Reinterpretation of the kinetic data and the non-steady state hypothesis (two-step mechanism) for the SN2 reaction between p-nitrophenoxide and methyl iodide in aprotic solvents containing water

Article abstract of DOI:10.1039/b302754f

Kinetic data obtained by conventional spectrophotometry for reaction of sodium p-nitrophenoxide with methyl iodide in degassed acetone are reported. The rate constants obtained from the first 10% of reaction do not differ significantly from those obtained over longer reaction times (e.g. 50% reaction)-the main criteria of Parker et al. (Org. Biomol. Chem., 2003, 1, 36-38) for a non-steady state two-step mechanism. Reactions are accelerated by crown ether, suggesting a mechanism via a free ion pair. Product studies by high performance liquid chromatography of reactions in aqueous acetonitrile (used by Parker et al.) show that the yield of methylated product is strongly affected by at least two base-neutralising side reactions.

Full text of DOI:10.1039/b302754f

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Reinterpretation of the kinetic data and the non-steady state
hypothesis (two-step mechanism) for the SN2 reaction between
p-nitrophenoxide and methyl iodide in aprotic solvents containing
water
Eduardo Humeres*a and T. William Bentleyb
a Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianopólis,
SC, Brazil
b Department of Chemistry, University of Wales, Swansea, Singleton Park, Swansea, Wales,
UK SA2 8PP
Received 13th March 2003, Accepted 16th April 2003
First published as an Advance Article on the web 29th April 2003
Kinetic data obtained by conventional spectrophotometry for reaction of sodium p-nitrophenoxide with methyl
iodide in degassed acetone are reported. The rate constants obtained from the first 10% of reaction do not differ
significantly from those obtained over longer reaction times (e.g. 50% reaction)—the main criteria of Parker et al.
(Org. Biomol. Chem., 2003, 1, 36–38) for a non-steady state two-step mechanism. Reactions are accelerated by crown
ether, suggesting a mechanism via a free ion pair. Product studies by high performance liquid chromatography of
reactions in aqueous acetonitrile (used by Parker et al.) show that the yield of methylated product is strongly affected
by at least two base-neutralising side reactions.
Table 1 Pseudo-first order rate constants obtained from slopes of
Introduction
plots of Ϫln Absorbance against time for reaction of sodium
p-nitrophenoxide with an excess of methyl iodide in acetone at 30.0 ЊCa
It has recently been suggested that the extents of reaction–time
profiles for reactions of p-nitrophenoxide (ArOϪ) with methyl
iodide (CH3I), obtained by stopped-flow spectrophotometry in
acetonitrile containing varying small amounts of water, deviate
significantly from those expected for the classical single-step
displacement of iodide; a non-steady state, two-step mechanism
was proposed to explain the observations that rate constants
obtained from the first 10% of reaction (i.e. the initial rate con-
stants) were slightly greater (1.1–1.7-fold) than corresponding
rate constants obtained from 50% of reaction.1 One of us has
recently reported conventional spectrophotometric kinetic
studies of the reaction of sodium p-nitrophenoxide with CH3I
in acetone and in aqueous mixtures,2 and Kondo et al. have
reported rate constants (obtained by titration of quenched
extracts) for reaction of tetramethylammonium p-nitrophen-
oxide with CH3I in dry acetonitrile.3 We now report additional
details of the spectrophotometric kinetic data, product studies
by high performance liquid chromatography (HPLC) of reac-
tions in aqueous acetonitrile, and a critical re-evaluation of the
non-steady state mechanism.1
MeI/M
Crown ether/M
103 kobs/sϪ1
0.054
0.107
0.187
0.107
0.107
0.000
0.000
0.000
0.104
0.230
1.15
2.28
4.00
11.7
27.3
a Followed by the disappearance of p-nitrophenoxide at 420 nm; good
linear fits to first order kinetics were observed over at least two half-lives
in acetone, and deviations disappeared after addition of crown ether;
sodium p-nitrophenoxide concentration ca. 10Ϫ5 M; average standard
deviation 3.3%.
monitored by stopped-flow.1 Good first order kinetics were not
observed unless the solvent was degassed, and if the solvent was
not degassed the initial rate constant was higher than the aver-
age rate constant. Other results (see below) provide a possible
explanation. Typical pseudo-first order rate constants are
summarised in Table 1; rate constants obtained from the initial
10% of reaction did not differ significantly (considering the
larger uncertainties) from those obtained by monitoring reac-
tions for longer times, even in the presence of water (Figs. 1 and
2). Addition of dicyclohexano-[18]-crown 6 increased reaction
rates—e.g., 0.1 M crown ether accelerated the reaction over
5-fold (Table 1).
Results
The disappearance of p-nitrophenoxide ion can readily be
monitored spectrophotometrically (λ = 420 nm, a wavelength
specific to the p-nitrophenoxide) at concentrations of about
10Ϫ5 M.1,2 Although pseudo-first order reactions could be
attained with concentrations of CH3I as low as 10Ϫ3 M, concen-
trations between 0.5 and 2 M were used for the stopped-flow
studies;1 even with this vast excess of CH3I, reaction times for
50% reaction were rather long (50–1600 s)1 for a method based
on rapid-mixing (ms range)—over relatively long reaction
times, diffusion of unreacted reagents into the spectrophoto-
meter cell could also occur. Our kinetic results (Table 1) were
obtained by conventional spectrophotometric measurements in
sealed, thermally-equilibrated cuvettes. with a 10-fold smaller
excess of CH3I (0.05–0.2 M).
The feasibility of monitoring reactions by HPLC analyses of
quenched aliquots was initially investigated using 5 × 10Ϫ5
M
p-nitrophenoxide solutions and a smaller excess of CH3I
(10Ϫ2 M); after several days at 25.0 ЊC the yellow solutions had
turned colourless. Similar results were obtained using more
CH3I (10Ϫ1 M) in a few hours of reaction at room temperature
(ca. 20 ЊC), and importantly, it was established by scanning
UV spectroscopy that after many half-lives the absorbance at
λ = 420 nm was zero (and also that the product solutions
absorbed strongly at 310 nm).
Reactions of p-nitrophenoxide with excess CH3I in acetone
were monitored spectrophotometrically for at least three half-
lives (Table 1), whereas no more than 50% of reaction was
Initially, yields of methyl ether product (ArOCH3) were low
(ca. 10%), and unreacted CH3I and p-nitrophenol were the only
other HPLC signals detected at 310 nm. Yields were increased
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 6 9 – 1 9 7 1
1969

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optimisation of A∞ as in the LSKIN program7 is not required,
and the error in the rate constant is reduced if the reaction is
monitored for longer times (Table 1).
The significance of degassing the solutions appears to be to
prevent partial quenching of the reaction by carbon dioxide. In
our spectrophotometric studies, all reagents (acetone, CH3I and
water) were degassed and protected from CO2. The absence of
secondary products and the stable absorbances in the presence
of excess base indicate that oxygen does not interfere with the
reaction (e.g. by phenolate oxidation) under our experimental
conditions. We also added iodine to reaction mixtures, but
no additional product was detected—iodine does react with
p-nitrophenol in aqueous solutions at 50 ЊC.8
Good pseudo-first order kinetics, for at least three half-lives,
were obtained for SN2 reactions of sodium p-nitrophenoxide
with an excess of CH3I in degassed dry acetone (Table 1,
Fig. 1), and good pseudo-first order kinetics were reported for
similar reactions of tetramethylammonium p-nitrophenoxide
in dry acetonitrile.3 It does not seem likely that reactions in
acetonitrile containing small amounts of water (0.04 to 2.0‚ v/v—
as used by Parker et al.1) will proceed by a different mechanism.
More likely, the presence of small amounts of water may intro-
duce competing base-quenching side reactions such as: (i) prior
presence or ingress of CO2, followed by a relatively slow hydra-
tion to give carbonic acid;9 (ii) photosolvolysis of CH3I (see
above), which could occur in the solution reservoirs or possibly
within the UV cell of a stopped-flow apparatus; (iii) prior pres-
ence of acetic acid, formed on heating acetonitrile during puri-
fication;10 (iv) possibly also hydrolysis of CH3I by hydroxide,
which may be present due to salt hydrolysis, depending on K
values and the water content of the solvent. As base-quenching
leads to the neutral phenol (ArOH), equilibria involving homo-
conjugate complexes [ArOH. . .ArOϪ] or [(ArOH)2. . .ArOϪ]11
may be significant. Also, the reactions are influenced by ion
pairing, which affects UV absorptions,12 and mechanistic
interpretations (see below).
Fig. 1 Pseudo-first order kinetics of the disappearance at 420 nm of
sodium p-nitrophenoxide, 10Ϫ5 M, at 30 ЊC in acetone, MeI 0.107 M,
in the presence of dicyclohexano-[18]-crown-6: ᭺, 43 mM; ∆, 71 mM;
ᮀ, 230 mM.
Fig. 2 Pseudo-first order kinetics of the disappearance at 420 nm of
sodium p-nitrophenoxide, 10Ϫ5 M, at 30 ЊC, MeI 0.107 M, in various
acetone–water mixtures. Acetone molar fraction: ∆, 1.0; ᭺, 0.60; ᮀ,
0.35; ∇, 0.10.
Rate enhancements in the presence of crown ether (Table 1)
are consistent with prior dissociation of p-nitrophenoxide to a
free anion, followed by reaction with CH3I, as suggested
independently for reactions in sulfolane at 40 ЊC.13 Also, the fit
to first order kinetics covers a greater extent of reaction when
crown ether is present (Table 1). The proposed mechanism is
shown in Scheme 1,2 where Kd is the equilibrium constant for
dissociation of the contact ion pair and k2 is the second order
rate constant for reaction between CH3I and the free anion.
when extra aliquots of base were added; also, when the reaction
mixture was protected from light, yields of ArOCH3 were
> 95%, indicating the possibility of acid production by photo-
solvolysis of CH3I. No other products were detected, even when
the reverse-phase HPLC column was sequentially eluted with
less polar eluents, including 100% methanol.
After 10Ϫ2 M aqueous sodium hydroxide solution was added
to 5 × 10Ϫ5 M p-nitrophenol in acetonitrile until a maximum
absorbance was achieved, the absorbance at 420 nm was stable
over a period of at least 20 minutes. However, partially neutral-
ised solutions gave a lower absorbance even when transferred
quickly (in the open air) from a cuvette to a flask and then back
to the cuvette. The solubility of carbon dioxide in acetonitrile at
25 ЊC is 0.28 M,4 so even though the partial pressure of CO2 in
air is only ca. 3 × 10Ϫ4 atmospheres, kinetically-significant
amounts of CO2 could dissolve in the acetonitrile. Both 10Ϫ2 M
sodium hydrogen carbonate and sodium carbonate also depro-
tonate p-nitrophenol, at least partially (as reaction of CO2 with
base gives HCO3Ϫ, base-quenching by CO2 will therefore be
incomplete).
Scheme 1 Ion pair dissociation followed by nucleophilic attack.
Ј
The observed second order rate constant (k2 ) is then given by
eqn. (1), where [Naϩ] is the concentration of free sodium ions.2
Ј
k2 = k2Kd/([Naϩ] ϩ Kd)
(1)
The mechanism proposed by Parker et al. is a reversible
second order process (Scheme 2)
Under steady state conditions the apparent second order rate
Discussion
Ј 2
constant (kapp), corresponding to k2 , is given by eqn. (2):1
Rates of reactions are usually reproducible to a precision of a
few %, and it is difficult to achieve a precision of < 1%.5,6 Initial
rates of reactions are more susceptible to errors, but the reliabil-
ity of the data for disappearance of p-nitrophenoxide ion is
improved because the absorbance at infinite time (A∞) is known
to be zero (see above). Consequently, the rate constant can
be obtained from the slope of a plot of Ϫln A against time,
kapp = kfkp/(kp ϩ kb)
(2)
Schemes 1 and 2 have three similar steps, and substituting
into eqn. (1), Kd = kf/kb and k2 = kp gives eqn. (3):
Ј
k2 = kfkp/([Naϩ]kb ϩ kf)
(3)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 6 9 – 1 9 7 1
1970

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Product studies were performed starting with a stock solu-
tion of p-nitrophenol (0.0138 g) in acetonitrile (10 ml) i.e. 9.9 ×
10Ϫ3 M; and 50 µL aliquots of the stock solution were diluted to
10 mL in a volumetric flask to give a 5 × 10Ϫ5 M solution, which
was neutralised by addition of aqueous sodium hydroxide (10Ϫ1
or 10Ϫ2 M); methyl iodide (up to 60 µL) was then added, and
aliquots (20 µL) were analysed by HPLC at 310 nm (absorbance
range 0.05).
Scheme 2 Mechanism of Parker et al.1
Eqn. (3) is the same form as eqn. (2), and according to
eqn. (3), the observed rate constant could vary slightly as the
reaction proceeds, because the term [Naϩ]kb varies slightly dur-
ing the reaction as one electrolyte (NaOAr) is replaced by
another (NaI). Consequently, there is no requirement for a non-
steady state hypothesis, such as that based on Scheme 2.1 Fur-
thermore, ion pairing was not considered in the recent study of
non-steady state elimination of HBr from 2-(p-nitrophenyl)-
ethyl bromide in alcohol–alkoxide,14 including a relatively high
concentration (0.3 M) of NaOEt in ethanol, solutions
known from conductimetric studies to involve substantial
ion-pairing.15
Acknowledgements
We are grateful to EPSRC (UK) for an equipment grant, and to
P. Douglas and D. N. Kevill for helpful discussions.
References
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Conclusions
Reaction of p-nitrophenoxide with an excess of CH3I in dry,
degassed acetone (Table 1) or dry acetonitrile3 shows good
pseudo-first order kinetics. Small deviations from first order
kinetics during the initial stages (ca. 10%) of reactions in very
dilute solutions (< 10Ϫ4 M) in the presence of small amounts of
water, leading to a recent suggestion of ‘the generality of the
two-step SN2 mechanism in solution’,1 can be interpreted either
by preferential reaction via a free anion (Scheme 1) and/or by
base-quenching side reactions.
9 F. A. Cotton and G. Wilkinson, Advanced Inorganic Chemistry,
4th edn., Wiley, New York, 1980, p. 366.
10 T. W. Bentley and S. J. Morris, J. Org. Chem., 1986, 51, 5005–5007.
11 J. F. Coetzee, Prog. Phys. Org. Chem., 1967, 4, 45–92.
12 G. Illuminati, L. Mandolini and B. Masci, J. Am. Chem. Soc., 1983,
105, 555–563.
13 E. S. Lewis and S. Vanderpool, J. Am. Chem. Soc., 1977, 99, 1946–
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15 S. F. Acree, Am. Chem. J., 1912, 48, 352.
Experimental
Materials and details of kinetic studies (Table 1) were as
described earlier.2 Product studies by HPLC were made using
Fisher HPLC grade solvents (acetonitrile,10 methanol and
water), and a Waters Nova-Pak C18 reverse phase column
usually eluted with 50% v/v methanol–water.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 6 9 – 1 9 7 1
1971