Benzenesulfonyl chloride with primary and secondary amines in aqueous media - Unexpected high conversions to sulfonamides at high pH

Article abstract of DOI:10.1139/v05-154

We have determined pH-yield profiles under pseudo-first-order conditions of the reactions of benzenesulfonyl chloride with a set of primary and secondary water-soluble alkylamines, and have found with certain amines, such as dibutylamine, a profile taking the form of a sigmoid pH-yield curve with relatively high yields of the sulfonamide persisting with increasing basicity up to and including 1.0 mol/L sodium hydroxide. This behaviour is quantitatively accounted for by invoking, in addition to the usual second-order reaction of the sulfonyl chloride with the amine, two third-order terms (i) one first-order in sulfonyl chloride, amine and hydroxide anion, and (H) another first-order in sulfonyl chloride and second-order in the amine. The importance of the third-order terms correlates approximately with the total number of alkyl carbon atoms in the amine, and this in turn is regarded as related to the hydrophobic character of the amine. Experiments to test this picture included: (i) observation of a bell-shaped curve with bis(2-methoxyethyl)amine, (H) in the reaction of dibutylamine in THF-H₂O (1:1), and also (iii) in the reaction of dibutylamine in 1.0 mol/L tetrabutylammonium bromide, and (iv) increase in the contributions of the third-order terms in 1.0 mol/L aqueous sodium chloride. Preparative reactions with dibutylamine, 1-octylamine, and hexamethylenimine in 1.0 mol/L aqueous sodium hydroxide with a 5% excess of benzenesulfonyl chloride gave, respectively, 94%, 98%, and 97% yields of the corresponding sulfonamides.

Full text of DOI:10.1139/v05-154

1525
Benzenesulfonyl chloride with primary and
secondary amines in aqueous media — Unexpected
high conversions to sulfonamides at high pH1
James F. King, Manjinder S. Gill, and Petru Ciubotaru
Abstract: We have determined pH–yield profiles under pseudo-first-order conditions of the reactions of benzenesulf-
onyl chloride with a set of primary and secondary water-soluble alkylamines, and have found with certain amines, such
as dibutylamine, a profile taking the form of a sigmoid pH–yield curve with relatively high yields of the sulfonamide
persisting with increasing basicity up to and including 1.0 mol/L sodium hydroxide. This behaviour is quantitatively ac-
counted for by invoking, in addition to the usual second-order reaction of the sulfonyl chloride with the amine, two
third-order terms (i) one first-order in sulfonyl chloride, amine and hydroxide anion, and (ii) another first-order in
sulfonyl chloride and second-order in the amine. The importance of the third-order terms correlates approximately with
the total number of alkyl carbon atoms in the amine, and this in turn is regarded as related to the hydrophobic character
of the amine. Experiments to test this picture included: (i) observation of a bell-shaped curve with bis(2-methoxyethyl)amine,
(ii) in the reaction of dibutylamine in THF–H2O (1:1), and also (iii) in the reaction of dibutylamine in 1.0 mol/L
tetrabutylammonium bromide, and (iv) increase in the contributions of the third-order terms in 1.0 mol/L aqueous so-
dium chloride. Preparative reactions with dibutylamine, 1-octylamine, and hexamethylenimine in 1.0 mol/L aqueous so-
dium hydroxide with a 5% excess of benzenesulfonyl chloride gave, respectively, 94%, 98%, and 97% yields of the
corresponding sulfonamides.
Key words: sulfonyl chlorides, primary and secondary amines, pH–yield profiles, organic synthesis in water, hydrophobic
effects.
Résumé : On a déterminé les profils pH–rendement dans des conditions de pseudo-premier ordre des réactions du
chlorure de benzènesulfonyle avec un ensemble d’alkylamines primaires et secondaires solubles dans l’eau et on a
trouvé avec certaines amines, telle la dibutylamine, que le profil de la courbe pH–rendement prend une forme sig-
moïde, avec des rendements relativement élevés de sulfonamide qui persistent avec une augmentation de la basicité jus-
qu’à l’hydroxyde de sodium 1,0 mol/L. Ce comportement peut être expliqué quantitativement en invoquant, en plus de
la réaction habituelle du deuxième ordre du chlorure de sulfonyle avec l’amine, deux termes de troisième ordre (i) une
du premier ordre en chlorure de sulfonyle, en amine et en ion hydroxyde et (ii) un autre du premier ordre en chlorure
de sulfonyle et du deuxième ordre en amine. L’importance des termes du troisième ordre donne une corrélation ap-
proximative avec le nombre total d’atomes de carbone de la chaîne alkyle de l’amine et ceci peut alors être considéré
comme relié au caractère hydrophobe de l’amine. Les expériences réalisées pour évaluer cette hypothèse incluent
(i) l’observation d’une courbe en forme de cloche avec la bis(2-méthoxyéthyl)amine et (ii) dans la réaction avec la di-
butylamine dans un mélange THF–H2O (1 : 1) et aussi (iii) dans la réaction de la butylamine dans le bromure de tétra-
butylammonium à 1,0 mol/L et (iv) une augmentation dans les contributions des termes du troisième ordre dans le
chlorure de sodium aqueux à 1,0 mol/L. Les réactions préparatives avec de la dibutylamine, de la 1-octylamine et de
l’hexaméthylèneimine dans de l’hydroxyde de sodium aqueux à 1,0 mol/L, en présence d’un excès de 5 % de chlorure
de benzènesulfonyle ont donné respectivement des rendements de 94 %, 98 % et 97 % des sulfonamides correspondants.
Mots clés : chlorures de sulfonyle, amines primaires et secondaires, profils pH–rendement, synthèse organique en mi-
lieu aqueux, effets hydrophobes.
[Traduit par la Rédaction] King et al. 1535
Received 7 April 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 25 November 2005.
J.F. King,2 M.S. Gill, and P. Ciubotaru. Department of Chemistry, The University of Western Ontario, London, ON N6A 5B7,
Canada.
1This article is part of a Special Issue dedicated to organic reaction mechanisms.
2Corresponding author (e-mail: scijfk@uwo.ca).
Can. J. Chem. 83: 1525–1535 (2005)
doi: 10.1139/V05-154
© 2005 NRC Canada

1526
Can. J. Chem. Vol. 83, 2005
Scheme 1.
Introduction
First order reaction
In recent times we have seen an increase of interest in the
use of water as a solvent for organic synthesis. Selectivity
and simplicity, and perhaps most significantly, cheapness,
low toxicity, and general environmental acceptability, are
among the benefits ascribed to reactions in water (1). Our
role in this revival has included pointing to eqs. [1] and [2]
for, respectively, (i) finding pHmax, the optimal pH for carry-
ing out reactions in water between a nucleophile (Nu) and a
hydrolysable electrophile (E), and (ii) pointing to the merits
of pH–yield profiles for seeing the variation in yield with
change in pH in such reactions when carried out under
pseudo-first-order conditions (2).
kw
PhSO2Cl + 2 H2O
PhSO2OH + Cl- + H3O+
Second order reactions
PhSO2Cl + H2O + OH-
kOH
PhSO2OH + Cl-+ H2O
kN
PhSO2NRR' + Cl-+ H3O+
PhSO2OH + Cl-+ RR'NH2
PhSO2Cl + RR'NH + H2O
PhSO2Cl + H2O + RR'NH
kGB
+
Third order reactions
kNN
-
+
PhSO2NRR' + Cl + RR'NH2
kNOH
PhSO2Cl + 2 RR'NH
PhSO2Cl + RR'NH + OH-
[1]
pHmax = 1/2 [log(kw/kOH) + pKw + pKa]
kN[Nu]
fp =
PhSO2NRR' + Cl-+ H2O
[2]
kw + kOH[OH−] + kN[Nu]
kN NuTKa /([H+] + Ka)
Cl
=
Cl
kw + kOHKw /[H+] + kN NuTKa /([H+] + Ka)
S
S
O
O
O
We were gratified to find in the reactions tested experi-
mentally, namely, benzenesulfonyl chloride with amines or
phenoxide anions, benzoyl chloride or acetic anhydride with
amines, and allyl bromide with β-dicarbonyl enolates, that
eq. [1] was invariably obeyed and eq. [2] commonly fol-
lowed. (Rate constants are defined in Scheme 1; [Nu] = con-
centration of free amine, NuT = [Nu] + [NuH+], i.e., the total
concentration of the amine species).
Ph
O
Ph
B
O
N
B
R'
R
H
H
H
1
2
B = H2O, RR'NH, OH-
Two forms of deviation from eq. [2] have been encoun-
tered, and to see how these may arise, it is appropriate to re-
call that conformance to eqs. [1] and [2] requires that the
rate law for the nucleophile–electrophile reaction in water be
given by eq. [3].
vention of hydrophobic effects. As a corollary to this con-
clusion, we wish to draw attention to the usefulness of pH–
yield experiments in the general problem of elucidating the
factors influencing the interaction of water with organic ma-
terials. The present paper is largely taken from two theses
(4); preliminary descriptions of our initial observations have
been given in conference presentations (5).
[3]
kobs = kw + kOH[OHG] + kN[Nu]
One form of deviation from eq. [2] was noted in the reac-
tions of benzenesulfonyl chloride with phenoxide anions (3)
and also with acetic anhydride and primary or secondary
amines (2b), and was ascribed to the consumption of a por-
tion (usually <10%) of the electrophile (E) by hydrolysis as-
sisted by the nucleophile (Nu) acting as a general base.
Addition of a term, kGB[Nu], to eq. [3], and modifying
eq. [2] by including the kGB[Nu] term in the denominator as
in eq. [4], led to quantitative agreement of theory and exper-
iment.
Results and discussion
Methods and materials
The products of the reactions showed acceptable IR and
1H and 13C NMR spectra, and, where the sulfonamide was
previously known, the properties were in accord with earlier
reports. Those sulfonamides not previously reported have
been characterized by spectra and high-resolution mass
spectrum (HR-MS) molecular weight determination as de-
scribed in the Experimental; further spectroscopic informa-
tion on the known compounds is given elsewhere (4).
Our procedures for rate measurement by pH-stat (6) and
determination of product yields by simple weighing of prod-
ucts (2) have already been described. In our initial experi-
ments, we encountered a difficulty in reproducing results at
high pH, and at least some of the problem is believed to
arise because of the high rates of the reactions being ob-
served and their sensitivity to mixing procedures. By using
very rapid stirring and making sure that the mixing protocols
varied as little as possible from one run to another, a fair
measure of reproducibility was generally observed; further
details are provided in the Experimental section. For reac-
[4]
fp =
kN NuTKa /([H+] + Ka)
kw + kOHKw /[H+] + (kN + kGB)NuTKa /([H+] + Ka)
The second deviation from eq. [2] was initially noted in
the reaction of benzenesulfonyl chloride with benzylamine
(Fig. 2 of ref. 2a); eq. [3] accurately predicts the yields for
pH values 6–11, but not for pH 12, where the experimental
yield is 65% and the predicted yield only 45%. We decided
to look more closely into this system and found, as is de-
scribed in this paper, an apparently hitherto unobserved
third-order reaction in which we have evidence of the inter-
© 2005 NRC Canada

King et al.
1527
Fig. 3. pH–yield profiles for the reaction of benzenesulfonyl
Fig. 1. pH–yield profiles for the reaction of benzenesulfonyl
chloride (initial concentration 7.8 × 10–4 mol/L) with primary
amines (0.01 mol/L) in water at 25.0 °C. Allylamine (᭹);
benzylamine (ٗ); and butylamine (᭡). Points are experimental
and lines are drawn using eq. [5] and the appropriate parameters
from Table 1.
chloride (initial concentration 7.8 × 10–4 mol/L) with secondary
amines (0.01 mol/L) in water at 25.0 °C: Dimethylamine (᭹);
dibutylamine (᭢); dipropylamine (᭿); and diethylamine (᭡).
Points are experimental and lines are drawn using eq. [5] and the
appropriate parameters from Table 1.
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
4
6
8
10
12
14
4
6
8
10 12 14
pH
pH
Fig. 4. pH–yield profiles for the reaction of benzenesulfonyl
chloride (initial concentration 7.8 × 10–4 mol/L) with secondary
amines (0.01 mol/L) in water at 25.0 °C: Morpholine (᭹);
piperidine (᭡); diallylamine (ٗ); and hexamethylenimine (᭢).
Points are experimental and lines are drawn using eq. [5] and the
appropriate parameters from Table 1.
Fig. 2. pH–yield profiles for the reaction of benzenesulfonyl
chloride (initial concentration 7.8 × 10–4 mol/L) with primary
amines (0.01 mol/L) in water at 25.0 °C: 2-Methoxyethylamine
(ٗ); 1-octylamine (᭹); and tert-butylamine (᭡). Points are ex-
perimental and lines are drawn using eq. [5] and the appropriate
parameters from Table 1.
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
4
6
8
10 12 14
pH
4
6
8
10 12 14
pH
tions on a scale too small for the weights to be informative,
yields were determined by quantitative UV analysis or by gas
chromatography as indicated in the Experimental section.
This observation that the amines with the largest number
of carbons showed the greatest tendency for a high yield of
sulfonamide at high pH suggested that the hydrophobic alkyl
groups could be leading to some form of association of or-
ganic molecules, especially at high pH where two factors,
(i) maximum concentrations of the (unprotonated) amines
and (ii) highest ionic strength due to the high concentration
of NaOH, combine to provide an environment most likely to
yield molecular association. One way of treating such hydro-
phobic factors would be to postulate two third-order terms
involving, respectively, (i) sulfonyl chloride and two mole-
cules of the amine (the kNN term) and (ii) sulfonyl chloride,
amine, and sodium hydroxide (the kNOH term). These are in-
cluded in the full reaction scheme shown in Scheme 1. The
rate constants derived from this treatment of the pH–rate and
pH–yield results are given in Table 1.
pH–yield profiles
Initial pH–yield profiles with primary and secondary
amines (Figs. 1–4) revealed a consistent pattern. The amines
with the smallest or most hydrophilic alkyl groups, e.g.,
allylamine and butylamine (Fig. 1), 2-methoxyethylamine
(Fig. 2), and morpholine and piperidine (Fig. 4) and, to a
lesser extent, dimethylamine (Fig. 3) and piperidine (Fig. 4),
showed roughly bell-shaped curves as observed earlier. Oth-
ers, however, notably dibutylamine (Fig. 3) and hexamethyl-
enimine (Fig. 4), showed sigmoid pH–yield curves strongly
reminiscent of simple titration curves. Other amines, e.g.,
diethylamine, dipropylamine, benzylamine, octylamine, and
tert-butylamine, showed intermediate behaviour, with a
clearly visible maximum yield near the expected pHmax, but
with the yield in the pH 13 to 14 region not near zero but
One should note in Scheme 1 that the simple second-order
reaction of the sulfonyl chloride with amine to yield the
sulfonamide (the kN reaction), as well as the simple hydroly-
sis term (kW term), are written with a molecule of water not
rather roughly half of that at pHmax
.
© 2005 NRC Canada

1528
Can. J. Chem. Vol. 83, 2005
Table 1. Rate constants for the reaction of benzenesulfonyl chloride with primary and secondary amines in water at 25.0 °C.
b
c
c
c
c
kNu
kN
kGB
kNN
kNOH
a
pKa
Amine
((mol/L)–1 s–1)
((mol/L)–1 s–1)
((mol/L)–1 s–1)
((mol/L)–2 s–1)
((mol/L)–2 s–1)
9.49
9.34
9.2
10.59
10.65
10.55
10.64
10.98
11
11.25
9.29
11.22
8.36
11.11
8.89
25
4.7×102
1.4×103
<1
2.5×102
3.0×103
<1
Allylamine
Benzylamine
2-Methoxyethylamine
Butylamine
Octylamine
tert-Butylamine
Dimethylamine
Diethylamine
Dipropylamine
Dibutylamine
Diallylamine
<0.1
1.2
<0.1
4.9
<0.1
0.09
10
<0.1
<0.1
<0.1
0.4
22.7
23.8
70.2
73
21.5
23.8
65.3
73
1
489
7.5×103
1.1×105
(3)
7.5×102
1.7×104
8.0×102
3.8×103
7.3×102
7.0×103
1.8×104
1.3×103
1.1×103
<1
499
6.1
8.9
4.6×104
6.0×102
5×102
4×103
<1
(2×102)
2.6×102
9.0×104
(1×102)
6.1
8.9
25.7
25.7
5.4
8.4×102
1.2×102
3.8×102
1.94
Piperidine
Morpholine
Hexamethylenimine
Bis(2-methoxyethyl)amine
899
126
440
1.94
60
6
60
<0.01
4.0×104
3.4×102
apKa values are from the collection of Jencks and Regenstein (7), except for the value for hexamethylenimine, which is from ref. 8, and that for bis(2-
methoxyethyl)amine, which was determined by the method of Albert and Serjeant (9).
bThe kNu values were obtained from pH-stat rate measurements of the reaction of benzenesulfonyl chloride (initial concentration 0.001 mol/L) with
0.01 mol/L solutions of the amine in water at 25.0 °C, as previously described (6). This procedure yields kNu as defined by the following modified form
of eq. [3]: kobs = kw + kOH[OHG] + kNu[Nu], where kNu = kN + kGB; Rogne’s values (10) for kw and kOH (3.06 × 10–3 s–1 and 40.4 (mol/L)–1 s–1, respectively)
were used.
cThe values of kN, kGB, kNN, and kNOH were obtained by an iterative manual least-squares procedure involving (i) assuming initially that kN ≈ kNu
(i.e., kGB ≈ 0) and finding (by the least-squares method) values for kNN and kNOH using eq. [5], (ii) evaluation of kGB from the three to five fp points at low-
est pH (believed to be only minimally influenced by kNN and kNOH) and finding the best least-squares fit within the constraint kN + kGB = kNu, and, where
appropriate, (iii) another round of least-squares calculations using both kN and kGB values carried out to obtain kNN and kNOH yielding minimal least-squares
sums. In the three cases for which kNu values were not measured, a preliminary value of kN was obtained by the best least-squares fit of the three to five
fp points at lowest pH, followed then by the procedure previously given for the other amines starting with kNu. The value preceded by the less than sign
(<) has been found to give a poorer least-squares fit than zero, i.e., the parameter is experimentally indistinguishable from zero. Parentheses enclosing a
few values indicate low reliability as indicated by a low sensitivity of the least-squares sum to change in that parameter.
required by minimal stoichiometry. This “extra” molecule of
water is included to reflect the high likelihood of general
base catalysis by water in these reactions in accord with
Jenck’s “libido rule” (11), which asserts that general base
catalysis is observed when the hydrogen being removed in
the reaction changes its acidity during the course of the reac-
tion from initially too weak to react with the general base, to
finally strong enough to readily protonate the general base.
In the present reaction of benzenesulfonyl chloride with an
amine, the hydrogen on the amine starts with a pKa around
35 and ends up in the absence of general base intervention in
an N-protonated sulfonamide with a pKa around –5 or lower
(12); note that water, the amine, and hydroxide anion (pKas
of conjugate acids are –1.7, -10, and 15.7, respectively) are
all capable of acting as general bases for sulfonamide forma-
tion. General base catalysis by a second molecule of water
in the simple hydrolysis of sulfonyl chlorides has been dis-
cussed elsewhere (13). The merit of looking at the simple
sulfonamide formation in this way becomes apparent on in-
spection of structures 1 and 2 whereby one may see that the
third-order terms (kNOH and kNN) are simply the aminolysis
analogues of the hydrolyses involving general base catalysis
by hydroxide and the amine, respectively.
With the addition of the third-order reactions, we obtain
eq. [5], the equation describing the pH–yield profile.
kN[Nu] + kNN[Nu]2 + kNOH[Nu][OH−]
[5]
fp =
kw + kOH[OH−] + kN[Nu] + kGB[Nu] + kNN[Nu]2 + kNOH[Nu][OH−]
Equation [5] may be expanded to be a function of [H+] (or
kOH, and kNu. With the other amines the same parameters
(including also a kGB term with some amines) in varying de-
grees of relative importance suffice to provide a satisfactory
fit to the observed pH–yield profiles.
By this treatment the only two reactions of any conse-
quence in this pH 13 to 14 region are the hydroxide pro-
moted reactions, the kOH reaction leading to the hydrolysis
pH) by substituting [Nu] = NuTKa/[H+] and [OH–] = KW/[H+].
As is shown in Figs. 5 and 6, by including the kNN and
kNOH terms the pH–yield profiles for three different initial
concentrations of dibutylamine are satisfactorily reproduced
by the same values of two parameters (kNN and kNOH), along
with, of course, the previously measured rate constants kw,
© 2005 NRC Canada

King et al.
1529
Fig. 6. pH–yield profiles for the reaction of benzenesulfonyl
chloride with dibutylamine (0.01 mol/L) showing the estimated
contributions of the individual sulfonamide forming reactions.
The individual reactions are each shown by a light line with the
appropriate subscript for that reaction from Scheme 1; the bold
line gives fp, the sum of the three component contributions.
Fig. 5. pH–yield profiles for the reaction of benzenesulfonyl
chloride with three concentrations of dibutylamine: 0.01 mol/L
(ٗ), 0.005 mol/L (᭡), and 0.001 mol/L (᭹). Points are experi-
mental and lines are drawn using eq. [5] and the appropriate pa-
rameters from Table 1.
1.0
0.8
0.6
0.4
0.2
0
4
6
8
10 12 14
pH
product and the kNOH process giving the sulfonamide, and
hence the product ratio (amide:acid) for the reaction in the
pH 13 to 14 region is given simply by the ratio of the rates
of these two processes, i.e., kNOH[Nu][OHG]/kOH[OHG]. At
high pH, NuT ≈ [Nu] and with cancelling of the [OHG]s, the
product ratio ≈ kNOHNuT/kOH. Similar reasoning from eq. [5]
gives fp14 ≈ kNOHNuT/(kNOHNuT + kOH), which in turn leads
to a serviceable approximation for obtaining a rough value
for kNOH, i.e., kNOH ≈ kOH/[(1/fp14 – 1)NuT], where fp14 is the
(actual or extrapolated) fractional yield at pH 14.
The case for the kNN term is perhaps less obvious than that
for kNOH but it appears appropriate to include it at this stage
because (i) it yields a substantially better fit to most ob-
served pH–yield curves, and (ii) it appears to be such an em-
inently likely process that its possible role would have to be
specifically examined anyway. As expected, the contribution
of the kNN term diminishes to negligible at very low amine
concentrations.
It should be mentioned that the kGB term is of limited im-
portance for most reactions in “straight” water. It was evi-
dently negligible (<1) for six of the amines and was found to
be less than 10% of kN in all cases except hexamethyl-
enimine; as will be discussed later, one of the effects of us-
ing 1 mol/L NaCl as solvent is a detectable increase in the
kGB term for certain amines.
An essential feature to notice in the rate constants in Ta-
ble 1 is the variation as the alkyl group increases in number
of carbon atoms. We illustrate by noting the pattern in kN for
the sequence dimethylamine, diethylamine, dipropylamine,
and dibutylamine (490, 6.1, 8.9, and 25.7 (mol/L)–1 s–1,
respectively). The drop in rate on changing from methyl to
ethyl is common among nucleophilic reactions of alkyl-
amines and is ascribed to increased nonbonding interactions
in the transition state with the extra carbon in the alkyl
group (14). With most nucleophilic reactions, however, the
following pattern is found: ethyl ≥ propyl ≥ butyl, etc. With
kN, however, there appears to be a small increase with size:
ethyl ≈ propyl < butyl. This, we suggest, points to a hydro-
phobic effect (1a, 15) even with the second-order terms.
The effect on the third-order rate constants is more dramatic,
with the kNOH values for diethylamine, dipropylamine,
and dibutylamine being 7.3 × 102, 7 × 103, and 1.8 ×
104 (mol/L)–2 s–1, respectively. In our view, it is fully con-
sistent with the influence of hydrophobic effects, to regard
both the second-order (kN) and third-order (kNOH) reactions
as proceeding by way of an initial amine – sulfonyl chloride
complex and that the complex reacts in a second step with
either water or hydroxide anion, respectively. The formation
of this complex is increased as the number of carbons in the
alkyl group(s) (and hence the hydrophobic character) of the
amine increases. With the second-order process, the second
step of the reaction is believed to involve reaction of this
complex with water acting as a general base as shown in
structure 2 (B = H2O). This reaction is comparatively slow,
and the transition states accordingly reflect well-developed
steric effects of the alkyl groups; increase of the “size” of
the alkyl group will therefore have two distinct effects:
(i) acceleration of the reaction by the hydrophobic effect;
and (ii) slowing of the reaction by the steric effect, with the
net result in this instance being a modest increase (approxi-
mately fourfold) on going from ethyl to butyl. With the
third-order (kNOH) process, the second step, namely reaction
of the complex with hydroxide anion (2, B = OH–), is a fast
reaction with an early transition state in which the steric ef-
fects of the alkyl groups plays a smaller role than the hydro-
phobic effect; the result is a 25-fold change on going from
diethylamine to dibutylamine.
Tests of the proposed mechanisms
The agreement of the observed and calculated pH–yield
curves and the consistency of the rate constants with a pic-
ture invoking a hydrophobic effect, though gratifying, is not
in itself sufficient to establish the mechanism outlined in
Scheme 1. Views on the complex field of hydrophobic ef-
fects (1a, 15) appear to concur in that the effect is (i) in-
creased by addition of certain solutes, especially salts such
as sodium chloride and sodium hydroxide, labeled as
“salting out”or “hydrophobic”, and (ii) diminished by other
solutes such as organic solvents (ethanol, DMSO, THF) or
certain other salts labeled as “salting in” or “antihydropho-
© 2005 NRC Canada

1530
Can. J. Chem. Vol. 83, 2005
Table 2. Rate constants for the reaction of benzenesulfonyl chloride with primary and secondary amines in mixed aqueous media at
25.0 °C.
b
b
b
b
b
kNu
kN
kGB
kNN
kNOH
pKa′ a
Amine
((mol/L)–1 s–1)
((mol/L)–1 s–1)
((mol/L)–2 s–1)
((mol/L)–2 s–1)
((mol/L)–2 s–1)
THF–H2O (1:1)
Aniline
Benzylamine
Dibutylamine
NaCl (1 mol/L in H2O)
Dimethylamine
Diethylamine
Dipropylamine
Dibutylamine
3.5
8.22
9.3
0.32
3.5
1.3
0.01
0.2
0.08
10.98
11.16
11.21
11.17
891
820
7.9
11.9
16.2
71
4.9×104
7.8×102
3.8×103
4.0×103
3.9×103
1.78×103
1.1×104
2.5×104
11.1
12.3
16.2
3.2
0.4
<0.1
aApparent pKa values determined in the specified media by the procedure of Albert and Serjeant (9). pH values were meter readings in the medium in
question, after standardization with aqueous buffers.
bRate constants were obtained as described in footnotes b and c of Table 1.
Fig. 7. pH–yield profiles for the reaction of benzenesulfonyl
chloride (initial concentration 7.8 × 10–4 mol/L) with amines
(0.01 mol/L) in THF–H2O (1:1) at 25.0 °C: aniline (∆), benzyl-
amine (᭺), and dibutylamine (ٗ). Points are experimental and
lines are drawn using eq. [5] and the appropriate parameters from
Table 2, plus kw = 1.5. × 10–4 s–1 and kOH = 1.8 (mol/L)–1 s–1 de-
termined from the pH–rate profile for this medium (4a).
in water alone; a third-order term (kNOH), somewhat reduced
relative to kN, is required to fit the curve adequately (4a).
It should be noted that the aq. THF experiments were also
of interest for the practical purpose of determining the ef-
fects of cosolvent on the validity of our pHmax equation
(eq. [1]) for use with amines with sufficiently low water sol-
ubility to make the experiment impracticable without addi-
tion of cosolvent. The chief effect of adding the organic
solvent appears to be the well-known lowering of the appar-
ent pKa of the amine; the pKa′ values are shown in Table 2.
pHmax values calculated from eq. [1] using pKa′ values deter-
mined in the solvent in question are in good accord with the
experimental ones. pHmax, as given in eq. [1], may be re-
1.0
0.8
0.6
0.4
0.2
0
garded as the average of pKa and pHi, with pHi = kW/kOH
+
Kw, where pHi is the inflection point in a pH–rate profile
(i.e., the pH at which kW = kOH[OH–]). Values of pHi for a
sizable array of electrophilic reagents were tabulated in our
earlier study (2a), and it was of interest to see the effect of
solvent change on pHi. We found, in fact, that the pHi values
are very similar: 9.88 in water (2a), 9.95 in THF–H2O (1:4),
and 9.92 in THF–H2O (1:1). This suggests that the effect of
the solvent change is similar for both the water and hydrox-
ide promoted reactions.
0
2
4
6
8
10 12 14
pH
bic”, such as guanidinium bromide or tetrabutylammonium
bromide. Accordingly, we have determined the effect of
adding examples of hydrophobic and antihydrophobic sol-
utes to the reaction mixtures and seeing the effect on the
pH–yield profiles.
Bis(2-methoxyethyl)amine
If indeed the effect noted at high pH with dibutylamine is,
in fact, due to hydrophobic association of benzenesulfonyl
chloride and dibutylamine, it is to be expected that a second-
ary amine of similar size and shape, but with relatively hy-
drophilic groups on the nitrogen atom, would show less of
this effect. To test this idea we have studied the reaction of
bis(2-methoxyethyl)amine ((CH3OCH2CH2)2NH), which is
an approximate isostere of dibutylamine in which one meth-
ylene group in each chain is replaced by the relatively polar
ether oxygen. The pH–yield profile for bis(2-methoxy-
ethyl)amine is shown in Fig. 8. As may be readily seen from
inspection of the curve or by inspection of the kNN and kNOH
values (Table 1), the results are consistent with a much re-
duced hydrophobic effect relative to dibutylamine.
Reactions in THF–H2O (1:1)
Our first venture was to carry out the reaction in aq. THF
(1:1). The results for aniline, benzylamine, and dibutylamine
are shown in Fig. 7. The curve for aniline is qualitatively
similar to that in water alone but with a lowered value for kN
(in water, kN = 4.6, kGB ≈ 0 (mol/L)–1 s–1 (2a); in THF–H2O
(1:1), kN = 0.32, kGB ≈ 0.006 (mol/L)–1 s–1; see Table 2). The
effect on the other two amines was much more striking —
and gratifying. With benzylamine there was no sign of any
hydrophobic effect and with dibutylamine only a small sign
of a possible third-order term was in evidence. Clearly, in
THF–H2O (1:1) the putative hydrophobic effect is very
much reduced.
Reactions in aq. NaCl solutions
pH yield profiles for dimethylamine, dipropylamine, and
dibutylamine in 1 mol/L aqueous sodium chloride solution
are shown in Fig. 9, and those for diethylamine in both 1
It is of interest that with THF–H2O (1:4), the pH–yield
profile for benzylamine is qualitatively very similar to that
© 2005 NRC Canada

King et al.
1531
Fig. 8. pH–yield profile for the reaction of benzenesulfonyl chlo-
ride (initial concentration 7.8 × 10–4 mol/L) with bis(2-
methoxyethyl)amine (0.01 mol/L). Points are experimental and
the line is drawn using eq. [5] and the appropriate parameters
from Table 1.
Fig. 10. pH–yield profiles for the reaction of benzenesulfonyl
chloride (initial concentration 7.8 × 10–4 mol/L) with diethylamine
(0.01 mol/L) in aq. NaCl at 25.0 °C: 1.0 mol/L (᭹) and
2.0 mol/L (᭺). Points are experimental and the line is drawn us-
ing eq. [5] as described for Fig. 9.
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
0
2
4
6
8
10
4
6
8
10
12
14
pH
pH
Fig. 9. pH–yield profiles for the reaction of benzenesulfonyl
chloride (initial concentration 7.8 × 10–4 mol/L) with amines
(0.01 mol/L) in aq. NaCl (1.0 mol/L) at 25.0 °C: dimethylamine
(᭿); dibutylamine (᭺); and dipropylamine (᭡). Points are exper-
imental and lines are drawn using eq. [5] and the appropriate pa-
The hydrophobic effect is expected to be stronger in so-
dium chloride solution than in water, and consistent with this
is the observation in the rise in the “plateau level”, i.e., the
value of fp in the pH range 11–14 with both dipropylamine
and dibutylamine, reflecting a small increase in kNOH relative
to kN on going from water to 1 mol/L NaCl solution.
The case of diethylamine is particularly interesting, show-
ing not only an increase in the plateau level (around pH 12
to 13), but also a further increase in fp presumably associated
with an increase of kNOH with change in ionic strength as the
pH changes from 13 to 14. If this picture is correct, it is in-
teresting — and surprising — that no analogous change in
the pH region 13 to 14 is apparent with dipropylamine or
dibutylamine. One possibility is that with these amines any
changes in kNOH are cancelled by other effects such as asso-
ciation of the amine with concomitant reduction in the con-
centration of the free amine and hence of the rate of the
reaction. It is of interest in this connection to look at the sol-
ubilities (at 25 °C) of these amines in water and 1 mol/L
NaCl solution: dibutylamine, 0.0348 and 0.0226 mol/L, re-
spectively; dipropylamine, 0.4434 and 0.2483 mol/L, respec-
tively; diethylamine, soluble in all proportions in both
media. The hydrophobic effect (salting out) clearly shows
with both dibutylamine and dipropylamine. Note that no line
is drawn through the points for 2 mol/L NaCl, as we were
unable to measure kw and kOH in this medium; the standard
kinetic plots did not yield straight lines pointing, not surpris-
ingly, to nonideal solution behaviour.
rameters from Table 2, plus kw = 2.74. × 10–3 s–1 and kOH
=
34.1 (mol/L)–1 s–1 determined from the pH–rate profile for this
medium (4b).
1.0
0.8
0.6
0.4
0.2
0
4
6
8
10
12
14
pH
and 2 mol/L NaCl solutions in Fig. 10; the derived rate con-
stants for the reactions in 1 mol/L NaCl are listed in Table 2.
In considering these results we must remember that much
of the effect of the sodium chloride is due to a change in
ionic strength, i.e., it leads to a more polar medium that is
more favorable than plain water to the development of
charge separation in the transition state. Most of the changes
that are observed in the reactions of dimethylamine are con-
sistent with such an ionic strength effect. We note, for exam-
ple, a modest increase in kN and, interestingly, a more
substantial effect (sevenfold increase) in kGB. This latter re-
sult is consistent with greater charge separation in the transi-
tion state in the kGB term than in the kN process. A sizable
increase in kGB (relative to kN) is also noted with diethyl-
amine along with a smaller increase with dipropylamine,
again presumably for the same reason.
It is evident that the full picture is probably very complex
and that an extensive study would be required for a more
complete understanding of the reactions in NaCl. It is our
view, however, that our observations, when taken with other
results presented in this study, are in full accord with the
presence of a hydrophobic effect on the kNOH terms of the
reactions of diethylamine, dipropylamine, and dibutylamine
in NaCl solutions.
Reactions in aqueous tetrabutylammonium bromide
solution
Solutions of tetrabutylammonium bromide are known to
lead to salting in of organic solutes. Accordingly, in the light
© 2005 NRC Canada

1532
Can. J. Chem. Vol. 83, 2005
Table 3. Observed % yields in the reactions of benzenesulfonyl chloride with primary and secondary
amines under preparative conditions.
% Yield below
pHmax (pH)
% Yield at
pHmax (pH)
% Yield in
1.0 mol/L NaOH
a
Amine
Butylamine
2-Methoxyethylamine
1-Octylamine
Dimethylamine
Diethylamine
Dibutylamine
Dipentylamineb
Morpholine
86.5 (8.2)
58.1 (7.0)
96.1 (8.5)
99.0 (10.2)
99.2 (9.5)
96.5 (10.3)
44.9, 44.0
56
98.3
91
87
94
97.8
73.2
89
51.7 (9.0)
77.7 (9.0)
94.3 (9.0)
44.8 (5.5)
75.5 (8.0)
85.1 (8.0)
94.8 (10.4)
88.4, 86.5 (10.6)
96.6 (10.5)
99.0 (9.15)
94.9 (10.55)
99.6 (10.6)
Piperidine
Hexamethylenimine
Diisobutylaminec
Diallylamine
97
69.9
76.9
59.0, 61.0
Bis(2-methoxyethyl)amine
91.0 (9.39)
Note: Benzenesulfonyl chloride (0.67 mL, 5.25 mmol) added to a solution (50 mL) of the amine (0.1 mol/L) either
(i) adjusted to the specified pH or (ii) in 1.0 mol/L aq. NaOH at 25 °C.
apHmax calculated from eq. [1] using the pKa values given in footnotes b and c and in Table 1.
bpKa = 11.18 (17).
cpKa = 10.50 (7).
presented to illustrate that the data for the reaction in
tetrabutylammonium bromide can indeed be readily accom-
modated on the basis of eq. [2] without invoking kNOH or
kNN. In other words, the phenomena leading to the sigmoid
pH–yield curve with benzenesulfonyl chloride and dibutyl-
amine in water would appear to have disappeared in the
tetrabutylammonium bromide solution, as predicted by the
hydrophobic effect picture.
Fig. 11. pH–yield profile for the reaction of benzenesulfonyl
chloride (initial concentration 0.001 mol/L) with dibutylamine
(0.01 mol/L) in aqueous tetrabutylammonium bromide (1.0 mol/L)
at 25.0 °C. Points are experimental. The line is drawn using
eq. [2] with kw = 3.06 × 10–3 s–1, kOH = 40.4 (mol/L)–1 s–1, and
kN = 71 (mol/L)–1 s–1 (see text).
1.0
0.8
0.6
0.4
0.2
0
Yields at high pH under preparative conditions
The pseudo-first-order conditions used in determining
most of the pH–yield profiles in this study involved low con-
centrations of the sulfonyl chloride with a 10-fold or greater
excess of the (total) amine. It is of interest to see to what ex-
tent the unusual features of reactions at high pH shown in
our pH–yield experiments show up under reaction conditions
more typical of organic synthesis.
Reactions were carried out by adding a 5% excess of
benzenesulfonyl chloride to a 0.1 mol/L solution of the
amine; these concentrations are distinctly higher than those
used in constructing the pH–yield profiles. As may be seen
from the results in Table 3, the yields at pHmax are high (usu-
ally close to or above 95%); yields below pHmax are invari-
ably lower though the difference is small in some cases. The
yields in 1.0 mol/L NaOH (“pH 14”) generally follow ex-
pectation based on pH–yield profiles. Some of the yields in
1.0 mol/L NaOH are high, e.g., octylamine (98.3%),
dipentylamine (97.8%), and hexamethylenimine (97.0%).
For these substrates, the high pH procedure is a simple and
surprisingly efficient procedure for preparing the benzene-
sulfonamides; note that the reaction leading to these yields is
primarily (99% or more) due to the kNOH term.
4
6
8
10
12
14
pH
of what has already been presented in this paper, it is to be
expected that the postulated hydrophobic effect would be re-
duced by carrying out the reaction in aqueous tetrabutyl-
ammonium bromide solution. In accord with this picture we
noted that the solubility of dibutylamine increased from
0.0348 mol/L in water to 0.0834 mol/L in 1.0 mol/L aque-
ous tetrabutylammonium bromide solution.
The pH–yield profile for the reaction of benzenesulfonyl
chloride (0.001 mol/L) with dibutylamine (0.01 mol/L) in
1 mol/L Bu4N+Br– at 25 °C is shown in Fig. 11. It is imme-
diately evident that the points form the normal bell shape as-
sociated with a system conforming to eq. [2] without any
need to invoke third-order terms. The line shown, which is
obtained from eq. [2] using the kw, kOH, and pKa parameters
for water plus kN = 71 (mol/L)–1 s–1 (a value obtained by a
manual least-squares fit to the experimental points), is
These results prompted us to see if any other electrophiles
reacted with dibutylamine with any sign of the involvement
of third-order terms. Accordingly, we compared preparative
runs at pH 11.40 (pHmax) and in 1.0 mol/L NaOH between
benzoyl chloride and dibutylamine and obtained yields of
© 2005 NRC Canada

King et al.
1533
97.5% and 84.2% (4a), respectively; neither this nor a lim-
ited number of points in a (partial) pH–yield profile pointed
to any sign of a third-order term. In addition, we had previ-
ously examined the pH–yield behaviour of acetic anhydride
with primary and secondary amines (2b), but had not specif-
ically looked at the reaction with dibutylamine. A pH–yield
profile of this reaction over the pH range 8.0–13.0 was
found (4b) to be well-described by eq. [4] with kN = 2.5 ×
103 (mol/L)–1 s–1 and kGB = 90 (mol/L)–1 s–1 taken with the
parameters previously used (2b). We conclude that neither
benzoyl chloride nor acetic anhydride shows a detectable
third-order term in its reaction with dibutylamine under our
conditions. It is probably not surprising that acetic anhydride
should show no detectable third-order term, since the anhy-
dride must be comparatively hydrophilic. The observation of
a third-order term with benzenesulfonyl chloride and the
failure to see any sign of a third-order term with its carbonyl
analogue, benzoyl chloride, raises the interesting question:
Why the difference? We have no firm evidence on the point,
but we note that the arrangement shown by 2 could be close
to an energy minimum for the electrophile–nucleophile com-
plex prior to any reaction. Movement of the electrons as
shown should take place readily and directly lead to the
sulfonamide in the favourable conformation in which the
free electron pair on the nitrogen is gauche to both oxygens
(16). With benzoyl chloride, on the other hand, no such fa-
vourable arrangement of the amine – acid chloride complex
comes readily to mind.
Experimental
Kinetic determinations were carried out with a pH-stat ap-
paratus consisting of a Radiometer pH meter (PHM 25)
equipped with GK2401B combination glass electrode (pH
range 0–14, temperature range 0–100 °C), and an Aminco
automatic burette with a 3 mL syringe reservoir. The reac-
tion vessel used was a Radiometer V520 vessel equipped
with a Radiometer V525 thermostatting jacket. The tempera-
ture was maintained with the aid of a Haake FJ constant
temperature circulating apparatus. Stirring was accomplished
with the use of a magnetic stirrer and the time was measured
with a Precision Scientific Co. electric timer. The pH appa-
ratus used for the pH–yield profiles consisted of either a
Sargent-Welch 6000 meter with a Fisher all range (pH 1–14)
combination electrode or a Radiometer pH meter (PHM 25)
as previously described. Evaporation of solvents was carried
out with a Büchi Rotovap apparatus connected to a water as-
pirator, and last traces of solvent were removed under vac-
uum until constant weight of the product was attained.
Melting points were obtained using either a Kofler hot stage
or a Gallenkamp apparatus and are uncorrected. H and 13C
1
NMR spectra were obtained using Varian Gemini 300 and
Varian Gemini 200 spectrometers. IR spectra were obtained
with either a PerkinElmer 2000 FT-IR spectrometer or a
Nicolet 205 FT-IR spectrometer. Reagent grade NaCl was
used in the experiments carried out in aqueous salt solutions;
in a few experiments with secondary amines, recrystallized
NaCl was used, but no significant difference from reagent
grade NaCl was detected. Benzenesulfonyl chloride and all
the amines were fractionally distilled prior to use. Dichloro-
methane was dried over calcium hydride and distilled prior
to use. The hydrochloride salts of amines were prepared by
addition of hydrogen chloride to solutions of the amines in
ether. The hydrochloride precipitates were collected by fil-
tration, recrystallized, and dried to constant weight; melting
points agreed with literature values. Authentic specimens of
the sulfonamides for comparison were typically prepared
from reaction of benzenesulfonyl chloride with excess amine
or with an equivalent amount of amine in the presence of
excess triethylamine, in dichloromethane at 0 °C to rt for 1–
3 h. The reaction mixture was treated with water; the aque-
ous layer was made acidic and was extracted with dichloro-
methane (3 × 50 mL). The organic layer was dried over
anhydr. MgSO4 and the solvent evaporated to the give the
corresponding sulfonamides in good yields (60%–90%).
Melting points (where previously reported) were in accord
Concluding comment
In this study we present evidence that the general reaction
of benzenesulfonyl chloride with primary and secondary
amines in water requires at least one, and probably two,
third-order terms (the kNOH and kNN terms, respectively). The
principal observation that led to this proposal was obtained
from pH–yield profiles, which showed, in all but the sim-
plest or most hydrophilic amines, higher yields of the
sulfonamide than predicted by the simplest mechanism. The
third-order terms show up especially with simple
alkylamines containing six or more alkyl carbon atoms, in
accord with the intervention of hydrophobic phenomena. Ex-
periments designed to disclose hydrophobic influences are in
accord with this view.
In principle, the existence of the third-order terms should
be detectable by conventional pH–rate studies, but as may be
seen from the rate constants in Table 1, the half-lives of the
reactions in the pH range in which the third-order terms are
important, are inconveniently short for at least the simpler
rate measurement techniques. The method of pH–yield pro-
files is a very easy procedure, which readily leads to infor-
mation on an array of pH-dependent processes. Use of this
procedure appears to be limited by variable yields under os-
tensibly identical conditions; this circumstance appears to
arise as a result of either (i) extremely fast reactions that
lead to difficulties with mixing effects or (ii) problems aris-
ing from low solubilities. Within the range in which repro-
ducible results are readily obtained, pH–yield profiles can be
a convenient source of valuable information, and further ex-
ploitation of the method is foreseen.
1
with literature values; all sulfonamides showed IR, H and
13C NMR spectra, and exact mass values in accord with the
assigned structures. Further details on known sulfonamides
may be found elsewhere (4); properties of previously un-
known sulfonamides are given in the following.
N-(2-Methoxyethyl)benzenesulfonamide
Clear liquid. IR (neat, cm–1) νmax: 3283 (br, s), 2930 (s),
2892 (s), 1448 (s), 1329 (s), 1162 (s), 1126 (s), 1090 (s),
1
1026 (w), 955 (w). H NMR δ: 3.12 (q, 2H), 3.23 (s, 3H),
3.38 (t, 2H), 5.44 (t, 1H, NH), 7.48–7.61 (m, 3H), 7.85–7.90
(m, 2H). 13C NMR δ: 42.7, 58.5, 70.4, 126.8, 129.0, 132.5,
139.8. HR-MS calcd. for C9H13NO3S: 215.0616; found:
215.0619.
© 2005 NRC Canada

1534
Can. J. Chem. Vol. 83, 2005
of the corresponding sulfonamide (product) of known con-
centrations in dichloromethane vs. the UV absorptions at
that particular wavelength.
N,N-Dipentylbenzenesulfonamide
Clear liquid. IR (neat, cm–1) νmax: 2958 (s), 2933 (s), 2872
(s), 1467 (w), 1447 (s), 1341 (s), 1157 (vs), 1091 (s), 1044
1
For reactions in THF–H2O, the previous procedure was
followed except that instead of water (500 mL), THF + H2O
(100 + 400 mL) was used for THF–H2O (20:80) and THF +
H2O (250 + 250 mL) was used for THF–H2O (50:50). After
the reaction was completed at a particular pH, the pH of the
reaction mixture was adjusted to 7 and most of the THF was
removed on the rotatory evaporator. The reaction mixture
was acidified to pH 2, followed by the workup as described
before. The yields are shown in Fig. 7 and the derived rate
constants listed in Table 2.
Reactions in tetrabutylammonium bromide (for reasons of
economy) were carried out on a relatively small scale:
benzenesulfonyl chloride (4.43 mg, 0.0251 mmol) in THF
(32 µL) was injected into 25 mL of an aqueous solution of
1.0 mol/L in Bu4N+Br– and 0.01 mol/L in dibutylamine ad-
justed to the desired pH as previously described. Workup in-
volved acidification to pH 1 with HBr, extraction with ether
(3 × 10 mL), drying of the extract with MgSO4, and evapo-
ration of the solvent to 25 mL. A known quantity of
nitrobenzene was added as internal standard and the amount
of sulfonamide determined by GC. Two larger scale runs us-
ing 0.032 mL of benzenesulfonyl chloride in 250 mL of a
solution 1 mol/L in tetrabutylammonium bromide and
0.01 mol/L in dibutylamine carried out as previously de-
scribed with simple weighing of the product, gave yields of
17% and 69% at pH 14.0 and 10.0, respectively, in agree-
ment with the smaller scale results.
(w), 950 (w). H NMR δ: 0.87 (t, 6H), 1.19–1.35 (m, 8H),
1.51 (quintet, 4H), 3.11 (t, 4H), 7.46–7.58 (m, 3H), 7.79–
7.83 (m, 2H). 13C NMR δ: 13.9, 22.2, 28.2, 28.8, 48.1,
126.9, 128.9, 132.1, 140.1. HR-MS calcd. for C16H27NO2S:
297.1763; found: 297.1766.
N-Phenylsulfonylhexamethylenimine
White solid, mp 34–34.5 °C. IR (cm–1) νmax: 3029 (w),
2936 (w), 1447 (w), 1331 (s), 1158 (vs), 1092 (w), 1045
1
(w). H NMR δ: 1.54–1.60 (m, 4H), 1.68–1.76 (br m, 4H),
3.27 (t, 4H), 7.47–7.56 (m, 3H), 7.78–7.81 (m, 2H). 13C
NMR δ: 26.8, 29.0, 48.1, 126.8, 128.9, 132.1, 139.4. HR-
MS calcd. for C12H17NO2S: 239.0980; found: 239.0982.
N,N-Bis(2-methoxyethyl)benzenesulfonamide
Pale yellow liquid, bp 160–162 °C (1 torr, 1 torr =
133.322 4 Pa). IR (cm–1) νmax: 2935 (s), 2883 (s), 1445 (s),
1337 (s), 1167 (s), 1120 (s), 941 (s), 735 (s), 685 (s), 590
1
(s). H NMR δ: 3.22 (s, 6H), 3.34, (t, 4H), 3.46 (t, 4H),
7.44–7.55 (m, 3H), 7.56–7.79 (m, 2H). 13C NMR δ: 48.5,
58.6, 71.3, 126.9, 128.8, 132.3, 139.7. HR-MS calcd. for
C12H19NO4S: 273.1034; found: 273.1028.
Reaction of benzenesulfonyl chloride with amines
Construction of pH–yield profiles
Benzenesulfonyl chloride (50 µL, 0.392 mmol) was
quickly injected from a 50 µL syringe into a vigorously
stirred solution of the amine (0.01 mol/L or 0.02 mol/L) in
water (500 mL) in a 800 mL beaker, previously adjusted to
the desired pH with dilute HCl or NaOH. The pH was main-
tained by dropwise addition of NaOH (0.5 mol/L or
0.1 mol/L) until it remained stable. The reaction mixture was
acidified to pH 2 with 1 mol/L H2SO4 and extracted with di-
chloromethane; the organic layer was dried over anhydr.
MgSO4, filtered, and the solvent was evaporated as previ-
ously described. The product was identified by comparison
Reactions under preparative conditions
Benzenesulfonyl chloride (0.67 mL, 5.25 mmol) was in-
jected into a solution of the amine (0.1 mol/L) in 50 mL of
water contained in a 100 mL beaker and previously adjusted
to the desired pH, and the mixture stirred until reaction was
complete (typically 1 to 2 h). The mixture was then acidified
to pH 2 with 1 mol/L H2SO4 and worked up by extraction
with dichloromethane as described for the pH–yield profiles
in water; yields are listed in Table 3.
1
of its H NMR with that of an authentic sample. The yields
were calculated from the constant weight of the product,
based on the theoretical yield, and shown as experimental
points in the figures. For the reactions at pH 14 and 13,
1 mol/L NaOH and 0.1 mol/L NaOH (500 mL), respectively,
were used. In the reaction with dimethylamine the beaker
was covered with Parafilm owing to the volatility of the
amine. Reactions in NaCl solutions were carried out simi-
larly, except for the use of 0.5, 1.0, or 2.0 mol/L NaCl solu-
tions in place of water.
Acknowledgements
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) for financial support
of this study. We thank Professor Mark Workentin for the
use of his GC apparatus and John Villella, Kevin Kulbaba,
and Rana Ibrahim for valuable preliminary experiments.
References
Reactions at lower concentrations required a modified
procedure. The reaction was conducted with amine concen-
trations of 0.002 or 0.001 mol/L and was carried out as
previosuly described except that the extracted solution of di-
chloromethane was dried over anhydr. MgSO4 and filtered
into a volumetric flask (100 or 250 mL) and the volume was
made up to mark with dichloromethane. The UV spectrum
of the solution was obtained and absorption at a particular
wavelength was recorded, for example, for N,N-dibutylben-
zenesulfonamide at λ = 275 nm. The yields were calculated
from a calibration curve, which was obtained from solutions
1. (a) R. Breslow. Acc. Chem. Res. 24, 159 (1991); (b) P.A.
Grieco. Aldrichimica Acta, 24, 59 (1991); (c) C.J. Li. Chem.
Rev. 93, 2023 (1993); (d) A. Lubineau, J. Augé, and Y.
Queneau. Synthesis, 741 (1994); (e) P.A. Grieco (Editor). Or-
ganic synthesis in water. Blackie Academic and Professional,
London. 1998; ( f ) C.J. Li and T.H. Chan. Organic reactions in
aqueous media. Wiley, New York. 1997; (g) R. Breslow. In
Green chemistry frontiers in benign chemical syntheses and
processes. Edited by P.T. Anastas and T.C. Williamson. Oxford
University Press, Oxford. 1998. Chap. 13; (h) C.-J. Li. In
Green chemistry frontiers in benign chemical syntheses and
© 2005 NRC Canada

King et al.
processes. Edited by P.T. Anastas and T.C. Williamson. Ox-
1535
11. W.P. Jencks. J. Am. Chem. Soc. 94, 4731 (1972).
ford University Press, Oxford. 1998. Chap. 14; (i) A. Lubineau
and J. Augé. Top. Curr. Chem. 206, 1 (1999).
12. J.F. King. In The chemistry of sulphonic acids, esters, and
their derivatives. Edited by S. Patai and Z. Rappoport. Wiley,
Chichester. 1991. Chap. 6. p. 249.
13. J.F. King and K.C. Khemani. Can. J. Chem. 67, 2162 (1989).
14. (a) J.-L.M. Abboud, R. Notario, J. Bertrán, and M. Solà. Prog.
Phys. Org. Chem. 19, 1 (1993); (b) W.A. Henderson, Jr. and
C.J. Schultz. J. Org. Chem. 27, 4643 (1962); (c) H.K. Hall, Jr.
J. Org. Chem. 29, 3539 (1964); (d) K. Okamoto, S. Fukui, I.
Nitta, and H. Shingu. Bull. Chem. Soc. Jpn. 40, 2350; 40,
2354 (1967).
15. (a) W. Blokzijl and J.B.F.N. Engberts. Angew. Chem. Int. Ed.
Engl. 32, 1545 (1993); (b) J.B.F.N. Engberts and M.J.
Blandamer. Chem. Commun. (Cambridge), 1701 (2001); (c) R.
Breslow. Acc. Chem. Res. 37, 471 (2004); (d) S. Otto and
J.B.F.N. Engberts. J. Org. Biomol. Chem. 1, 2809 (2003).
16. (a) T. Jordan, H.W. Smith, L.L. Lohr, Jr., and W.N. Lipscomb.
J. Am. Chem. Soc. 85, 846 (1963); (b) W.B. Jennings and R.
Spratt. Chem. Commun. (Cambridge), 1418 (1970); (c) J.F.
King, K.C. Khemani, S. Skonieczny, and N.C. Payne. Rev.
Heteroatom Chem. 1, 80 (1988).
2. (a) J.F. King, R. Rathore, J.Y.L. Lam, Z.R. Guo, and D.F.
Klassen. J. Am. Chem. Soc. 114, 3028 (1992); (b) J.F. King,
Z.R. Guo, and D.F. Klassen. J. Org. Chem. 59, 1095 (1994).
3. J.Y.L. Lam. Ph.D. thesis, The University of Western Ontario,
London, Ontario. 1992.
4. (a) M.S. Gill. Ph.D. thesis, The University of Western Ontario,
London, Ontario. 1996; (b) P. Ciubotaru. M.Sc. thesis, The
University of Western Ontario, London, Ontario. 1999.
5. (a) J.F. King, M.S. Gill, and D.F. Klassen. Pure Appl. Chem.
68, 825 (1996); (b) J.F. King, M.S. Gill, and P. Ciubotaru.
Sixth European Symposium on Organic Reactivity (ESOR-
VI), Louvain-la-Neuve, Belgium. July 1997. Abstract OC31.
6. J.F. King, S. Skonieczny, and J.Y.L. Lam. J. Am. Chem. Soc.
114, 1743 (1992).
7. W.P. Jencks and J. Regenstein. Handbook of biochemistry and
molecular biology. 3rd ed. Vol. 1. Edited by G.D. Fasman.
CRC Press, Cleveland. 1976. p. 305.
8. S. Bergström and G. Olofsson. J. Solution Chem. 7, 497 (1978).
9. A. Albert and E. P. Serjeant. Ionization constants of acids and
bases: a laboratory manual. Methuen, London. 1962.
10. O. Rogne. J. Chem. Soc. B, 1294 (1968).
17. N.F. Hall and M.R. Sprinkle. J. Am. Chem. Soc. 54, 3469
(1932).
© 2005 NRC Canada