Kinetic evaluation of the solvolysis of isobutyl chloro-and chlorothioformate esters

Article abstract of DOI:10.3762/bjoc.7.62

The specific rates of solvolysis of isobutyl chloroformate (1) are reported at 40.0 °C and those for isobutyl chlorothioformate (2) are reported at 25.0 °C, in a variety of pure and binary aqueous organic mixtures with wide ranging nucleophilicity and ionizing power. For 1, we also report the first-order rate constants determined at different temperatures in pure ethanol (EtOH), methanol (MeOH), 80% EtOH, and in both 97% and 70% 2,2,2- trifluoroethanol (TFE). The enthalpy ΔH≠ and entropy ΔS≠ of activation values obtained from Arrhenius plots for 1 in these five solvents are reported. The specific rates of solvolysis were analyzed using the extended Grunwald-Winstein equation. Results obtained from correlation analysis using this linear free energy relationship (LFER) reinforce our previous suggestion that side-by-side addition-elimination and ionization mechanisms operate, and the relative importance is dependent on the type of chloro-or chlorothioformate substrate and the solvent.

Full text of DOI:10.3762/bjoc.7.62

Kinetic evaluation of the solvolysis of
isobutyl chloro- and chlorothioformate esters
Malcolm J. D’Souza*1, Matthew J. McAneny1, Dennis N. Kevill*2,
Jin Burm Kyong*3 and Song Hee Choi3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 543–552.
1Department of Chemistry, Wesley College, 120 N. State Street,
Dover, DE 19901-3875, USA, 2Department of Chemistry and
Biochemistry, Northern Illinois University, DeKalb, IL 60115-2862,
USA and 3Department of Chemistry & Applied Chemistry, Hanyang
University, Ansan-si, Gyeonggi-do, 426-791, Korea
doi:10.3762/bjoc.7.62
Received: 07 February 2011
Accepted: 13 April 2011
Published: 29 April 2011
Email:
Guest Editor: J. Murphy
Malcolm J. D’Souza* - dsouzama@wesley.edu; Dennis N. Kevill* -
dkevill@niu.edu; Jin Burm Kyong* - jbkyong@hanyang.ac.kr
© 2011 D’Souza et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
addition–elimination; Grunwald–Winstein equations; ionization;
isobutyl chloroformate; isobutyl chlorothioformate; solvolysis
Abstract
The specific rates of solvolysis of isobutyl chloroformate (1) are reported at 40.0 °C and those for isobutyl chlorothioformate (2) are
reported at 25.0 °C, in a variety of pure and binary aqueous organic mixtures with wide ranging nucleophilicity and ionizing power.
For 1, we also report the first-order rate constants determined at different temperatures in pure ethanol (EtOH), methanol (MeOH),
80% EtOH, and in both 97% and 70% 2,2,2-trifluoroethanol (TFE). The enthalpy (ΔH≠) and entropy (ΔS≠) of activation values
obtained from Arrhenius plots for 1 in these five solvents are reported. The specific rates of solvolysis were analyzed using the
extended Grunwald–Winstein equation. Results obtained from correlation analysis using this linear free energy relationship (LFER)
reinforce our previous suggestion that side-by-side addition–elimination and ionization mechanisms operate, and the relative impor-
tance is dependent on the type of chloro- or chlorothioformate substrate and the solvent.
Introduction
Alkyl chloro- and chlorothioformate esters are frequently used development of compounds that are designed to either stimu-
precursors [1-4] in the synthesis of pharmaceutical intermedi- late or block other chemicals from interacting with targeted
ates. Hence, it is important to comprehend the correlations receptors. The effects of solvent variation upon the available
between their chemical structure, chemical reactivity, and specific rates of solvolysis of adamantyl [5,6], methyl [7], ethyl
solvent effects. This knowledge can then be applied to the [8], 2,2,2-trichloro-1,1-dimethylethyl [9], n-propyl [10], iso-
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Beilstein J. Org. Chem. 2011, 7, 543–552.
propyl [11,12], n-octyl [13], and neopentyl [14] chloroformate formation where the halogen atom is in a trans position with
esters, and those of methyl [15], ethyl [8], and isopropyl [16] respect to the alkyl group. In Figure 1, the molecular structures
chlorothioformate esters have been successfully analyzed using for syn-isobutyl chloroformate (1), syn-isobutyl chlorothiofor-
the extended [17-19] Grunwald–Winstein equation mate (2), phenyl chloroformate (3), phenyl chlorodithioformate
(Equation 1). In Equation 1, k and k0 are the specific rates of (4), and isopropyl chloroformate (5), and their corresponding
solvolysis in a given solvent and in the standard solvent (80% 3-D structures 1', 2', 3', 4' and 5' are shown in the most stable
ethanol), respectively, l estimates the sensitivity to changes in geometries for RXCXCl (where X = S or O) which exist in a
solvent nucleophilicity (NT), m represents the sensitivity to conformation where the C=X is syn with respect to R.
changes in the solvent ionizing power YCl, and c is a constant
(residual) term.
In a recent review [17], commemorating the 60th anniversary of
the Grunwald–Winstein equation, we previously published
reported analyses [5-8,10,11,13,39-49] that were obtained using
Equation 1, with examples of several alkyl and aryl chloro-,
chlorothio-, chlorothiono-, and dithiochloroformate esters. For
these esters, we proposed [17] side-by-side addition–elimina-
tion (AN + DN) and ionization (SN1) solvolytic mechanisms,
with proportions that were dependent on the type of RXCXCl
(X = O or S) substrate, solvent nucleophilicity, and the ionizing
ability of the solvents studied.
(1)
Kevill and Anderson developed NT scales based on the solvol-
yses of the S-methyldibenzothiophenium ion [20,21] for consid-
erations of solvent nucleophilicity, and Bentley et al. have
recommended YCl scales [22-25] based on the solvolyses of
adamantyl derivatives for estimating the sensitivity to solvent
ionizing power.
At one extreme when R = Ph in phenyl chloroformate
(PhOCOCl, 3), due to the presence of two electronegative
In reactions where the reaction center is adjacent to a π-system, oxygen atoms and the planarity of the phenoxy group (3'), com-
or in α-haloalkyl aryl compounds that proceed via anchimeric pound 3 [17,39,40] was found to solvolyze in all of the 49
assistance (k∆), Kevill and D’Souza proposed the addition of an solvents studied solely by an addition–elimination (AN + DN)
aromatic ring parameter (hI) term [26-28] to Equation 1 to give pathway (Scheme 1) with formation of the tetrahedral inter-
Equation 2. In Equation 2, h represents the sensitivity of solvol- mediate as the rate-determining step. When both oxygens are
yses to changes in the aromatic ring parameter I.
replaced by the more polarizable sulfur as in phenyl
chlorodithioformate (PhSCSCl, 4) [17,40,45], the mechanism of
reaction was found to completely switch over to an ionization
(SN1) pathway (Scheme 2) in all of the pure and binary aqueous
organic mixtures studied. This tendency to follow an ionization
process in such sulfur-for-oxygen substitutions occurs primarily
as a result of the formation of a more favored resonance-stabi-
lized transition-state (Scheme 2) [40,45].
(2)
Lee [29], Bentley [30] and others [3,31-38], used computa-
tional and experimental evidence to show that the chlorofor-
mate and chlorothioformate esters always exist in a syn con-
Figure 1: Molecular structures of syn-isobutyl chloroformate (1), syn-isobutyl chlorothioformate (2), phenyl chloroformate (3), phenyl chlorodithiofor-
mate (4), and isopropyl chloroformate (5). The 3-D images for syn-isobutyl chloroformate (1'), syn-isobutyl chlorothioformate (2'), phenyl chlorofor-
mate (3'), phenyl chlorodithioformate (4'), and isopropyl chloroformate (5') are also shown.
544

Beilstein J. Org. Chem. 2011, 7, 543–552.
Scheme 1: Stepwise addition–elimination mechanism through a tetrahedral intermediate for solvolysis of chloroformate esters.
Scheme 2: Unimolecular solvolytic pathway for the dithioformate esters.
We have since recommended [17] that the l (1.66) and m (0.56) inhibitors of the enzyme elastase [66]. In Figure 1, the 3-D
values obtained by using Equation 1 for the solvolyses of 3, and images of isobutyl chloroformate (1') and isobutyl chlorothio-
values of l (0.69) and m (0.95) obtained for the solvolyses of 4, formate (2') are presented. In these figures, it is clear that the
be taken as appropriate standards for the bimolecular isopropyl group is pushed out of the plane due the presence of a
addition–elimination and unimolecular ionization (without frag- carbon atom next to the ether or thioether atom in 1' and 2'.
mentation) pathways, respectively. The appreciable sensitivity This could have an impact on any potential steric or electronic
to solvent nucleophilicity (0.69) seen in the ionization–solvol- effects, due to presence of the isobutyl group, on the specific
ysis of 4, points to strong rear-side nucleophilic solvation of the rates of reaction.
developing resonance-stabilized carbocation. Another useful
tool for mechanistic studies is the l/m ratio. We have found [17] In this article we present determinations of the specific rates of
that values >2.7 are typical of solvolytic mechanisms reaction for isobutyl chloroformate (iBuOCOCl, 1) at 40.0 °C
proceeding by an addition–elimination pathway with the addi- and of isobutyl chlorothioformate (iBuSCOCl, 2) at 25.0 °C in a
tion-step being rate-determining (Scheme 1). Ratios between variety of pure and binary aqueous organic solvents with wide
0.5 and 1.0 signify a unimolecular ionization mechanism with ranging nucleophilicity and ionizing power values. Using Equa-
strong rear-side nucleophilic solvation of the developing reso- tion 1, we analyze in detail values for l and m obtained for 1 and
nance-stabilized transition-state, while l/m values <<0.5 are in- 2 compared to those of the recommended standards (3 and 4)
dicative of an ionization–fragmentation process.
for such substrates, and also in comparison to the l and m values
of other previously reported alkyl chloro- and chlorothiofor-
Early studies by other groups favored competing SN1 and SN2 mate esters. We will also seek evidence for any changes in
pathways for the alkyl chloro-, chlorothio-, chlorothiono-, and mechanism due to the presence of the isobutyl group. For 1, we
dithiochloroformates [50-59]. Upon evaluating the rates of report studies at additional temperatures in five organic solvents
hydrolysis in aqueous solvents, Queen [54,55] suggested that to determine the corresponding values of the enthalpy (ΔH≠)
with increasing electron donation to the chlorocarbonyl group in and entropy (ΔS≠) of activation.
alkyl chloro- and chlorothioformates, the positive entropies and
low solvent isotope effects pointed to a mechanism involving a Results and Discussion
unimolecular acyl–halogen bond fission. More recent studies on The specific rates of solvolysis of 1 at 40.0 °C and of 2 at
alkyl and aryl chlorothio-, chlorodithio-, and chlorothionofor- 25.0 °C, are reported in Table 1. Also presented in Table 1 are
mate esters favor a stepwise mechanism via a zwitterionic tetra- the NT and YCl values needed for the multiple correlation
hedral intermediate [60-65].
analysis of the assembled data using Equation 1.
Isobutyl chloroformate (1) and isobutyl chlorothioformate (2) For 1, we report in Table 2 the first-order rate constants deter-
have found use as specific precursors in novel synthetic routes mined at different temperatures in pure ethanol (EtOH),
for the preparation of peptidyl carbamate and thiocarbamate methanol (MeOH), 80% EtOH, 97% 2,2,2-trifluoroethanol
545

Beilstein J. Org. Chem. 2011, 7, 543–552.
Table 1: Specific rates of solvolysis (k) of isobutyl chloroformate (1) and isobutyl chlorothioformate (2), in several binary solvents and literature values
for NT and YCl.
1 at 40.0 °C
104 k (s−1)b
2 at 25.0 °C
105 k (s−1)b
Solventa
NTc
YCld
100% MeOH
90% MeOH
3.28 ± 0.04
6.25 ± 0.03
2.27 ± 0.14
4.63 ± 0.22
7.57 ± 0.19
0.17
−0.01
−0.06
−0.40
0.37
−1.2
−0.20
0.67
1.46
−2.50
−0.90
0.00
0.78
1.38
2.02
−2.39
−0.80
0.17
1.00
2.83
2.85
2.96
3.16
1.89
0.63
0.60
−0.48
−1.42
5.17
4.41
3.83
80% MeOH
8.74 ± 0.08
70% MeOH
11.6 ± 0.2
100% EtOH
0.848 ± 0.053
1.97 ± 0.05
1.01 ± 0.09
1.22 ± 0.10
2.99 ± 0.13
90% EtOH
0.16
80% EtOH
2.65 ± 0.02
0.00
70% EtOH
3.28 ± 0.02
−0.20
−0.38
−0.58
−0.35
−0.37
−0.42
−0.52
−3.30
−2.55
−1.98
−1.73
−1.76
−0.94
−0.64
−0.34
0.08
60% EtOH
4.19 ± 0.05
50% EtOH
5.12 ± 0.05
90% Acetone
80% Acetone
70% Acetone
60% Acetone
97% TFE (w/w)
90% TFE (w/w)
70% TFE (w/w)
50% TFE (w/w)
80% T-20% E
60% T-40% E
50% T-50% E
40% T-60% E
20% T-80% E
97% HFIP (w/w)
90% HFIP (w/w)
70% HFIP (w/w)
0.113 ± 0.027
0.316 ± 0.002
0.652 ± 0.004
1.02 ± 0.02
0.201 ± 0.015
1.06 ± 0.09
0.0511 ± 0.0007
0.0690 ± 0.0004
0.263 ± 0.005
0.775 ± 0.002
0.0289 ± 0.0005
0.106 ± 0.001
6.01 ± 0.10
11.7 ± 0.8
40.8 ± 2.3
1.47 ± 0.09
0.688 ± 0.007
0.299 ± 0.021
0.465 ± 0.016
0.521 ± 0.027
66.0 ± 2.9
0.283 ± 0.008
0.561 ± 0.006
−5.26
−3.84
−2.94
48.2 ± 1.6
78.4 ± 2.0
aSubstrate concentration of ca. 0.0052 M; binary solvents on a volume–volume basis at 25.0 °C, except for TFE-H2O and HFIP-H2O (1,1,1,3,3,3-
hexafluoro-2-propanol/water) solvents which are on a weight–weight basis. T-E are TFE-ethanol mixtures. bWith associated standard deviation.
cReferences [20,21]. dReferences [22-25].
(TFE) and 70% TFE. The corresponding enthalpy (ΔH≠) and important role. The very negative entropies of activation
entropy (ΔS≠) of activation values obtained from Arrhenius observed for 1 in the aqueous alcohols are typical for substrates
plots for 1 in these five mixtures are also reported in Table 2. that undergo solvolysis by a bimolecular process. The negative
entropies of activation (−28.6 to −30.4 cal mol−1 K−1) in EtOH,
The l, m, and c values obtained for 1 and 2, together with the MeOH and 80% EtOH are similar to those observed for the
multiple correlation coefficients (R) and the F-test values are simplest primary alkyl chloroformate, methyl chloroformate
reported in Table 3, together with corresponding values from (MeOCOCl) [67], where attack at the acyl carbon in an addi-
the literature for solvolyses of other chloroformate and tion–elimination (AN + DN) process was indicated as the rate-
chlorothioformate esters.
determining step. In order to evaluate the details of the interac-
tions at the transition-state for 1, we statistically analyzed (using
As can be seen in Table 1, the pseudo first-order rate constants Equation 1) the rates of reaction using multiple regression
for 1 and 2 gradually increase as the amount of water is analysis. In all 22 solvents we obtained l = 1.11 ± 0.14, m =
increased in the binary aqueous–organic solvents. This observa- 0.43 ± 0.08, R = 0.886, F-test = 35, and c = 0.01 ± 0.10. The
tion holds true even in the highly ionizing fluoroalcohols and poor correlation coefficient and rather low F-test value was a
can be attributed to solute–solvent interactions in the transition- strong indication of the possibility of superimposed dual mecha-
state where both nucleophilicity and ionizing power play an nisms occurring within the range of solvent systems studied.
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Beilstein J. Org. Chem. 2011, 7, 543–552.
Table 2: Specific rates for solvolysis of isobutyl chloroformate (1) at various temperatures and the enthalpies and entropies of activation.
Solventa
Temp. (°C)
104 k (s−1)
ΔH≠ (kcal mol−1)b
ΔS≠ (cal mol−1K−1)b
40.0
45.0
50.0
55.0
3.27 ± 0.05
4.63 ± 0.04
6.85 ± 0.06
9.54 ± 0.07
100% MeOH
14.1 ± 0.3
−29.6 ± 0.9
40.0
45.0
50.0
55.0
0.848 ± 0.005
1.27 ± 0.01
1.89 ± 0.02
2.71 ± 0.02
100% EtOH
80% EtOH
70% TFE
15.2 ± 0.05
14.0 ± 0.1
20.6 ± 0.4
21.5 ± 0.2
−28.6 ± 0.2
−30.4 ± 0.3
−13.8 ± 1.3
−14.3 ± 0.6
40.0
45.0
50.0
55.0
2.65 ± 0.02
3.85 ± 0.05
5.53 ± 0.05
7.732 ± 0.08
40.0
45.0
50.0
55.0
0.263 ± 0.006
0.468 ± 0.004
0.775 ± 0.004
1.26 ± 0.01
40.0
55.0
60.0
65.0
0.0511 ± 0.0007
0.266 ± 0.003
0.429 ± 0.009
0.704 ± 0.006
97% TFE
aVolume–volume basis at 25.0 °C. bWith associated standard error.
As mentioned in the introduction, PhOCOCl (3) was shown to correlation with R = 0.913, F-test = 101, slope = 0.62 ± 0.06,
solvolyze in all of the 49 solvents studied by the addition–elimi- and c = −0.08 ± 0.08. It is further observed in Figure 2 that the
nation process with a rate-determining addition step [39,40]. four aqueous TFE mixtures clearly lie above the line of best fit.
Using the similarity model concept [68], a plot of log (k/k0) for Removal of these four points significantly improves the correla-
iBuOCOCl (1) in the 22 solvents studied against log (k/k0) for tion analyses between 1 and 3 with results of R = 0.988, F-test =
PhOCOCl (3) is shown in Figure 2. This plot results in a weak 659, slope = 0.947 ± 0.04 and c = −0.02 ± 0.03. This indicates
that the mechanism of reaction for 1 and 3 in the remaining 18
pure and binary solvents (no aqueous TFE solvents) are iden-
tical.
For 1, analysis was performed for 18 solvents (no aqueous TFE)
using Equation 1, and we obtained (reported in Table 3) l = 1.82
± 0.15, m = 0.53 ± 0.05, R = 0.957, F-test = 82, and c = 0.18 ±
0.07. Such improvements seen in the correlation coefficient and
F-test values for solvolyses of 1 on removal of the four aqueous
TFE mixtures indicate that the data is now robust (Figure 3).
The l/m ratio of 3.43 falls within the range (shown in Table 3)
observed for the other alkyl chloroformate esters in the more
nucleophilic solvents.
Previous solvolytic studies with primary alkyl chloroformates
such as methyl chloroformate (MeOCOCl) [7], ethyl chlorofor-
Figure 2: The plot of log (k/k0) for iBuOCOCl (1) against log (k/k0) for
PhOCOCl (3).
mate (EtOCOCl) [8], and n-propyl chloroformate (n-PrOCOCl)
[10] provided evidence that a bimolecular association–dissocia-
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Beilstein J. Org. Chem. 2011, 7, 543–552.
these three substrates in the more nucleophilic solvents (listed
in Table 3) are almost identical in value (2.74, 2.84, and 2.79,
respectively) and are very similar to the value of 2.94 observed
for 3.
The only two branched alkyl chloroformates that have been
studied in detail using a Grunwald–Winstein analysis are iso-
propyl chloroformate (iPrOCOCl) [11,12] and neopentyl chlo-
roformate (neoPenOCOCl) [14]. The secondary alkyl chlorofor-
mate, iPrOCOCl (5) [11,12], was found to solvolyze in a
majority of the solvents studied by a mechanism similar to that
proposed for the tertiary 1- or 2-adamantyl chloroformates
[5,6]. This pathway included a unimolecular fragmentation–
ionization process with loss of carbon dioxide [5,6,11,12]. For
5, in nine of the more nucleophilic solvents the l/m ratio of 3.38
(Table 3) was a typical value for an addition–elimination
(association–dissociation) mechanism [12].
Figure 3: The plot of log (k/k0) for isobutyl chloroformate (1) against
1.82 NT + 0.53 YCl in eighteen pure and binary solvents. The points for
the four aqueous TFE values were not included in the correlation.
They are added here to show the extent of their deviation.
We have proposed that neopentyl chloroformate (neoPenO-
COCl) [14] solvolyzes in the HFIP rich mixtures with a
tion (addition–elimination) process was favored in the more Wagner–Meerwein 1,2-methyl shift leading to the formation of
nucleophilic solvents, while an ionization pathway was domi- a tertiary pentyl cation. In 13 of the more nucleophilic solvents
nant in the highly ionizing solvents, including the fluoroalco- the l/m ratio of 3.67 (Table 3) for neoPenOCOCl was found to
hols with high fluoroalcohol content [7,8,10]. The l/m ratios for be typical of a bimolecular AN + DN process [14].
Table 3: Correlation of the specific rates of solvolysis of iBuOCOCl and iBuSCOCl (this study) and several other chloroformate and chlorothioformate
esters (values from the literature), using the extended Grunwald–Winstein equation (Equation 1).
Substrate
na
lb
mb
cb
l/m
Rc
Fd
Mechanism
PhOCOClg
2-AdOCOClg
1-AdOCOClg
MeOCOClg
EtOCOClg
49
19
11
19
28
7
1.66 ± 0.05
0.03 ± 0.07
0.08 ± 0.20
1.59 ± 0.09
1.56 ± 0.09
0.69 ± 0.13
1.57 ± 0.12
0.40 ± 0.12
1.35 ± 0.22
0.28 ± 0.04
1.82 ± 0.15
1.76 ± 0.14
0.36 ± 0.10
0.69 ± 0.05
1.48 ± 0.18
0.79 ± 0.06
0.66 ± 0.08
0.38 ± 0.11
0.42 ± 0.13
1.74 ± 0.17
0.62 ± 0.08
0.56 ± 0.03
0.48 ± 0.04
0.59 ± 0.05
0.58 ± 0.05
0.55 ± 0.03
0.82 ± 0.16
0.56 ± 0.06
0.64 ± 0.13
0.40 ± 0.05
0.59 ± 0.04
0.53 ± 0.05
0.48 ± 0.06
0.81 ± 0.14
0.95 ± 0.03
0.44 ± 0.06
0.85 ± 0.07
0.93 ± 0.07
0.72 ± 0.09
0.73 ± 0.09
0.48 ± 0.07
0.92 ± 0.11
0.15 ± 0.07
−0.10 ± 0.09
0.06 ± 0.08
0.16 ± 0.07
0.19 ± 0.24
−2.40 ± 0.27
0.15 ± 0.08
−2.45 ± 0.27
0.18 ± 0.07
−0.32 ± 0.06
0.18 ± 0.07
0.14 ± 0.08
−2.79 ± 0.33
0.18 ± 0.05
0.08 ± 0.08
−0.27 ± 0.18
−0.16 ± 0.31
−0.28 ± 0.10
−0.37 ± 0.13
0.19 ± 0.23
−2.29 ± 0.13
2.95
0.06
0.14
2.74
2.84
0.84
2.79
0.63
3.38
0.47
3.43
3.67
0.44
0.72
3.36
0.93
0.71
0.53
0.58
3.63
0.67
0.980
0.971
0.985
0.977
0.967
0.946
0.947
0.942
0.960
0.982
0.957
0.977
0.938
0.987
0.949
0.987
0.961
0.961
0.961
0.946
0.983
568
130
133
171
179
17
A–Ee
If
If
A–E
A–E
SN1
A–E
SN1
A–E
If
n-PrOCOClg
22
6
83
11
iPrOCOClg
9
35
16
18
13
8
176
82
iBuOCOClh
A–E
A–E
SN1
SN1
A–E
SN1
SN1
SN1
SN1
A–E
SN1
neoPenOCOClg
226
18
PhSCSClg
MeSCOClg
31
12
8
521
40
95
EtSCOClg
iPrSCOClg
iBuSCOCli
PhSCOClg
19
19
15
16
6
96
97
73
55
44
an is the number of solvents. bWith associated standard error. cMultiple Correlation Coefficient. dF-test value. eAddition–elimination. fIonization–frag-
mentation. gSee text for references giving the source of this data. hNo 97–50% TFE. iNo 100%, 90% EtOH and MeOH, no 20% T-80% E.
548

Beilstein J. Org. Chem. 2011, 7, 543–552.
The higher errors associated with the l values, and the higher Grunwald–Winstein analysis using Equation 1 for isobutyl
l/m ratios observed for iBuOCOCl (1), iPrOCOCl (5), and chlorothioformate (2) in all 20 solvents studied (Table 1)
neoPenOCOCl, in the more nucleophilic solvents (3.43, 3.38, resulted in l = 0.34 ± 0.18, m = 0.57 ± 0.13, R = 0.873, F-test =
and 3.67, respectively) when compared to the l/m ratio obtained 27, and c = −0.11 ± 0.17. This scatter can be resolved by
for 3 (2.95), is due to a limited range of solvents in which the excluding the rate data for 2 in 100% EtOH, 90% EtOH, 100%
AN + DN mechanism is operative. This view is supported by the MeOH, 90% MeOH, and 20% T-80% E. In the remaining 15
multiple regression analysis of 3 in the same 18 solvents used solvents, the correlation coefficient (R) improves significantly
for 1, where an AN + DN mechanism is proposed, which yields l to 0.961, the F-test value rises to 73, l = 0.42 ± 0.13, m = 0.73 ±
= 1.96 ± 0.14, m = 0.49 ± 0.05, R = 0.965, F-test = 101, and c = 0.09, and c = −0.37 ± 0.13 (Table 3). A plot of log (k/k0) for
0.23 ± 0.07 such that the l/m ratio for 3 is 4.00.
isobutyl chlorothioformate (2) against 0.42 NT + 0.73 YCl is
shown in Figure 4 with the five deviating points included.
As shown in Table 1, the nucleophilicity (NT) values for the
four aqueous TFE solvents range from a very low value of
−3.30 in 97% TFE (w/w), to −1.73 in 50% TFE (w/w), while
the ionizing power values (YCl) vary only slightly (2.83–3.16).
A plot of log (k/k0)1 against NT in these four solvents results in
a slope (l) = 0.72 ± 0.22 (0.08 probability that the term is statis-
tically insignificant), R = 0.919, F-test = 11, and c = 0.51 ±
0.54. This l value is within the magnitude seen in aqueous fluo-
roalcohols for other alkyl chloroformate esters that undergo an
ionization mechanism with strong rear-side solvation of the
resonance-stabilized intermediate (Table 3).
In Table 4, the methanolysis and ethanolysis specifc rate order
is shown to be kMeOCOCl > kEtOCOCl ≈ kn-PrOCOCl ≈ kiBuOCOCl
≈ kOctOCOCl > kiPrOCOCl. As previously pointed out and shown
in Figure 1, the presence of an additional carbon in the 3-D
image of iBuOCOCl (1'), pushs the isopropyl group out of the
plane of the ether oxygen. As a result, access to the carbonyl
carbon in iBuOCOCl (1') is not hindered by the presence of a
branching alkyl group (1', Figure 1), and the observed rate order
in EtOH and MeOH (Table 4) suggests that any steric or induc-
tive or hyperconjugative effect due to the presence of the
Figure 4: The plot of log (k/k0) for isobutyl chlorothioformate (2)
against 0.42 NT + 0.73 YCl in 15 pure and binary solvents. The points
for the 100% EtOH, 90% EtOH, 100% MeOH, 90% MeOH, and 20%
T-80% E were not included in the correlation. They are added to show
the extent of their deviation.
isobutyl group in 1 is, at best, negligible. On the other hand, the The l/m ratio of 0.58 obtained for 2 in these 15 solvents is
inductive effect and competing hyperconjugative release of the similar in magnitude to the previously observed ratios for
isopropyl group in 5 does have an impact on its rates of ethanol- methyl- (MeSCOCl) [15], ethyl- (EtSCOCl) [8], isopropyl-
ysis and methanolysis.
(iPrSCOCl) [16], and phenyl- (PhSCOCl) chlorothioformates
Table 4: A comparison of the specific rates of solvolysis of MeOCOCl, EtOCOCl, n-PrOCOCl, iPrOCOCl, iBuOCOCl, and n-OctOCOCl in common
solvents at 25.0 °C.
MeOCOCl
105 k (s−1)a
EtOCOCl
105 k (s−1)b
n-PrOCOCl
105 k (s−1)c
iPrOCOCl
105 k (s−1)d
iBuOCOCl
105 k (s−1)e
n-OctOCOCl
105 k (s−1)f
Solvent
100% MeOH
100% EtOH
80% EtOH
97% TFE
15.6
3.51
17.2
8.24
2.26
8.88
2.20
4.19
1.09
3.92
12.3
19.7
9.89
2.36
8.51
2.39
7.37
7.31
7.92
8.17
0.086
0.481
0.023
0.611
0.062
0.591
70% TFE
0.857
aValue obtained using Arrhenius plots with the values reported at different temperatures in reference [67]. bRates are reported at 24.2 °C in reference
[8]. cReference [10]. dReference [12]. eExtrapolated value obtained using Arrhenius plots with the values reported at different temperatures in Table 2.
fReference [13].
549

Beilstein J. Org. Chem. 2011, 7, 543–552.
[40,46,47] in solvents where an SN1 mechanism was said to be inductive ability of the isobutoxy group being much greater
operative. The range of the l/m ratios, from 0.53 to 0.93, for than that of the corresponding sulfur analog. The observed rate
these chlorothioformate esters (Table 3) is similar to the l/m order is completely reversed in 97% TFE (aqueous) to
ratio of 0.73 obtained for phenyl dithiochloroformate (4), the kiBuSCOCl >> kiBuOCOCl, where 2 is a 100-fold faster than 1. In
recommended standard for understanding ionization mecha- the highly ionizing fluoroalcohols an ionization mechanism
nisms in acyl containing systems.
(SN1) is proposed to prevail for both substrates: This rate order
signifies that the hyperconjugative release from the sulfur atom
Hence we suggest that in these 15 solvents, 2 solvolyzes by a in 2 to the developing acylium ion is the dominant factor.
dominant unimolecular ionization process with significant rear-
side solvation of the developing acylium ion intermediate. For Conclusion
the five solvents (100% EtOH, 90% EtOH, 100% MeOH, 90% Correlation analysis of the solvolysis of isobutyl chloroformate
MeOH, and 20% T-80% E) whose data points lie above the (1) and isobutyl chlorothioformate (2) in a variety of pure and
regression line (Figure 4), a dominant superimposed binary aqueous organic solvents was successfully analyzed
addition–elimination mechanism (AN + DN) is proposed. The using the extended Grunwald–Winstein equation (Equation 1).
rate order shown in Table 5, of kMeSCOCl ≈ kEtSCOCl ≈ kiPrSCOCl In both compounds side-by-side addition–elimination (with a
≈ kiBuSCOCl, is for the methanolysis and ethanolysis of these rate-determining addition step) and unimolecular SN1 type
alkyl chlorothioformate esters at 25.0 °C. In pure methanol and mechanisms are believed to be possible.
ethanol a dominant association–dissociation (addition–elimina-
tion) mechanism, with rate-limiting addition, is believed to be In a majority of the solvents studied it is proposed that 1
effective in all four substrates. This rate order indicates that the solvolyzes by a bimolecular addition–elimination (AN + DN)
inductive ability of the alkyl thioether group is almost inde- process due to the inductive ability of the isobutoxy group,
pendent of the type of alkyl group present. In Table 5, for whereas in the four aqueous TFE mixtures a predominant uni-
solvolysis in the least nucleophilic and most highly ionizing molecular SN1 mechanism with rear-side solvation of the devel-
solvent, 97% HFIP (w/w), a rate order of kMeSCOCl << kEtSCOCl oping carbocation is suggested.
< kiBuSCOCl << kiPrSCOCl is observed. This demonstrates that
the hyperconjugative release during the formation of the devel- For 2, due to a more proficient hyperconjugative release, a
oping resonance-stabilized carbocation intermediate is more dominant unimolecular ionization (SN1) mechanism with strong
efficient for isopropyl chlorothioformate (5) when compared to rear-side nucleophilic solvation is proposed for all solvents
2, as the presence of the additional carbon pushes the isopropyl except 100% EtOH, 90% EtOH, 100% MeOH, 90% MeOH,
group out of the plane of the thioether atom in 2' (Figure 1). and 20% T-80% E. In these five solvents an AN + DN process is
This opinion is supported by an increase seen in the l/m ratio in believed to dominate.
the order of kMeSCOCl < kEtSCOCl < kiBuSCOCl < kiPrSCOCl.
Experimental
As shown from Table 4 and Table 5, the kiBuSCOCl < kiBuOCOCl The isobutyl chloroformate (98%, Sigma-Aldrich) and isobutyl
rate order applies in methanol and ethanol where the chlorothioformate (96%, Sigma-Aldrich) were used as received.
addition–elimination mechanism is dominant. This is due to the Solvents were purified and the kinetic runs carried out as previ-
Table 5: A comparison of the rates of solvolysis of MeSCOCl, EtSCOCl, iPrSCOCl, and iBuSCOCl, in selected common solvents at 25.0 °C.
MeSCOCl
105 k (s−1)a
EtSCOCl
105 k (s−1)b
iPrSCOCl
105 k (s−1)c
iBuSCOCl
105 k (s−1)d
Solvent
100% MeOH
100% EtOH
80% EtOH
97% TFE
2.00
0.884
2.44
0.986
1.92
13.9
3.21
3.48
13.9
2.15
0.430
2.68
5.98
10.2
54.3
39.2
36.1
81.3
1.99
1.21
13.7
49.8
69.5
212
376
437
659
2.27
1.01
2.99
6.01
11.7
40.8
66.0
48.2
78.4
90% TFE
70% TFE
97% HFIP
90% HFIP
70% HFIP
aReference [15]. bRates are reported at 24.2 °C in reference [8]. cReference [16]. dSee Table 1.
550

Beilstein J. Org. Chem. 2011, 7, 543–552.
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ously described [5,39]. A substrate concentration of approxi-
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specific rates and associated standard deviations, as presented in
Table 1, were obtained by averaging all of the values from
duplicate runs.
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Multiple regression analyses were carried out using the Excel
2007 package from the Microsoft Corporation. The 3-D-views
presented in Figure 1, were generated using the KnowItAll®
Informatics System, ADME/Tox Edition, from BioRad Labora-
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Acknowledgements
The research in the USA was supported by grant number 2 P2O
RR016472-010 from the National Center for Research
Resources (NCRR), a component of the National Institutes of
Health (NIH). This IDeA Network of Biomedical Research
Excellence (INBRE) grant to the state of Delaware (DE) was
obtained under the leadership of the University of Delaware,
and the authors sincerely appreciate their efforts. Matthew J.
McAneny completed a part of this research under the direction
of Dr. Malcolm J. D’Souza as an undergraduate research assis-
tant in the DE-INBRE sponsored Wesley College Directed
Research Program.
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