Microwave-mediated Newman-Kwart rearrangement in water

Article abstract of DOI:10.1039/c6ra20676j

For the first time the unimolecular Newman-Kwart rearrangement is performed in pure water. The elevated temperatures required for the 1,3-aryl shift are easily accomplished by microwave irradiation. Differently functionalized substrates underline the expe

Full text of DOI:10.1039/c6ra20676j

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Microwave-mediated Newman-Kwart rearrangement in water
Ina Hoffmann and Jürgen Schatza
Received 00th January 20xx,
Accepted 00th January 20xx
For the first time the unimolecular Newman-Kwart rearrangement is performed in pure water. The elevated temperatures
required for the 1,3-aryl shift are easily accomplished by microwave irradiation. Differently functionalized substrates
underline the expected influence on the reaction rate regarding the electronic and steric effects of the substituents. The
utilization of supramolecular additives enables an increase in conversion. Besides, the conduction in a microwave reactor
allows for a rapid collection of kinetic data affording the reaction rate constants of the rearrangement of distinct
substrates as well as the Arrhenius constant and activation parameters of the conversion of 2- and 4-nitrophenyl-O-
thiocarbamate.
DOI: 10.1039/x0xx00000x
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Introduction
The thermally induced reaction of O-arylthiocarbamates to
their corresponding S-arylthiocarbamates is commonly known
as the Newman-Kwart rearrangement (NKR) and was first
discovered in the 1960s.1–3 In light of the easy availability of
various phenols 1, their facile conversion to N,N-dimethyl O-
arylthiocarbamates
of the NKR product
2
as well as the readily achieved cleavage
by hydrolysis, methanolysis, or reduction,
Scheme 1 i) Dimethylthiocarbamoyl chloride (DMTCC), DABCO (NaH for less-acidic
phenols), solvent, ≥ 50 °C; ii) NKR: solvent or neat, ∆ (conventional or microwave); iii)
aqueous NaOH, methanolic KOH, or LiAlH4.
3
the NKR is one of the most synthetically attractive routes for
the formation of thiophenols from phenols
(Scheme 1).4–6
4
1
Both thiophenols and similarly accessible sulfur-containing
compounds such as sulfoxides, sulfones, thioethers, and
sulfonic acids contribute to a broad field of applications
including agrochemicals, dyestuffs, medicinal chemistry, chiral
ligands, molecular switches, organocatalysts, dendrimers and
supramolecular assemblies.5–7 Not least, the NKR can be
R
O
S
R
O
S
NMe2
NMe2
5
utilized for the synthesis of specific arenes from phenols
desulfurization of the corresponding thiophenols
1 by
Fig. 1 Four-center 1,3-oxathietane transition state.
4.
200-300 °C to accomplish the high activation energy (EA, ∆G‡).8
Electron withdrawing groups (EWG) attached to the negative
The NKR proceeds via first-order kinetics and is based on an
intramolecular migration of an aryl moiety from an oxygen
cyclohexadienyl moiety facilitate the OAr
therefore, either reduce the reaction temperature or reaction
time.9,10 N,N-Dimethyl O-arylthiocarbamates
bearing one
→SAr migration and
atom to a sulfur atom (OAr
→SAr), which is thermodynamically
driven by the formation of a strong carbon-oxygen double
bond and the simultaneous cleavage of the weaker carbon-
sulfur double bond.8 This 1,3-aryl shift can also be considered
as an intramolecular nucleophilic aromatic substitution with
sulfur attacking the ipso-carbon atom. The rearrangement
proceeds via a zwitterionic four-membered cyclic transition
2
EWG in ortho position can be even more easily converted due
to the rotational restriction around the aryl-oxygen bond,
which entails a loss in entropy and the associated higher order
in the transition state.11,12 On the downside, doubly ortho,
sterically hindered, and electron donating substituents (EDG)
decrease the reaction rate and therefore, require
temperatures approaching 300 °C or prolonged reaction
times.13 The general harsh reaction conditions not only cause
undesired side reactions and charring, but also pose a safety
issue for the organic chemist. Notably, Harvey et al. performed
the NKR at only 100 °C yielding quantitative conversions for
state 5 (Fig. 1), requiring elevated temperatures in the range of
several N,N-dimethyl O-arylthiocarbamates 2 by means of
[Pd(tBu3P)2] as catalyst.14 In addition to that, Perkowski et al.
utilized
a
commercially available photooxidant, which
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efficiently promoted the NKR at ambient temperature.15
A
Table 1 Synthesis of O-arylthiocarbamates 2a-h from phenols 1a-ha
convenient alternative to at least circumvent the safety issue
stemming from high reaction temperatures is the conduction
of the rearrangement in a microwave (MW) reactor under
small-scale autoclaves conditions.7,8,13,16 Further advantages
compared to the conventional heating in an oil-bath are for
instance the rapid access to high reaction temperatures as well
as the fast cooling with compressed air at the end of the
reaction, improved purity profiles, energy efficient in-core
volumetric heating of the reaction medium, and practicability
in terms of handling, i.e., accurate control of reaction
parameters and if necessary, the rapid collection of several
data points needed for a kinetic study.16,17 Moseley et al.
investigated the NKR under MW irradiation and found no
substantial difference between conventional heating and MW
radiation.7 However, for the first time a solvent rate effect was
experimentally described, showing an enhancement of the
conversion with increasing polarity of the solvent. This is not
Entry
R
2-NO2
4-NO2
3-NO2
4-CN
t [h]
3.8
2.5
5.8
3.0
1.5
2.5
5.0
3.7
Yield [%]
NKR substrate
1
2
3
4
5
6
7
8
92
91
93
88
96
84
83
59
2a
2b
2c
2d
2e
2f
4-COMeb
4-Br
4-F
2g
2h
4-OMe
a
Reaction conditions: phenol 1 (1 eq), DMTCC 6 (1.1 eq), DABCO (1.3 eq), NMP,
50 °C.7 b DMTCC 6 (1.2 eq), DABCO (2.5 eq), DMF, 65 °C.43
surprising considering the highly polar transition state 5, which
should be stabilized by polar solvents, and therefore enhance
the reaction rate with decreasing EA. Addressing green
chemistry, now the question arises to what extent water,
Results and discussion
possessing a dielectric constant (εr) of 78, is able to stabilize
the transition state 5 18
.
Substrates and scope
Over the last decades water has received increasing attention
as solvent in organic synthesis and promoted an intriguingly
diverse field of reactions ranging from pericyclic reactions over
transition-metal catalysis to reactions with carbenes and
radicals just to name a few.18–22 In addition to the obvious
benefits towards organic solvents of being inexpensive, non-
flammable, non-toxic, and readily available, in many cases
water is able to enhance both the reaction rate and the
reaction selectivity due to hydrophobic effects.23–25 One
alternative way to increase the reaction rate and selectivity or
rather overcome solubility issues of non-polar substrates in
water, is the utilization of supramolecular additives such as
cyclodextrines or calix[n]arenes, which encapsulate the
hydrophobic reactants in their cavities by non-covalent
interactions while being water-soluble themselves.26–33
The substrates utilized for NKR, i.e., O-arylthiocarbamates 2a-
h
, were chosen to cover both steric and electronic effects on
the rearrangement (Table 1). Electron-withdrawing nitro-
groups substituted in ortho- 2a, meta- 2c, and para-position 2b
of the arene should display the conversion dependency on the
substitution pattern within one group regarding both steric
and electronic characteristics, whereas further EWGs as well as
EDGs substituted in para-position should be compared purely
regarding their electronic influence. Besides, all O-
arylthiocarbamates 2a-h as well as S-arylthiocarbamates 3a-h
are known from literature and the results, i.e., conversion and
reaction rates can be well correlated with Hammet
constants.44
σ
The syntheses of the substrates proceeded in a single-step
reaction starting from readily available, less acidic phenols 1a-
However, to our knowledge the sheer NKR has so far not been
performed in pure water.34 Notably, owing to the fact, that the
NKR can be conducted neat,1,5,8,9,11,35–40 this paper does not
claim more environmentally benign reaction conditions, but
rather demonstrates the attempt to lower EA by means of the
highly polar and green solvent water. In this context we
decided to carry out the rearrangements in pure water by
means of MW irradiation. Though water is known to be only a
medium absorber (loss tangent (tanδ) = 0.123), it can be
rapidly heated well above its boiling point in closed vessels and
has already been successfully utilized in many microwave-
assisted reactions.17,41,42
In this paper, we report the effect of differently functionalized
substrates utilizing electron-donating as well as electron-
withdrawing substituents, the conversion dependency with
and without MW irradiation, the influence of supramolecular
additives (cf. Fig. 3), i.e. cucurbit[6]uril, imidazolio- and
sulfocalix[n]arenes, and finally, a more in-depth kinetic study
of 2- and 4-nitrophenyl O-thiocarbamate investigating the
h
, DABCO and dimethylthiocarbamoyl chloride (DMTCC) 6
according to the procedures of Moseley and DeCollo.7,43 Direct
precipitation by addition of water afforded products in good to
excellent yields (59-96%), most of them being highly crystalline
with the exception of substrates 2d (4-CN), 2g (4-F), and 2h (4-
OMe), which were recrystallized from ethanol.
For our initial substrate screenings we decided to conduct the
NKR of substrates 2a-h, all being completely insoluble in water
at room temperature, at 180 °C and determine the
conversions after 20 min (Table 2). At this temperature solely
the rearrangements of 2-nitro 2a (> 99%) and 4-nitrophenyl-O-
thiocarbamate 2b (99%) resulted in quantitative and excellent
yields. The less strongly electron-withdrawing substrates 2d (4-
CN, 9%) and 2e (4-COMe, 15%) gave conversions being seven
to eleven times lower, while the electronically disfavored O-
arylcarbamates 2c (3-NO2) and 2f-h (4-Br, 4-F, 4-OMe) did not
convert at all or not considerably (Table 2, Entry 6 2%). By
raising the temperature over 200 °C to 210 °C, 220 °C for 3-
effect of water in terms of a possible transition-state
stabilization.
5
nitrophenyl-O-thiocarbamates 2c respectively, the 3-nitro 2c
4-fluoro 2g, and 4-methoxy 2h substrates remained
,
2 | J. Name., 2012, 00, 1-3
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Table 2 NKR of O-arylthiocarbamates 2a-h at given temperatures and substituent
relating Hammett σ constantsa
irradiation affects the NKR in pure water. Therefore the
rearrangement of substrate 2a was additionally conducted
neat and in water for one using a pressure tube placed inside a
heat-on plate and for another applying a conventional oil-bath
and reflux condenser. Table 3 shows that the conversion
decreased in the order microwave > neat >> pressure tube >
reflux, unambiguously indicating a microwave effect for water.
Under usual reflux conditions 2-nitrophenyl-O-thiocarbamate
2a did not convert at all, whereas a build-up of pressure
slightly facilitated the reaction, which implies the
conformational loss of freedom in the transition-state and a
negative volume of activation (Table 3, Entry 3 6%). With
increasing temperatures the bond angle of water widens and
its dielectric constant decreases. As a result, approaching
temperatures greater or equal to 150 °C, water becomes
increasingly non-polar, enhancing the ability to solubilize
hydrophobic substrates.42,45 As compared to the MW-assisted
rearrangement, water did not function as pseudo-organic
solvent at the thermal experiments, where the NKR substrate
2a was barely dissolved. Therefore, the quantitative
conversion by means of MW is probably due to the rapid
achievement of the adjusted temperature and especially, an
Entry
R
σ
Conv. [%]
Conv. [%]
Conv. [%]
at 180 °C
at 200 °C
at 210 °C
1
2
3
4
5
6
7
8
2-NO2
4-NO2
3-NO2
4-CNd
4-COMe
4-Br
̶
> 99 (89)b
̶
̶
+ 0.778
+ 0.710
+ 0.628
+ 0.516
+ 0.232
+ 0.062
99
0
̶
̶
0
0c
81
64
4
9
46
42
3
15
2
4-F
0
0
0
4-OMe
-
0.268
0
0
0
a
Reaction conditions: O-arylthiocarbamat 2a-h (500 ꢀmol, 0.2 M), MW
irradiation, H2O (2.5 mL), 20 min. b Isolated yield in parentheses. c 220 °C. d Apart
from conversion some product degradation occurred.
unconverted and the rearrangement of 4- bromophenyl-O-
thiocarbamate 2f increased by 2%. In our case a further
enhancement of the temperature was not feasible due to the
maximum limit of pressure (20 bar), which has almost been
reached, and additionally, an integrated security limit of 250 °C
of the applied microwave reactor. A quick solution might be
the addition of inorganic salts in order to increase the
transformation of microwave energy into heat, the utilization
of larger reaction vessels or concentrations, and/or prolonged
reaction times. On the other hand both electronically favored
effective internal heating (in-core) resulting in
interaction of MW energy with solvent and substrate.
a direct
The solvent-free conduction yielded a conversion of 88% after
10 min at 180 °C. Besides, the determined reaction rate
constants (k) reveal the neat reaction to be about two and a
half times slower than the MW-mediated rearrangement.
Overall, the usage of MW energy and water as reaction
medium for the NKR appears to be an effective combination as
has already been shown in many reactions before.41,42 In
addition to that, this method is generally beneficial in terms of
easy workup and safe reaction control.
substrates 4-cyano- 2d (9
→
46→81%) and 4-acetylphenyl-O-
thiocarbamate 2e (15→42→64%) underwent a significant
increase in conversion with rising temperature. On the whole
the results of this coarse investigation are in good agreement
with the substituent constants of Hammett (σ) also depicted in
Table 2. However, the values of the nitro substrate substituted
in meta-position 2c differ as expected, due to the insufficient
stabilization of the negative cyclohexadienyl fragment in the
Supramolecular additives
In recent studies we could show that supramolecular additives
such as sulfocalix[n]arenes can efficiently increase the catalytic
activity of Suzuki and metathesis reactions performed in pure
water.27,46 The ability to solubilize hydrophobic reactants and
an improved mass transfer are characteristics, which make
water-soluble calix[n]arenes valuable for reactions in aqueous
media or neat water. This tempted us to investigate the
influence of macrocyclic additives on the NKR. Therefore we
transition state 5.
As a result of our kinetic survey, which will be discussed later
on, the rearrangement of 2-nitrophenyl-O-thiocarbamate 2a
pointed out to be quantitative inside of 10 min at 180 °C
(cf. Fig. 6). With this in hand we were interested in how MW
Fig. 2 Influence of supramolecular additives on conversion based on the NKR of
4-acetylphenyl-O-thiocarbamate 2e (reaction conditions: 2e (500 ꢀmol, 0.2 M),
additive (0.5 mol%), MW, H2O (2.5 mL), 20 min, 200 °C).
Table 3 Comparison of NKR of 2-nitrophenyl-O-thiocarbamate 2a conducted in 10 min
at 180 °C under different reaction conditionsa
Entry
Condition
microwave
neat
Conversion [%]
k [s-1]
8.63 ⋅ 10-3
3.51 ⋅ 10-3
n/d
t [s]
½
1
2
3
4
> 99
88
6
80.3
197
n/d
n/d
SC[8]C8
63
pressure tube
reflux
CU[6]
SC[6]C3
45
43
42
0
n/d
a
Reaction conditions: 2-nitrophenyl-O-thiocarbamate 2a (500 ꢀmol, 0.2 M), H2O
without additive
(2.5 mL), 10 min, 180 °C. n/d = not determined.
0
25
50
conversion [%]
75
100
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Cl
Cl
N
Cl
N
Mes
iPr
N
Me
N
N
N
SO3Na
O
O
N
N
N
N
O
O
O
O
O
O
O
6
3
k
2
2
n
9
10
11
m = k + 1
7a SC6C3
7b SC8C8
8 CU[6]
ImC4C3
Fig. 3 Used supramolecular additives for the NKR in pure water (left: sulfocalix[n]arenes
7a-b, middle: cucurbit[6]uril 8, right: imidazolio calix[4]arenes 9-11).
Table 4 Reaction rates and half-lives of the NKR of distinct substrates at 200 °C
chose the rearrangement of 4-acetylphenyl-O-thiocarbamate
2e at 200 °C in 20 min (42% conversion, cf. Table 2) and added
Entry
R
k [s-1]
t
[s]
σ
½
1
2
3
4
5
2-NO2
4-NO2
4-CN
3.30 ⋅ 10-2a
1.42 ⋅ 10-2
8.95 ⋅ 10-4
6.51 ⋅ 10-4
1.15 ⋅ 10-5
21.0
48.8
̶
three different host compounds at
a concentration of
+ 0.778
+ 0.628
+ 0.516
+ 0.232
0.5 mol% (Fig. 2 and Fig. 3). The reactions with cucurbit[6]uril
8
774
4-COMe
4-Br
1.07 ⋅ 103
and SC6C3 7a resulted in hardly increased conversions of 43%
and 45%, respectively, whereas the employment of SC8C8 7b
gave an 21% improvement versus the rearrangement without
additive. As described above, at elevated temperatures water
acts as pseudo-organic solvent and is able to dissolve non-
polar substrates. Owing to the fact that the substance probe is
automatically cooled with compressed air after the reaction
and thus, the organic product precipitated from water at
ambient temperature, it is not detectable if the reactant had
been fully dissolved afore. Therefore, we assume that SC8C8
7b contributes to an additional stabilization of the transition
6.04 ⋅ 104
Extrapolated from measurements at 140-180 °C using k = 4.06 ⋅ 1012 -1 ⋅ exp(-
s
a
128 kJ mol-1/R ⋅ 473.15 K) (cf. Fig. 7).
100
75
50
25
0
2-nitro
4-nitro
4-cyano
4-acetyl
4-bromo
state
5 and an either fully or faster solubilization by
encapsulating the hydrophobic NKR substrate in its cavity. A
possible reason for the conversion difference of the two
sulfocalix[n]arenes 7a,b may be an enhanced surface-activity
of SC8C8 7b due to its larger hydrophobic tails. In general, the
increased conversion might also derive from an enlarged loss
tangent, i.e. the addition of salts, in our case 0.5 mol% SC8C8
7b, improves the MW absorbance due to ionic conduction.
In a second experiment, cationic imidazolio calix[4]arenes (9-
0
200
400
600
800
time [s]
Fig. 4 Dependency of conversion on time of the NKR of distinct substrates at 200 °C.
Solid lines indicate fit-values calculated from rate constants in Table 4.
11) were employed to possibly stabilize the transition state
5
of the NKR of 3-nitrophenyl-O-thiocarbamate 2c at 180 °C (cf.
Fig. 3). However, none of the cations initiated the
rearrangement, which underlines that the electronically
disfavored 3-nitro substrate 2c requires higher temperatures
to overcome the activation barrier.
5
4-NO2
4-CN
4
4-COMe
4-Br
3
2
1
0
Kinetic study
Reaction rates The unimolecular NKR proceeds via a first-order
reaction. The reaction rate constants were ascertained by
applying equation 1 to at least five experimentally determined
data points. Besides, all rearrangements were conducted
employing substrate concentrations of 0.2 M.
0
0.2
0.4
0.6
0.8
1
σ
Fig. 5 Hammett plot of log k - log kRef vs. σ. kRef surrogates kH (R = H), which was not
experimentally determined and was defined as the y-intercept (log kRef = -6.19) from
the plot of log k vs. σ at σ = 0.
4 | J. Name., 2012, 00, 1-3
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100
80
60
40
20
0
Ø 180 °C
Ø 170 °C
Ø 165 °C
Ø 160 °C
Ø 150 °C
Ø 140 °C
0
200
400
600
time [s]
800
1000
1200
Fig. 6 Dependency of the conversion on time of the rearrangement of 2-nitro-O-
thiocarbamate 2a at temperatures ranging from 140 to 180°C. Points indicate the
experimental data from two measurements and the solid lines are the fit-values
calculated using the averaged reaction rates (cf. Fig. 7). Averaged standard deviation of
3.30 · 10-2
200
180
170
165
160
150
140
1.42 · 10-2
8.63 · 10-3
Ø k-values is 2.92 ⋅ 10-4 s-1
.
3.93 · 10-3
3.16 · 10-3
2.40 · 10-3
ꢄ ꢁ ꢅ ∙ ꢆꢇꢈ∙ꢃ
ꢀ ꢂ
ꢀ ꢂ
ꢁ
(1)
ꢃ
2-nitro
4-nitro
2.47 · 10-3
1.53 · 10-3
As described in literature,1,7,9,12,16 substituents differing in their
electronic characteristics, have strong impact on the
1.63 · 10-3
1.37 · 10-3
a
reactivity of the NKR and additionally, are in good agreement
with the Hammett σ constants. This correlation could also be
seen for the rearrangement in pure water (vide supra) and
should now be further investigated regarding the
corresponding reaction rates. For this purpose, several NKRs of
para-substituted substrates, i.e. nitro- 2b, cyano- 2d, acetyl-
2e, and bromophenyl-O-thiocarbamate 2f, were conducted at
200 °C. The rate constant of the substrate bearing the nitro
group in ortho position 2a was extrapolated from
measurements at 140-180 °C using equation 2 (cf. Fig. 8). Fig. 4
shows the exponential curves of the respective reactants
displaying a reaction rate enhancement in the order 2-nitro >
4-nitro >> 4-cyano > 4-acetyl >> 4-bromo, which is still in line
with the substituent constants of Hammett and former
literature (cf. Fig. 5). The σ values, the corresponding rate
constants, and the half-lives are depicted in Table 4. The
rearrangement of substrate 2a is additionally promoted due to
the steric restriction in the ortho position and would be
completely converted in about three minutes. As opposed to
that, the quantitative rearrangement of 4-bromophenyl-O-
thiocarbamate 2f would be feasible within five days.
7.70 · 10-4
4.74 · 10-4
2.90 · 10-4
2.05 · 10-4
0
0.01
0.02
k [s-1]
0.03
0.04
Fig. 7 Averaged rate constants of 2-nitrophenyl-O-thiocarbamate 2a and rate constants
of 4-nitrophenyl-O-thiocarbamate 2b at temperatures ranging from 140-200 °C. The
reaction rate constants of substrate 2a at 200 °C and substrate 2b at 165 °C were
extrapolated using equation 2.
0.00205
-2.5
0.00215
-3.41
0.00225
0.00235
0.00245
fit
exp data
-3.5
-4.5
-5.5
-6.5
-7.5
-8.5
Arrhenius and activation parameters The more thorough
investigation of both nitro substrates 2a and 2b involve the
prior determination of various reaction rate constants at
different temperatures (Fig. 6 and 7), whose correlation is
given in the Arrhenius equation (2).
1/T [K-1]
Fig. 8 Arrhenius plot of 2-NO2 substrate 2a. Points indicate the experimental data based
on averaged k-values. Solid line represents the calculated fit-values using ln A = 29.0
and EA/R = 15.4 ⋅ 103 K.
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Table 5 Arrhenius and activation parameters for the NKR of 2-NO2- 2a and 4-NO2-O-
arylthiocarbamate 2ba
On the other hand, the activation entropy decreases with
higher order in the transition-state, i.e. loss of rotational and
translational degrees of freedom, as compared to the initial
state and becomes more negative with higher restriction.
However, this conflicts with the lower negative activation
entropy and the accelerated reaction rate constant of the
Entry
R
A [s-1]
EA
[kJ mol-1]
128
∆H‡
∆S‡
[kJ mol-1]
124.0 ± 0.1
109.7 ± 0.2
[J mol-1 K-1]
-15.0 ± 0.3
-51.6 ± 0.4
b
1
2
2-NO2
4.06 ⋅ 1012
5.05 ⋅ 1010
4-NO2
113
sterically more restricted 2-nitrophenyl-O-thiocarbamate 2a
.
a
b
∆ = difference between ground and transition state. Average value from two
measurements.
Experimental section
ꢊꢋ
ꢌ∙ꢍ
ꢉ ꢄ ꢁ ∙ ꢆꢇ
(2)
General
Chemicals were purchased from commercial sources and used
without further purification. O-Arylthiocarbamates 2a-h were
prepared according to the published procedure.7,43 Imidazolio
calix[4]arenes 9-11 were utilized by the courtesy of Dr. Markus
Frank47 and alkylated sulfocalix[n]arenes 7a,b were utilized by
the courtesy of Silvia Onodi.48 Maldi-ToF spectra were
As was expected, for one the reaction rates increase with
higher temperatures and for another the beneficial steric
acceleration of the ortho substrate 2a is mirrored in the
reaction rates, being lower for the para substrate 2b at every
temperature.
For both carbamates the Arrhenius constant (A) and EA were
determined by plotting the k-values according to equation 3
recorded on
a Shimadzu Biotech AXIMA Confidence. IR
spectroscopy was performed on a Varian 660-IR spectrometer.
NMR spectra were recorded in CDCl3 using a Bruker Avance
(cf. Fig.
8 for 2-NO2 substrate 2a) and the activation
parameters, i.e. activation enthalpy (∆H‡) and activation
entropy (∆S‡), were calculated using equation 4 and 5:
1
400 operating at 400.13 MHz for H-NMR and 100.62 MHz for
13C-NMR. Chemical shifts (δ) are indicated in parts per million
(ppm) relative to the internal standard (δH = 7.24 ppm, δC
=
ꢐꢑ
(3)
(4)
(5)
ꢎꢏ ꢉ ꢄ ꢎꢏ ꢁ −
77.23 ppm). The conversions of the Newman-Kwart
rearrangements were determined by comparing the integrated
proton signals of the methyl groups of O- 2a-h and S-aryl-N,N-
dimethylthiocarbamate 3a-h. All conventional NKRs (with
exception of the solvent-free experiment) were stirred at
highest rate using a MR Hei-Tec from Heidolph®.
ꢒ ∙ ꢓ
∆ꢔ‡ ꢄ ꢐꢑ − ꢒ ∙ ꢓ
ꢁ
∆ꢕ‡ ꢄ ꢒ ꢖꢎꢏ − ꢎꢏ
ꢓ
ꢉꢗ
ℎ
− 1ꢘ
Microwave-mediated Newman-Kwart rearrangement
Table 5 shows the results for both systems. EA and the
activation enthalpy, which is smaller by the product of R T, are
The microwave-assisted reactions were performed employing
an Initiator+ from Biotage (fourth generation microwave
⋅
each higher for the 2-NO2 substrate 2a. Moreover, the
comparison with the values of Gilday et al., who performed
the NKR of 2-nitrophenyl-O-thiocarbamate in poorly polar
dichlorobenzene, even reveals the EA in water to be higher by
the factor of 12 kJ mol-1 diminishing the assumption of a
synthesizer). For
a
general procedure, O-aryl-N,N-
mol) and H2O (2.5 mL) were
dimethylthiocarbamate (500
ꢀ
placed in a sealed 2-5 mL vial. The reactant was stirred for a
fixed time of 30 s and subsequently heated to the selected
temperature not exceeding 400 W. All data on the reaction
time exclude the heating time. After the sample was stirred at
the respective temperature and time, it was automatically
cooled down to approximately 50 °C and was afterwards
allowed to further cool down to room temperature. The
possible transition-state
5
stabilization.16 On the contrary,
comparing our results of the rearrangement of 4-nitrophenyl-
O-thiocarbamate 2b with literature, where the NKR has also
been conducted in
a
highly polar solvent, i.e.
dimethylacetamide, the activation barrier could be reduced by
approximately 11 kJ mol-1 in pure water.
product was extracted with CDCl3 (3
subsequently used for 1H-NMR analysis.
× 600 ꢀL) and
The evaluation of the ∆S‡-values is not as straightforward. On
the one hand the entropy of activation is increasing with
extending reaction rate constant. This correlation is given in
the Eyring equation (6) and is also in line with our obtained
results for the ortho- 2a and para-nitro substrate 2b. Similar
∆S‡-correlations had been found for the NKR of 2- and 4-
methylphenyl-O-thiocarbamate, which was ascribed to the
restriction of the free rotation around the carbon-oxygen bond
in the ground state.12
Preparative Newman-Kwart rearrangement
2-Nitrophenyl-N,N-dimethyl-S-thiocarbamate 3a H2O (2.5 mL)
and 2-nitrophenyl-N,N-dimethyl-O-thiocarbamate 2a (113 mg,
500 ꢀmol) were placed in a sealed 2-5 mL vial. The reactant
was stirred for a fixed time of 30 s and subsequently heated to
180 °C. After stirring 10 min at this temperature, the sample
was automatically cooled down to approximately 50 °C and
was afterwards allowed to further cool down to room
temperature. The product was extracted with DCM
∆ꢙ‡
∆ꢚ‡
ꢌꢍ
ꢉꢗꢓ
ℎ
ꢌ
(6)
ꢉ ꢄ
∙ ꢆ ∙ ꢆꢇ
(3 × 600 ꢀL) and dried over MgSO4. DCM was removed by a
rotatory evaporator and the product was dried under high
6 | J. Name., 2012, 00, 1-3
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vacuum. 101 mg (447
ꢀ
mol, 89%); yellow oil; IR (ATR): ꢛꢜ (cm-1) The fusion of MW irradiation and water, as environmentally
C=O), 1590 (w, aryl, C=C), benign reaction medium, not only affords quantitative
C=C), 1461 (m, CH3, δC-H), 1352 (s, NO2, N=O), Newman-Kwart rearrangements, but simultaneously meets
= 1667 (s, N,N-disubstituted amide,
ν
ν
ν
1570 (w, aryl,
739 (m, aryl,
ν
νC-H); further absorption bands: 1524 (s), 1406 two key principles of green chemistry, i.e. “energy-efficient
(w), 1300 (w), 1254 (m), 1092 (s), 1054 (m), 902 (m), 852 (m), synthesis” and “safer solvents”.49 The transfer to a pilot or
1
781 (m), 724 (m), 682 (m), 650 (m), 524 (w), 434 (w); H-NMR production scale is an important topic, which has to be studied
(400.13 MHz, CDCl3, 298 K): δH (ppm) = 2.98 (s, 3H), 3.08 (s, in future.
3H), 7.49 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.67 (d, J =
7.7 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H); 13C-NMR (100.62 MHz,
Acknowledgements
CDCl3, 298 K): δC (ppm) = 37.26, 124.45, 124.93, 130.03,
132.38, 138.32, 152.49, 164.51; MS (Maldi-ToF, dhb): calc. for
Generous support of the “Solar Technologies go Hybrid”
(SolTech) initiative initiated by the Government of Bavaria is
gratefully acknowledged.
2
+
•
C9H10N2O3S: 226.04, found: m/z = 101 [M - C2H2 + 2 H ], 181
[M - NO2 + H+], 227 [M + H+].
Conventional Newman-Kwart rearrangements
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ARTICLE
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8 | J. Name., 2012, 00, 1-3
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