Mechanisms of acid decomposition of dithiocarbamates. 5. Piperidyl dithiocarbamate and analogues

Article abstract of DOI:10.1021/jo801015t

(Chemical Equation Presented) In this work, the acid cleavage at 25°C in 20% v/v aqueous ethanol of a series of analogues of piperidine dithiocarbamate X(C₂H₄)₂NCS₂ ^- (X = CH₂, CHCH₃, NH, NCH₃, S, O) was studied. The pH-rate profiles were obtained in the range of H_o -5 and pH 5. They all presented a dumbell shaped curve with a plateau from which the pH-independent first-order rate constant k_o (or the specific acid catalysis k_H) was calculated, in addition to the acid dissociation constant of the free (pK_a) and conjugate acid (pK⁺) species of the DTC. LFERs of the kinetically determined pK_a and pK⁺ versus pK_N (pK_a of parent amine) were used to characterize the reactive species and the structure of the transition state of the rate-determining step. For X = CH₂, CH₃CH the values of k_H agree with those of alkDTCs in the strong base region of the Bronsted plot of log k_H versus pK_N where the transition state is close to a zwitterion formed by intramolecular water-catalyzed S-to-N proton transfer of the dithiocarbamic acid. However, when X = NH, CH₃N, O, S, the reactive species is the DTC anion, which is as reactive as an arylDTC, and similarly, the pK⁺ values correspond to a parent amine that is about 3-4 pK units more basic. The solvent isotope effect indicated that the acid decomposition of these dithiocarbamate anions is specifically catalyzed by a Hydron anchimerically assisted by the heteroatom through a boat conformation.

Full text of DOI:10.1021/jo801015t

Mechanisms of Acid Decomposition of Dithiocarbamates. 5.
Piperidyl Dithiocarbamate and Analogues
Eduardo Humeres,* Byung Sun Lee, and Nito Angelo Debacher
Department of Chemistry, UniVersidade Federal de Santa Catarina, 88040-900 Floriano´polis, SC, Brazil
humeres@mbox1.ufsc.br
ReceiVed May 11, 2008
In this work, the acid cleavage at 25 °C in 20% v/v aqueous ethanol of a series of analogues of piperidine
dithiocarbamate X(C2H4)2NCS-2 (X ) CH2, CHCH3, NH, NCH3, S, O) was studied. The pH-rate profiles
were obtained in the range of Ho -5 and pH 5. They all presented a dumbell shaped curve with a plateau
from which the pH-independent first-order rate constant ko (or the specific acid catalysis kH) was calculated,
in addition to the acid dissociation constant of the free (pKa) and conjugate acid (pK+) species of the
DTC. LFERs of the kinetically determined pKa and pK+ versus pKN (pKa of parent amine) were used to
characterize the reactive species and the structure of the transition state of the rate-determining step. For
X ) CH2, CH3CH the values of kH agree with those of alkDTCs in the strong base region of the Brφnsted
plot of log kH versus pKN where the transition state is close to a zwitterion formed by intramolecular
water-catalyzed S-to-N proton transfer of the dithiocarbamic acid. However, when X ) NH, CH3N, O,
S, the reactive species is the DTC anion, which is as reactive as an arylDTC, and similarly, the pK+
values correspond to a parent amine that is about 3-4 pK units more basic. The solvent isotope effect
indicated that the acid decomposition of these dithiocarbamate anions is specifically catalyzed by a Hydron
anchimerically assisted by the heteroatom through a boat conformation.
Introduction
The mechanism of acid decomposition of carbamates,10-12
monothiocarbamates,12 and dithiocarbamates13-15 (DTC) relies
heavily on the structure and the pKa of the conjugate acid of
the parent amine (pKN) (eq 1). The mechanisms of decomposi-
tion of DTCs in the range of pKN 1-11 may occur by a rate-
Apart from their use in agriculture as fungicides, herbicides,
and insecticides,1 the dithiocarbamates are extensively used in
the rubber industry as accelerators and antioxidants.2 They are
also used in the control of pollution by heavy metals3,4 and in
the pharmaceutical industry.5-9
(7) Schreck, R.; Meier, B.; Maennel, D. N.; Droege, W.; Baeuerle, P. A. J.
Exp. Med. 1992, 175, 1181–1194.
(8) Takamune, N.; Misumi, S.; Shoji, S. Biochem. Biophys. Res. Commun.
2000, 272, 351–356.
(9) Lee, B. H.; Bertram, B.; Schmezer, P.; Frank, N.; Wiessler, M. J. Med.
Chem. 1994, 37, 3154–3162.
(10) Caplow, M. J. Am. Chem. Soc. 1968, 90, 6795–6803.
(11) Johnson, S. L.; Morrison, D. L. J. Am. Chem. Soc. 1972, 94, 1323–
1334.
(12) Ewing, S. P.; Lockshon, D.; Jencks, W. P. J. Am. Chem. Soc. 1980,
102, 3072–3084.
(1) Thorn, G. D., Ludwig, R. A. The Dithiocarbamates and Related
Compounds; Elsevier: Amsterdam, 1962.
(2) Sato, H.; Koshimura, K. Japan Pat. Kokai Tokkyo Koho JP 03247636
A2 5 Nov. 1991.
(3) Malathi, K. J. Radioanal. Nucl. Chem. 1995, 191, 403–411.
(4) Suzuki, S. Japan Pat. Kokai Tokkyo Koho JP 07171541 A2, 11 Jul, 1995.
(5) Medford, R. M.; Offermann, M. K.; Alexander, R. W. PCT Int. Appl.
WO 9409772 A1, 11 May, 1994.
(6) Loegering, D. J.; Richard, C. A. H.; Davison, C. B.; Wirth, G. A. Life
Sci. 1995, 57, 169–176.
(13) Humeres, E.; Debacher, N. A.; Sierra, M.; Franco, J. D.; Schutz, A. J.
Org. Chem. 1998, 63, 1598–1603.
10.1021/jo801015t CCC: $40.75
Published on Web 08/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7189–7196 7189

Humeres et al.
determining step of N-protonation to form a zwitterion, a rate-
determining C-N breakage of this zwitterion, or through a new
water-catalyzed mechanism.13,15
22.6-23.0 ppm,24-28 wheras for the axial group it is 18.8 ppm.30
The equatorial N-CH3 presents a signal at 46.427-47.222 ppm
and ∼37.2 ppm22 when it is in the axial position. Therefore, in
the case of 4-methylpiperidylDTC, the 4-methyl group (δ )
22.2 ppm) is in the equatorial position as well as the N-CH3
group of 4-methylpiperazylDTC (δ ) 49.8 ppm). The N-CH3
group in N-methylpiperidine prefers the equatorial position and,
depending on the solvent, the equatorial-axial barrier amounts
24-26,29
to 2.4-3.0 kcal mol-1
.
Piperidyl dithiocarbamate presented a preferred conformation
with the DTC group in the equatorial position when complexed
with Cr (δ ) 209.7 ppm), Mo (δ ) 211.6 ppm), and W (δ )
213.0 ppm).30 For the DTC group of the pipDTC sodium salt,
we observed δ ) 204.5 ppm, so we assigned the position of
this group as equatorial. We also did this for piperazyl
dithiocarbamate, where δ ) 210.9 ppm. The DTC signals of
4-methylpiperidylDTC and 4-methylpiperazylDTC appeared at
207.1 and 207.9 ppm, respectively, and we concluded that both
compounds had undergone tetrahedral inversion to produce the
trans-conformation.
General acid catalysis was not observed in the acid cleavage
of alkyl dithiocarbamates (alkDTC) because the pKa of the
N-protonated zwitterionic intermediate is much lower than that
of the solvated proton, and general acid catalysis is expected
only for acids stronger than Hydron.14 ArylDTCs decomposed
ca. 104-fold faster than alkDTCs with similar pKN. Proton
inventory15 and theoretical calculations16 showed that the rate
acceleration was due to a multiproton transition state where an
S-to-N proton transfer occurred through a water molecule. The
driving force to reach the transition state is the consequence of
the required torsion of the C-N bond that inhibits the resonance
with the thiocarbonyl group and the aromatic moiety, increasing
the basicity of the nitrogen and making the proton transfer
thermodynamically favorable.
pH-Rate Profiles. The pH-rate profiles of the acid cleavage
of cycloDTCs were all similar to those found for simple
alkDTCs13 and arylDTCs.15 They showed a dumbell-shaped
curve as shown in Figure 1 for piperidylDTC. The observed
+
The dithiocarbamates from heterocyclic secondary amines
(I),17-21 analogues of piperidine, were considered to constitute
an independent series because of their high reactivity, although
no mechanism was proposed to explain their behavior.12
first-order rate constant can be expressed by eq 2 where aH
)
antilog(-pH or Ho). The value of ko was obtained from the
average value of kobs at the plateau of the profile; pKa and pK+
are the acid dissociation constants of the dithiocarbamic acid
and its conjugate acid, respectively.
ko
kobs
)
(2)
Ka
aH
aH
K+
+
+ 1 +
+
The reaction can be kinetically described as occurring
according to Scheme 1 through the species SH+2 , SH, or S-.
The rate constant ko represents the rate constant of the
decomposition through the free dithiocarbamic acid (k1 in
Scheme 1), and it is kinetically equivalent to kHKa ) kOHKw/
K+, where kH and kOH are the specific acid and base catalysis
rate constants, respectively. However, the alternative of specific
base-catalyzed decomposition cannot be considered because ko
is of the order of 0.10-1.0 s-1 and K+ ≈ 103, so kOH should be
ca. 1017 M-1 s-1, much larger than the diffusion-controlled rate
constant. The values of ko and kH are shown in Table 1, together
with the pKa and pK+ obtained from the pH-rate profiles of
the acid decompositions of the series of piperidylDTC and
analogues according to eq 2. Considering ko, the acid decom-
position of cycloDTCs is about 102-fold faster than that of
alkDTCs5 from parent amines with pKN ≈ 10, but it is 102-fold
slower than the acid decomposition of arylDTCs.13,15
This work aims to answer relevant questions about the
reactivity of the dithiocarbamate analogues to piperidine, the
mechanisms involved in their acid decomposition, and the role
in the reaction of the heteroatom at the 4-position.
Results and Discussion
cis-trans Conformation. The 4-methyl group of 4-meth-
ylpiperidine and 4-N-methylpiperazine is in the equatorial
conformation.22-27 Both compounds present the possibility of
cis-trans conformation when forming the dithiocarbamate. The
13C NMR chemical shift of the equatorial 4-methyl group is
(14) Humeres, E.; Debacher, N.; Sierra, M. M. S. J. Org. Chem. 1999, 64,
1807–1813.
(15) Humeres, E.; Debacher, N.; Franco, J. D.; Lee, B. S.; Martendal, A. J.
Org. Chem. 2002, 67, 3662–3667.
(16) Garc´ıa, J. I.; Humeres, E. J. Org. Chem. 2002, 67, 2755–2761.
(17) Franchini, G. C.; Giusti, A.; Preti, C.; Tassi, L.; Zannini, P. Polyhedron
1985, 4, 1553–1558.
Acid Dissociation Constants of cycloDTCs. The relationship
between the acid dissociation constants calculated from the
(18) Fabretti, A. C.; Forghieri, F.; Giusti, A.; Preti, C.; Tosi, G. Inorg. Chim.
Acta 1984, 86, 127–131.
(19) Forghiere, F.; Preti, C.; Tassi, L.; Tosi, G. Polyhedron 1988, 7, 1231–
1237.
(25) Robinson, M. J. T. J. Chem. Soc., Chem. Commun. 1975, 844–845.
(26) Appleton, D. C.; McKenna, J.; McKenna, J. M.; Sims, L. B.; Walley,
A. R. J. Am. Chem. Soc. 1976, 98, 292–293.
(20) Altamura, M.; Giannotti, D.; Perretta, E.; Sbraci, P.; Pestellini, V.;
Arcamone, F. M. Bioorg. Med. Chem. Lett. 1993, 3, 2159–2164.
(21) De Filippo, D.; Deplano, P.; Devillanova, F.; Trogu, E. F.; Verani, G.
J. Org. Chem. 1973, 38, 560–563.
(22) Crabb, T. A.; Katritzky, A. R. In AdVances in Heterocyclic Chemistry;
Academic Press: Orlando, 1984; Vol. 36, pp 1-173.
(23) Booth, H.; Little, J. H. Tetrahedron 1967, 23, 291–297.
(24) Crowley, P. J.; Robinson, M. J. T.; Ward, M. G. J. Chem. Soc., Chem.
Commun. 1974, 825–826.
(27) Eliel, E. L.; Kandasamy, D.; Yen, C.-Y.; Hargrave, K. D. J. Am. Chem.
Soc. 1980, 102, 3698–3707.
(28) Pretsch, E.; Simon, W.; Seibl, J.; Clerc, T. Tables of Spectral Data for
Structure Determination of Organic Compounds, 2nd ed.; Springer-Verlag: New
York, 1989.
(29) Crowley, P. J.; Robinson, M. J. T.; Ward, M. G. Tetrahedron 1977, 33,
915–925.
(30) Yih, K-H.; Chen, S-C.; Lin, Y-C.; Lee, G-H.; Wang, Y. J. Organomet.
Chem. 1995, 494, 149–155.
7190 J. Org. Chem. Vol. 73, No. 18, 2008

Mechanisms of Acid Decomposition of Dithiocarbamates
FIGURE 1. pH-rate profile of the acid decomposition of piperidylDTC in 20% aqueous ethanol at 25 °C: 9, buffer succinate; b, buffer formate;
2, HCl; 3, H2SO4; [, HClO4. The continuous theoretical line was calculated from eq 2 (r ) 0.999, sdy ) 0.014).
higher basicity of the nitrogen (pK( linearly related to pK+)
can be explained as a consequence of the torsional effect of the
water molecule that catalyzes the reaction, decreasing the
double-bond character of the C-N bond and also decreasing
the resonance of the nitrogen and the aromatic ring.15 The proton
transfers from the S-H dissociation and N-protonation, and
C-N bond breakdown are concerted, with no formation of a
zwitterionic intermediate.16 In fact, the pK’s calculated from
the rate constants represent the acidity of the S-H and N+-H
bonds of the transition state and the deviation of the kinetically
calculated pK’s from the titration values is indicative of its
structure.31
SCHEME 1. Kinetic Scheme of the Hydrolyses of
cycloDTCs
This analysis can be extended to the acid cleavage of
cycloDCTs. The pKa values of alkDTCs, including those
determined by titration, follow eq 3 in Table 2. The dissociation
constants of the thiocarbamic acids of the cycloDTCs are very
close to the relationship of alkDTCs (Figure 2a), and considering
the standard deviation, the values of both series produced the
same LFER (Table 2, eq 4). Therefore, for this series the
dithiocarbamate moiety at the transition state of the rate-
determining step is similar to an anion.
A different situation can be observed in Figure 2b for the
dissociation constants of the conjugate acids. There is a clear
distinction between piperidyl- and 4-methylpiperidyl dithiocar-
bamates and the other members of the series with a heteroatom
in the 4-position. The N-basicity of all members of the series
is higher than that of an alkDTC of similar pKN, and for those
containing a heteroatom, the increase is more than 3 pK units
(eqs 6 and 7, Table 2). This fact will be discussed below.
BrOnsted Plot. The plot of the log of the calculated specific
acid catalysis rate constants kH versus the pKN of the leaving
amine of the acid decomposition of alkDTCs (Figure 3) shows
a change in the rate-determining step near pKN 9 from
N-protonation to form a zwitterion intermediate to the C-N
bond breakdown of this intermediate.13 At a pKN near 10, a
minimum of kH indicates a change of mechanism with a
subsequent fast increase of the rate constant in relation to the
basicity of the parent amine. This change of the rate constant
pH-rate profiles and the pKN values of the parent amines is
related to the mechanism of acid decomposition of the dithio-
carbamates. There must be three events for the acid cleavage
to occur: S-H dissociation, N-H protonation, and C-N bond
breakdown. AlkDTCs decompose by specific acid catalysis
through a zwitterion intermediate,13,16 and pKa and pK+
calculated from the pH-rate profiles correspond to the ther-
modynamic values obtained by titration as can be observed in
Figure 2. The initial state is the dithiocarbamate anion S- (after
S-H dissociation),12,13 and the protonation occurs on the
nitrogen, which presents a basicity similar to the conjugate acid
SH2+ because pK( of the nitrogen, N+-H bond of the zwitterion
SH(, is linearly related to pK+ (Scheme 2).13 However, for
arylDTCs, which decompose by a concerted water-catalyzed
mechanism, there is a considerable difference between the pK
values obtained from the pH-rate profiles and those obtained
by titration (Figure 2). The pKa values of the arylDTCs in Figure
2a are much higher than those of the alkDTCs with similar
pKN’s, corresponding to alkyl amines with basicities of about
5-7 units of pK more basic than the pKN of the parent anilines
(Table 2, eqs 3 and 5). The difference in the dissociation
constants of the conjugate acids is even higher, and the pK+’s
of the aryl series are similar to those of the alkyl amines that
are ca. 8 pK units more basic. Alkyl- and arylDTCs follow
different linear relationships between pK+ and pKN (Table 2,
eqs 6 and 8).
The initial state of the arylDTCs is the dithiocarbamic acid
SH (Scheme 2), and the lower acidity of the sulfur (pKa) and
(31) Kurz, J. L. Acc. Chem. Res. 1972, 5, 1–9.
J. Org. Chem. Vol. 73, No. 18, 2008 7191

Humeres et al.
TABLE 1. Acid Dissociation and Rate Constants Related to the Acid Cleavage of Piperidyl Dithiocarbamate and Analogues in 20% Aqueous
Ethanol at 25 °Ca
b
b
c
no. order
X
pKN1
11.16 ( 0.04d e
pKN2
pKa
pK+
102 ko (s-1
)
10-2 kH (M-1 s-1
)
2.2f,g
1.6
4.9
6.8
4.8
,
1
2
3
4
5
6
CH2
CH3CH
HN
CH3N
S
3.4 ( 0.2
3.1 ( 0.1
3.0 ( 0.5
3.0 ( 0.5
2.65 ( 0.05
2.85 ( 0.05
-3.2 ( 0.2
-3.0 ( 0.2
-2.6 ( 0.5
-2.8 ( 0.5
-3.25 ( 0.05
-3.45 ( 0.05
8.83 ( 0.08
12.3 ( 0.3
48.8 ( 0.9
68.26 ( 0.01
108 ( 5
e h
,
11.07
9.81 ( 0.04d e i j
5.6 ( 0.1d e i j
,
, ,
, , ,
9.18j
4.81j
(-6.2)
8.7 ( 0.2j,k
l m
,
, , ,
, ,
O
8.5 ( 0.1d i j n
(-3.6)m o p
116 ( 5
8.2
c
a This work unless indicated. b pKa of the conjugate acid of the parent amine. From the pH-rate profile where HoX ) -(X + log CH ). d CRC
Handbook of Chemistry and Physics, 64th ed.; Weast, R.C., Ed.; CRC Press: Cleveland, 1983–1984. e Handbook of Biochemistry; Sober, H. A., Hart,
R. A., Eds.; CRC Press: Cleveland, 1968. f kH ) 48.3 M-1 s-1 (ref 21). g kH ) 100 and 117 M-1 s-1; Takami, F.; Ikawa, K.; Tokuyama, K.; Shigeru,
W.; Maeda, T. Chem. Pharm. Bull. 1974, 22, 275-279. h For 3-methylpiperidine. i Hetzer, H.B.; Robinson, R.A.; Bates, R.G. J. Phys. Chem. 1968, 72,
2081-2086. j De Filippo, D.; Devillanova, F.; Trogu, E. F.; Verani, G. Gazz. Chim. Ital. 1974, 104, 1227-1235. k Krishnamurthy, M.; Babu, K.S.;
Muralikrishna, U. Curr. Sci. 1988, 57, 598-600. l For dimethylsulfide. m Arnett, E.M. Prog. Phys. Org. Chem. 1963, 1, 223-403. Bagno, A.; Scorrano,
G. Acc. Chem. Res. 2000, 33, 609-616. n Hetzer, H.B.; Bates, R.G.; Robinson, R.A. J. Phys. Chem. 1966, 70, 2869-2872. o For diethylether and
dioxane. p Somera, N.; do Amaral, L. Anais da I Conf. F´ıs. Qu´ım. Org. Brazil, 1982, 133-140.
+
is incompatible with a Brφnsted slope and with the increased
instability of the zwitterion and slower C-N bond cleavage.
The methyl-, ethyl-, and n-butylDTC and also piperidyl- and
4-methylpiperidylDTC are in this range. Theoretical calculations
indicated that in this case the reaction was water-catalyzed.16
Scheme 3 shows the mechanism where in the first step there is
a water-assisted intramolecular S-to-N proton transfer through
the transition state TS2. The transition state structure corre-
sponds to a situation where the proton from the SH group has
been almost completely transferred to the water molecule. This
arrangement looks very similar to a Hydron coordinated to a
dithiocarbamate anion. The formation of the zwitterionic
intermediate II is followed by the C-N cleavage through
transition state TS3. For arylDTCs, both processes are concerted
with only one transition state (TS1). Because of the above
considerations, for pip- and MepipDTC, the rate-determining
TS should be TS1. The involvement of the water in this
transition state is consistent with the higher value of pK+ for
these two compounds as shown in Figure 2b.
Activation Parameters. There is a clear difference between
the mechanisms involved in the decomposition of the alicyclic
amine dithiocarbamates and those with an heteroatom in position
4, as was observed from the dependency of pK+ on pKN (Figure
2b) and the Brφnsted plot (Figure 3). Table 3 compares the
activation parameters of several dithiocarbamates. The increase
in reactivity of phenylDTC with respect to 2-ammonium-
ethylDTC is mainly due to a decrease in the enthalpy of
activation. The magnitude of ∆Sq is practically the same for
both. The rate-determining step of the 2-ammonium-ethylDTC
is the N-protonation to form the zwitterion intermediate, and
for the arylDTC it is the concerted water-catalyzed decomposi-
tion as was explained above.
of 2-substituted ethylammonia, X-CH2-CH2-NH3+, was used to
compare the effect when X ) CH2 and O in the series
X(C2H4)2NCS-2 . As can be observed in Figure 4, the pKN of
piperidinium correlates very well with the ethylammonium
series, whereas the pKN of the N-protonated morpholine is ca.
3 pK units higher than expected, indicating that the effect of
the heteroatom is not only inductive. The effect may be a
consequence of a strong intramolecular H-bonding (O-H· · ·N)
through a water molecule as reported in conformational studies
of methyl-hydroxypiperidine,32 quinolizidine,33 and dimethy-
lamino naphthalene systems.34 Proton transfers involving oxygen
and nitrogen acids and bases can be dramatically slowed by
internal hydrogen bonding. When the proton accepted by the
nitrogen is placed in a tight hydrogen bond, the nitrogen behaves
as a stronger base and the pKa is higher than expected.35
However, this explanation is insufficient because if the conjugate
acid of morpholine forms an intramolecular hydrogen bond with
the 4-oxygen through a water molecule, the second N+-H bond
should dissociate normally, which should decrease the rate of
dissociation by a factor not higher than 2. We have to conclude
that the two N+-H bonds are not equivalent and that the
conjugate acid looks more like a Hydron hydrogen-bonded to
morpholine as shown in structure III.
We concluded above that the decomposition of pipDTC is
water-catalyzed and that the rate-determining step is the
N-protonation that produces the zwitterion. The enthalpy of
activation is 19 kcal mol-1, similar to that of the 2-ammonium-
ethylDTC, but ∆Sq is nearly zero. The activation parameters of
the morpholyl and thiomorpholylDTC are very similar: ∆Hq
(15 kcal mol-1) and ∆Sq -9 cal mol-1 K-1, indicating a
common mechanism with higher steric requirement to reach the
transition state.
The reason for the increase of 3 pK units of the pKN is that
the rate of N-deprotonation of III is about 3 orders of magnitude
slower than that of the series of 2-substituted ethylammonia,
as has been observed for p-aminosalicylate ion,36 because the
(32) Aaron, H. S. Top. Stereochem. 1979, 11, 1–52.
(33) Aaron, H. S.; Ferguson, C. P. Tetrahedron Lett. 1968, 59, 6191–6194.
(34) Pozharskii, A. F.; Ryabtsova, O. V.; Ozeryanskii, V. A.; Degtyarev,
A. V.; Starikova, Z. A.; Sobczyk, L.; Filarowski, A. Tetrahedron Lett. 2005,
46, 3973–3976.
(35) Kresge, A. J. Acc. Chem. Res. 1975, 8, 354–360.
(36) Eigen, M.; Kruse, W.; Maass, G.; de.Maeyer, L. Prog. React. Kinet.
1964, 2, 285–318.
Nature of the Nitrogen-Heteroatom Interaction. The study
of the inductive effect of substituents on the pKN in the series
7192 J. Org. Chem. Vol. 73, No. 18, 2008

Mechanisms of Acid Decomposition of Dithiocarbamates
FIGURE 2. Dependence of pKa and pK+ of dithiocarbamic acids on the pKN of the parent amine at 25 °C; alkDTC, in water; cycloDTC, and
arylDTC, in 20% aqueous ethanol; b, alkDTC, pK titration values; empty symbols, pK values calculated from the pH-rate profile; O, arylDTC;
0, alkDTC; 4, cycloDTC, X(C2H4)2NCS-2 , X ) 1, CH2; 2, CHCH3; 3, NH; 4, NCH3; 5, S; 6, O. The dashed lines indicate the standard deviation
of the line drawn considering only the alkDTC series.
SCHEME 2. Mechanistic Paths of the Acid Decomposition
of Dithiocarbamates
Kinetic Solvent Isotope Effect. MorpholylDTC. The inverse
kinetic solvent isotope effect of the acid decomposition of
sodium morpholyl dithiocarbamate in 20% v/v EtOL/L2O at 25
°C, 1 M L2SO4, µ ) 1 (KCl) was kDo O/koH O ) 1.87 ( 0.25.
This value is much lower than those observed for alkyl and
arylDTCs (Table 4) and suggests that there is a different
mechanism operating in this acid decomposition.
2
2
As shown above, considering the dissociation constants of
thiocarbamic acids, the reactive species of the initial state of
the decomposition of the cycloDTC series is the dithiocarbamate
anion, and the measured solvent isotope effect is the ratio of
the specific acid catalysis rate constants kL. The relationship ko
) kHKa from Scheme 1 produced eq 9. Dithiocarbamic acids
are weak and present low isotopic fractionation factors (φS-L
)
0.40-0.46).37 The KaL ratio can be calculated from eq 10
considering l ) 0.69, the isotopic fractionation factor of the
Hydron.38 Consequently, for morphDTC kD/kH ) 2.43.
positive charge is distributed between the Hydron-oxygen and
the nitrogen, making this atom more basic.
J. Org. Chem. Vol. 73, No. 18, 2008 7193

Humeres et al.
SD
TABLE 2. LFER of the Dissociation Constants of Some Dithiocarbamates at 25 °Ca
equation
series
n
r
3
4
5
6
7
8
alkDTC
pKa ) (0.54 ( 0.05)pKN - (2.40 ( 0.47)
pKa ) (0.48 ( 0.05)pKN - (1.76 ( 0.49)
pKa ) (0.29 ( 0.02)pKN + (1.39 ( 0.09)
pK+ ) (0.49 ( 0.05)pKN - (9.14 ( 0.45)
pK+ ) (0.68 ( 0.12)pKN - (9.13 ( 1.10)
pK+ ) (0.53 ( 0.04)pKN - (5.40 ( 0.15)
18
24
5
9
4
0.941
0.896
0.991
0.970
0.970
0.993
0.292
0.336
0.078
0.129
0.126
0.124
alkDTC and cycloDTCb
arylDTC
alkDTC
cycloDTCc
arylDTC
5
b
a AlkDTC, in water; CycloDTC and ArylDTC, in 20% aqueous ethanol. X(C2H4)2NCS-2, X ) 1, CH2; 2, CHCH3; 3, NH; 4, NCH3; 5, S; 6, O.
Compounds 1-6. c Compound 3-6.
The transition state for O to N Hydron transfer is
1-ꢁ
ꢁ
O----L----N
where ꢁ is the bond order of the bond being formed. In the
initial state ꢁ ) 0 and there is no SIE, while inversed SEI occurs
at ꢁ > 0.9.13,39 Since the maximum primary SEI (kD/kH)mpraix
)
11.4,13 for morpholylDTC ꢁ ) 0.95. At equilibrium, ꢁ ) 1,
+-L1
+
and from eq 12 (φO
) 0.69, φL -N ) 0.97) the primary
3
SEI at equilibrum is 1.41. This value implies that the secondary
SEI is very close to 1.0 and consequently the primary SEI would
be higher than the equilibrium value. The concerted mechanism
a for morpholylDTC should therefore be disregarded. The
stepwise mechanism a to b cannot be distinguished because
+
+-L1
the ratio φO -L /φO
) 1.
3
ꢀ
+
kD
L3-N
(
(
)
)
(12)
FIGURE 3. Brφnsted plot of the rate constants of the specific acid
catalysis and the pKN of the leaving amine for the acid decomposition
of dithiocarbamates in water at 25 °C: O, arylDTC, in 20% aqueous
ethanol; 0, alkDTC, in water; 4, cycloDTC, in 20% aqueous ethanol;
X(C2H4)2NCS-2 , X ) 1, CH2; 2, CHCH3; 3, NH; 4, NCH3; 5, S; 6, O.
( )
(
)
kH
ꢀO -L
+
equil
)
1
pri
Let us consider mechanism b in Scheme 4 where the initial
state is a Hydron hydrogen-bonded to the Omorph and the nitrogen
of the DTC anion. In this case the SEI is given by eq 13, and
the secondary SEI can be estimated from eq 14 considering ꢁ
) 0.95. Therefore, the primary SIE is 1.20.
kD kDo O KHa
2
)
(9)
T1
T3
ꢀT2
ꢀ
kHo O KDa
2
kH
ꢀ
kD
kH
(
O-L1)( O-L2
)
(
O-L3-N
)
)
(13)
(
)) (
)
ꢀO -L ꢀO -L
ꢀO -L
KaH
KaD
1
sec
1
pri
+
+
+
l3
ꢀS-L
(
1)(
(
)
)
) 1.30
(10)
2
ꢁ
ꢀO-L
kD
(
)
i
)
) 2.02
(14)
(15)
( )
2
(
)
kH
ꢀO -L
+
The heterocyclicDTC members of the series (X ) N, CH3-
N, O, S) showed pK+ values that correspond to parent amines
that are ca. 3 pK units more basic. This effect has been related
to water catalysis in the rate-determining step.15,16 It was shown
above that in the case of morpholonium ion III, the effect of
the Omorph on the nitrogen occurs through a Hydron. It is quite
reasonable to assume that the mechanism of acid decomposition
of the heterocyclicDTCs occurs by the rate-determining transi-
tion states shown in Scheme 4. Mechanism a in Scheme 4
assumes that the initial state is the Omorph-protonated DTC anion
with a hydrogen-bonded water molecule and that at the TS there
are two concerted proton transfers: O to O and O to N. The
SIE is given by eq 11 where the functions φi are the fractionation
factors of the hydrogenic positions.
sec
(
)
i
sec
ꢀTO3-L -N ) ꢀO -L
ꢀ
1-ꢁ
ꢁ
+
+
L3-N
(
)
(
)
3
3
From eq 15 φ TO-3 L
can be calculated as 0.95, and by the
3-N
same procedure φ TO-1 L ) φ OT -2 L ) 0.98. Considering eq 13,
1
2
+
+-Li
φO
) 0.72. If the change of φO-L from 1.0 to 0.69 (φO
)
-L
is proportional to the charge on the O+-L bond, the charge
shown by the Hydron is only 89% from expected as a
consequence of the interaction between O-4 of the morpholyl
ring and the Hydron in the initial state. The Hydron must be
also weakly hydrogen-bonded to the nitrogen in the initial state
because the low basicity of this atom when bound to the DTC
group.13
Mechanism b is consistent with an initial state where a
T1
O-L2
T2
Hydron is hydrogen-bonded to the Omorph and the nitrogen, and
ꢀ
ꢀ
kD
kH
(
(
)
)
(
(
O-L1-O-L3-N
)
)
a late transition state with the characteristic of a zwitterion.
Intramolecular Specific Acid Catalysis. The mechanism of
decomposition of the heterocyclic members of the series must
be similar to that proposed for morpholylDTC, considering the
smooth change of reactivity shown by the Brφnsted plot that is
consistent with a common mechanism and the pK+-pKN
relationship (Figure 2b) that indicates an increase of the basicity
)
(11)
(
) (
)
ꢀO-L
ꢀO -L ꢀO-L
+
1)(
2
sec
3
pri
(37) Schowen, R. L. Prog. Phys. Org. Chem. 1972, 9, 275–332.
(38) Melander, L.; Saunders, W. H., Jr. Reaction Rates of Isotopic Molecules;
Wiley: New York, 1980; Chapter 7.
7194 J. Org. Chem. Vol. 73, No. 18, 2008

Mechanisms of Acid Decomposition of Dithiocarbamates
SCHEME 3. Mechanisms of the Acid Decomposition of Aryl and Alkyl Dithiocarbamates from Strong Basic Amines
TABLE 3. Activation Parameters for Some Selected Dithiocarbamates in 20% v/v Aqueous Ethanol
a
b
R-DTC
pKN
ko (s-1
)
∆Gq (kcal mol-1
)
∆Hq (kcal mol-1
)
∆Sq (cal mol-1 K-1
)
phenyl
4.58
7.52
11.16
8.69
2.80c
16.81 ( 0.74
21.14 ( 0.72
19.52 ( 0.77
17.45 ( 0.63
17.35 ( 1.05
15.10 ( 0.37
19.49 ( 0.36
19.21 ( 0.38
14.79 ( 0.32
14.78 ( 0.52
-5.74 ( 1.25
-5.54 ( 1.19
1.03 ( 1.3
- 8.94 ( 1.06
-8.64 ( 1.77
d
2-AmEt
20.9 × 10-4
8.83 × 10-2
1.08
piperidyle
thiomorpholylf
morpholyle
8.45
1.16
a At 25 °C. b Standard state 1 M, at 25 °C. c 0.1 M H2SO4, µ ) 1.0 (KCl).15 d In water, µ ) 1.0 (KCl).13 e At 3.6 M HCl. f At 2.4 M HCl.
SCHEME 4. Kinetic Solvent Isotope Effect and Mechanism
of the Acid Decomposition of Morpholyl Dithiocarbamate
FIGURE 4. LFER of pKN versus the inductive substituent constant σI
+
for the series of 2-substituted ethylammonia X-(CH2)2-NH3 (9);
2(CH2), piperidino; 2(O), morpholino.
The basicity of the heteroatom in the series varies by about
12 pK units and the nature of the hydrogen bond X · · ·H· · ·O+
may change from a protonated X+-H for piperazyl and
N-methylpiperazyl to H-O+ for morpholyl and thiomorpholyl.
As mentioned above, it is possible that mechanism a (Scheme
4) proceeds stepwise through b for the N-protonated members.
TABLE 4. Solvent Isotope Effect for the Acid Decomposition of
some Dithiocarbamates at 25 °C.
R
kDo /kHo
ethyl
phenyl
morpholyl
3.05 ( 0.10a
2.51 ( 0.04b
1.87 ( 0.25
a Reference.13 b Reference.15
With the present results we cannot distinguish between a
stepwise formation of the zwitterion followed by the expulsion
of the DTC moiety (Scheme 5) and a concerted process of
N-protonation and C-N bond breakage. However, perusal of
the activation parameters of phenylDTC and also those of
morpholyl and thiomorpholylDTC shows that they have the
same enthalpy of activation of 15 kcal mol-1 (Table 3), although
the steric requirements for the cyclic compounds are higher (∆Sq
-9 cal mol-1 K-1) as a consequence of the strained boat
conformation.
of nitrogen by more than 3 pK units in the transition state due
to the strain of the NsH hydrogen bond of the boat conforma-
tion. That magnitude is the same observed for the increase of
pKN observed for morpholine when compared to the alkyl series
(Figure 4). This step is an intramolecular specific acid catalysis
as has been observed in dithiocarbamates for acids that are
similar to, or more acid than, Hydron.14
J. Org. Chem. Vol. 73, No. 18, 2008 7195

Humeres et al.
SCHEME 5. Mechanism of Acid Decomposition of the
Heterocyclic Members of the Series of Analogues of
Piperidine Dithiocarbamate
for C5H8NOS2Na·1.5H2O: C 28.3 (28.5), H 5.2 (5.9), N 6.6 (6.6),
S 30.2 (28.5). 13C NMR (D2O), δ(ppm): 210.7 (CS2), 67.5 (C-2),
39.9 (C-3), 39.5 (C-5), 52.8 (C-6). IR: 538 cm-1 (SCS), 635 cm-1
(C-S), 891 cm-1 (CdS), 979 cm-1 (CSS), 1022 cm-1 (C-N), 1112
cm-1 (CdS), 1215 cm-1 (C-N), 1417 cm-1 (-NdC-S-), 1461
cm-1 (-N-CdS), 1624 cm-1 (CdN), 2851 cm-1 and 2898 (C-H).
4-Methylpiperidyl Dithiocarbamate, Sodium Salt. UV-vis
(H2O): λmax 262 and 280 nm. 13C NMR (D2O), δ(ppm): 207.1 (CS2),
53.5 (C-2), 35.2 (C-3), 31.6 (C-4), 22.2 (CH3). IR: 678 cm-1 (SCS),
866 cm-1 (CSS), 999 cm-1 (CdS), 1132 cm-1 (C-N), 1448 cm-1
(-NdC-S-), 1648 cm-1 (CdN).
Thiomorpholyl Dithiocarbamate, Sodium Salt. UV-vis
(H2O): λmax 262 and 286 nm. 13C NMR (D2O), δ(ppm): 210.3 (CS2),
55.4 (C-2,6), 28.4 (C-3,5). IR: 563 cm-1 (SCS), 615 cm-1 (C-S),
924 cm-1 (CSS), 997 cm-1 (C-N), 1138 cm-1 (CdS), 1185 cm-1
(C-N), 1410 cm-1 (-NdC-S-), 1459 cm-1 (-N-CdS), 1624
cm-1 (CdN).
Piperazyl Dithiocarbamate, Sodium Salt. UV-vis (H2O): λmax
264 and 286 nm. 13C NMR (D2O), δ(ppm): 210.9 (CS2), 51.8 (C-
2,6), 45.0(C-3,5). Substitution on the two nitrogens would have
made four magnetically equivalent carbons. IR: 553 cm-1 (SCS),
655 cm-1 (C-S), 897 cm-1 (CdS), 1000 cm-1 (CSS), 1148 cm-1
(CdS), 1208 cm-1 (C-N), 1417 cm-1 (-NdC-S-), 1459 cm-1
(-N-CdS), 1616 cm-1 (C)N).
4-Methylpiperazyl Dithiocarbamate, Sodium Salt. UV-vis
(H2O): λmax 260 and 286 nm. 13C NMR (D2O), (ppm): 207.9 (CS2),
43.3 (C-2,6), 51.8(C-3,5), 49.8(CH3). IR: 594 cm-1 (SCS), 847 cm-1
(CdS),998cm-1 (CSS),1142cm-1 (CdS),1465cm-1 (-NdC-S-),
1693 cm-1 (CdN).
Conclusions
It is proposed that the acid cleavage of a series of analogues
of piperidine dithiocarbamate X(C2H4)2NCS-2 (X ) CH2,
CHCH3, NH, NCH3, S, O) occurs through two mechanisms.
Piperidine and 4-methylpiperidine dithiocarbamates decompose
by intramolecular water-catalyzed S-to-N proton transfer through
a rate determining transition state whose structure is close to a
zwitterionic intermediate, followed by a fast expulsion of the
dithiocarbamate moiety.
The heterocyclic members of the series (X ) NH, CH3N, O,
S) decompose from their dithiocarbamate anion in the boat
conformation by specific catalysis of the Hydron hydrogen-
bonded to the heteroatom. The N-protonated zwitterion inter-
mediate expels the DTC moiety in a fast step. Alternatively,
the N-protonation may occur concerted with the DTC expulsion.
Kinetics. The rate of disappearance of the dithiocarbamates was
followed at λmax for more than 4 half-lives, and the first-order rate
constants (kobs) for the pH-rate profiles were calculated by the
spectrophotometer software from the average of at least three runs
with correlations no less than 0.99. The acidity ranged from HXo -
5 to pH 5. For acid concentrations higher than 0.01 M the acidity
was calculated from HXo ) -(X + log CH ), where X is the excess
+
acidity function and CH is the acid molarity.40,41 The ionic strength
+
of the runs at pH > 0 was kept constant at 1.0 by addition of KCl.
Buffers were used for runs at pH 5-3. No general acid catalysis
was observed for formate buffer at pH 3 in the range of 0.05-0.5
Mforpiperidyl-,4-methylpiperidyl-,andthiomorfolyldithiocarbamate.
Kinetic Solvent Isotope Effect. The rate constant of the acid
decomposition of sodium morpholyl dithiocarbamate in 20% v/v
EtOD/D2O at 25 °C, 1 M D2SO4, µ ) 1 (KCl), was ko ) 1.94 (
0.18 s-1. The deuterium content of the acid solution was 89.97%,
measured by NMR. Linear extrapolation gave ko ) 2.15 ( 0.20
Experimental Section
Materials. All reagents were of analytical grade and were used
without further purification, except when indicated. Deuterium oxide
(Sigma, 99.8% D) and deuterated ethanol (Aldrich, 99.5% D) were
previously deoxygenated. Deuterated sulfuric acid (99.5% D) was
from Aldrich. The deuterium content of the kinetic solution was
calculated from the NMR spectrum using acetone as internal
standard. Morpholine, p.a. 99%, Riedel-de Hae¨n, was left for 2 h
over KOH pellets and distilled under vacuum. Isopropanol was left
over CaO overnight and subsequently distilled (bp 82.4 °C). The
distilled water employed was deionized and deoxygenated.
Sodium Piperidyl Dithiocarbamate and Analogues. All of
these salts were obtained by adding 20 mmol of the corresponding
amine diluted in diethyl ether, 1.5 mL (24.8 mmoles) of carbon
disulfide, and 1 g (25 mmoles) of NaOH in an erlenmeyer flask
capped with a septum. The mixture was magnetically stirred for
4 h (X ) CH2, O) or 24 h (X ) S, NH, CH3N) at room temperature.
The product was crystallized in isopropanol, filtered, washed with
cold isopropanol and acetone, and dried under vacuum over
phosphorus pentoxide.
s-1 at 100% D. In 20% v/v aqueous EtOH ko was 1.16 ( 0,05 s-1
,
and in consequence the inverse kinetic solvent isotope effect was
kDo 2O/kHo 2O ) 1.87 ( 0.25.
Activation Parameters. Activation parameters were calculated
from ko values in the range of 15.0-30.0 °C by least-squares fitting
to the Eyring equation (eqs 16 and 17).
∆Hq
R
1
Ti
∆Sq
R
ki
kB
h
ln ) -
+ ln
+
(16)
(17)
(
)
Ti
∆Gq ) ∆Hq - T∆Sq
Piperidyl Dithiocarbamate, Sodium Salt. UV-vis (H2O): λmax
262 and 280 nm. Elemental analysis: calculated (experimental) for
C6H10NS2Na.2H2O: C 32.9 (32.2), H 6.4 (6.7), N 6.4 (6.0), S 29.2
(29.9). 13C NMR (D2O), δ(ppm): 204.5 (CS2), 54.5 (C-2), 27.2 (C-
Acknowledgment. A scholarship for B.S.L. and a research
fellowship for E.H. of the Brazilian Conselho Nacional de
Pesquisa Cient´ıfica e Tecnolo´gica (CNPq) are gratefully
acknowledged.
1
3), 23.2 (C-4), 25.0 (C-5), 52.4 (C-6). H NMR (D2O), δ(ppm):
3.7 (4H), 6.3 (6H), 6.9 (H2O). IR: 518 cm-1 (SCS), 616 cm-1
(C-S), 854 cm-1 (CdS), 966 cm-1 (CSS), 1070 cm-1 (C-N), 1130
cm-1 (CdS), 1222 cm-1 (C-N), 1422 cm-1 (-NdC-S-), 1470
cm-1 (-N-CdS), 1624 cm-1 (CdN), 2850 cm-1 and 2930 (C-H).
Morpholyl Dithiocarbamate, Sodium Salt. UV-vis (H2O):
JO801015T
(39) Schowen, K. B. J. In Transition States of Biochemical Processes;
Gandour, R. D., Schowen, R. L., Eds.; Plenum: New York, 1978; Chapter 6.
(40) Cox, R. A. Acc. Chem. Res. 1987, 20, 27–31.
λmax 262 and 286 nm. Elemental analysis: calculated (experimental)
(41) Cox, R. A. AdV. Phys. Org. Chem. 2000, 35, 1–66.
7196 J. Org. Chem. Vol. 73, No. 18, 2008