The
energy of a carbocation-like transition state is expected to
be greatly stabilized by substitution of an alkyl group for
a hydrogen. These factors therefore appear to overcome
the well-characterized tendency of alkyl-for-hydrogen
Acknowledgment
This work was supported by the National Cancer Institute
(NIH) by grant RO1 CA52881.
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12. Pezacki JP, Shukla D, Lusztyk J, Warkentin J. J. Am. Chem. Soc.
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