Castro et al.
JOCArticle
S-2,3,4,5,6-Pentafluorophenyl 4-nitrophenyl thiocarbonate
of the kinetics. The HPLC analysis at the end of these reactions
showed only traces (less than 1%) of 4-nitrophenol formation,
attributed to either the hydrolysis of the S-aryl O-4-nitrophenyl
thiocarbonate product or the direct nucleophilic reaction of the
substrate.
1
(16): H NMR (400 MHz, CDCl3) δ (ppm) 7.50 (d, 2H, J =
9.1 Hz), 8.35 (d, 2H, J = 9.1 Hz); 13C NMR (100 MHz, CDCl3)
δ (ppm) 155.1, 152.4, 150.3, 146.2, 144.9, 141.1, 136.5, 132.9,
125.8, 121.9, 119.4; 19F NMR (200 MHz, CDCl3) δ (ppm)
-128.3 (Forto), -140.3 (Fpara), -162.7 (Fmeta).
For the reactions of thiocarbonate 10 with piperidine (0.1 M,
pH 10.8) and morpholine (0.08 M, pH 8.9) in the same experi-
mental conditions as those of the kinetic measurements of the
reactions with the other substrates, two analyses were per-
formed at the end of the reactions: (i) The absorbance at
400 nm was compared with that of a sample of 4-nitrophenol
at the same conditions, and also with the final absorbance
obtained in the reaction of the substrate, at the same concentra-
tion as 4-nitrophenol in the previous experiment, with NaOH.
(ii) By HPLC analysis, the signal of 4-nitrophenol in the mixture
at the end of the reactions was compared (with respect to
retention time and UV-vis spectrum) with that corresponding
to 4-nitrophenol and quantified in comparison with a calibra-
tion curve. Both results show 60% 4-nitrophenol and 40%
3-chlorobenzenethiol in the final mixture.
Anal. Calcd for C13H4F5NO4S: C, 42.75; H, 1.10; N, 3.84; S,
8.78. Found: C, 42.51; H, 1.23; N, 3.96; S, 8.53.
Kinetic Measurements. The kinetics of the reactions were
analyzed through a diode array spectrophotometer in 44 wt %
ethanol-water, at 25.0 ( 0.1 °C and an ionic strength of 0.2 M
(maintained with KCl). The reactions were followed at the
300-500 nm wavelength range.
The reactions were studied under at least 10-fold excess of
total amine (free amine þ its conjugate acid) or total phenol (free
phenoxide þ phenol) over the substrate, the initial concentra-
tion of the latter being 2.5 ꢁ 10-5 M. Under these conditions
pseudo-first-order rate coefficients (kobsd) were found through-
out, the kinetics being measured for at least five half-lives at the
corresponding wavelengths. These were 400 nm, when following
4-nitrophenoxide ion formation, for the reactions of thiocarbo-
nates 8, 9, and 11, and 310 nm, when following the formation of
the corresponding 4-nitrophenyl carbamate for the aminolysis
of thiocarbonate 16. In all the reactions the pH was maintained
constant by the buffer formed by partial protonation of the
nucleophile or by the addition of an external buffer.
The reactions of thiocarbonate 16 with piperazine and piper-
azinium ion were studied at pH 7.2-8.1, where mixtures of both
amines are present. In these cases the kN values were obtained
through eqs 2 and 3. In these equations kNobsd is a global
nucleophilic rate constant (corresponding to the mixture of
nucleophiles), [N]tot is the total piperazine (piperazine þ piper-
azinium ion) concentration, FN and FNH are the molar fractions of
piperazine and piperazinium ion, respectively, and kN and kNH are
their corresponding nucleophilic rate constants. The values of
Computational Study. One of the most relevant achievements
of the research work carried out in the field of theoretical
physical organic chemistry has been the introduction of reactiv-
ity indexes to analyze reactivity, selectivity, and site activation in
modern texts of Organic Chemistry.25 On the basis of these
concepts, it has been proposed that the regional electrophilicity
of a chemical fragment, given by the global electrophilicity index
weighted by the electrophilic Fukui function, can be taken as a
measure of the ability of the group to depart from a molecule
with the bonding electron pair.3 The nucleofugality index ν(PG)
has been given by the following definition:3
X
νðPGÞ ꢂ
ωk
ð4Þ
kεPG
where ωk is the local or the condensed to atom electrophilicity,
obtained by multiplying the global electrophilicity w, proposed
by Parr et al.,25,26 by the corresponding electrophilic Fukui
finction.3 The permanent group (PG) dependence on the nu-
cleofugality index is stressed in eq 4. The nucleofugality index
will be used to rank the heterolytic group detachment ability in
the series of thiocarbonates experimentally studied in this work.
Following the experimental results, these substrates may be
classified as described in Table 3. Ab initio HF/6-311G (d,p)
calculations were performed with the Gaussian 98 suite of
programs27 in order to evaluate the electronic quantities re-
quired to calculate the ground state electrophilicity index for the
series of thiocarbonates considered in the present study.
k
Nobsd were obtained as the slopes of linear plots of kobsd vs. [N]tot
at constant pH. The nucleophilic rate constants for the reactions
of thiocarbonate 16 with piperazine (kN) and piperazinium ion
(kNH) were determined through eq 3, as described.4
kobs ¼ k0 þ kNobs½Nꢀtot
ð2Þ
ð3Þ
kNobs ¼ FN kN þ FNH kNH
The kobsd values obtained and the experimental conditions for
the studied reactions are shown in Tables S1-S6 in the Support-
ing Information.
Product Studies. For the SA aminolysis of thiocarbonates 9
and 11 and the phenolysis of 8, 9, and 11, 4-nitrophenolate anion
(96((4)%) was identified as one of the products of the reactions,
by comparison of both the UV-vis and HPLC spectra, after
completion of these reactions, with those of an authentic sample
of 4-nitrophenol, under the same reaction conditions. For the
reactions of 8, 9, and 11, only traces (not quantified) of the
corresponding benzenethiolates were detected by HPLC analy-
sis, being these traces attributed to the formation of these
compounds either by the parallel hydrolysis of the substrates
or by their nucleophilic reactions.
In the reactions of thiocarbonates 9 and 11 with morpholine,
the formation of the corresponding 4-nitrophenyl carbamate
was not detected by HPLC analysis (less than 1%), with this
compound, therefore, being disregarded (or being insignificant)
as one of the reaction products.
Acknowledgment. We thank MECESUP of Chile
(projects PUC-0004 and RED QUIMICA UCH-0601) and
FONDECYT of Chile (projects 1060593, 1095145, and
1070715) for financial support. M.C. thanks CONICYT of
Chile for a doctoral fellowship and project AT-24080020.
Supporting Information Available: Kinetics conditions and
results for the reactions of thiocarbonates 8, 9, 11, 16 (Tables
S1-S6), NMR spectra of thiocarbonates 8, 9, 10, 11, 16, and
atom coordinated and absolute energies of calculated structures
for thiocarbonate 1-19 (Table S7). This material is available
(25) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry. Part A:
Structure and Mechanisms, 5th ed.; Springer: Berlin, Germany, 2007; pp
945-951.
For the reactions of thiocarbonate 16 with morpholine, the
corresponding 4-nitrophenyl carbamate was identified as one of
the products by comparison of its retention time in HPLC with
that of an authentic sample, under the same reaction conditions
ꢀ
(26) Parr, R. G.; Szentpaly, L. V.; Liu, S. J. Am. Chem. Soc. 1999, 121,
1922.
(27) Frisch, M. J. et al. , GAUSSIAN 98, Revision A.6; Gaussian, Inc.,
Pittsburgh, PA, 1998.
J. Org. Chem. Vol. 74, No. 23, 2009 9179