Chloroform as a hydrogen atom donor in barton reductive decarboxylation reactions

Article abstract of DOI:10.1021/jo400927y

The utility of chloroform as both a solvent and a hydrogen atom donor in Barton reductive decarboxylation of a range of carboxylic acids was recently demonstrated (Ko, E. J. et al. Org. Lett. 2011, 13, 1944). In the present work, a combination of electronic structure calculations, direct dynamics calculations, and experimental studies was carried out to investigate how chloroform acts as a hydrogen atom donor in Barton reductive decarboxylations and to determine the scope of this process. The results from this study show that hydrogen atom transfer from chloroform occurs directly under kinetic control and is aided by a combination of polar effects and quantum mechanical tunneling. Chloroform acts as an effective hydrogen atom donor for primary, secondary, and tertiary alkyl radicals, although significant chlorination was also observed with unstrained tertiary carboxylic acids.

Full text of DOI:10.1021/jo400927y

Article
pubs.acs.org/joc
Chloroform as a Hydrogen Atom Donor in Barton Reductive
Decarboxylation Reactions
Junming Ho,† Jingjing Zheng,‡ Ruben Meana-Paneda,‡ Donald G. Truhlar,*,‡ Eun Jung Ko,§
́
̃
G. Paul Savage,*,∥ Craig M. Williams,*,§ Michelle L. Coote,*,† and John Tsanaktsidis*,∥
†ARC Centre of Excellence for Free-Radical Chemistry and Biotechnology, Research School of Chemistry, Australian National
University, Canberra, ACT, Australia
‡Department of Chemistry, Supercomputing Institute, and Chemical Theory Center, University of Minnesota, Minneapolis,
Minnesota 55455-0431, United States
§School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Queensland, Australia
∥CSIRO Materials Science and Engineering, Clayton South, 3169 Victoria, Australia
S
* Supporting Information
ABSTRACT: The utility of chloroform as both a solvent and
a hydrogen atom donor in Barton reductive decarboxylation of
a range of carboxylic acids was recently demonstrated (Ko, E.
J. et al. Org. Lett. 2011, 13, 1944). In the present work, a
combination of electronic structure calculations, direct
dynamics calculations, and experimental studies was carried
out to investigate how chloroform acts as a hydrogen atom
donor in Barton reductive decarboxylations and to determine
the scope of this process. The results from this study show that hydrogen atom transfer from chloroform occurs directly under
kinetic control and is aided by a combination of polar effects and quantum mechanical tunneling. Chloroform acts as an effective
hydrogen atom donor for primary, secondary, and tertiary alkyl radicals, although significant chlorination was also observed with
unstrained tertiary carboxylic acids.
subset of this synthetically important reaction class.3−8
Fundamental to the Barton decarboxylation protocol is the
alkyl thiohydroxamic ester 3, also known as the Barton ester,
INTRODUCTION
■
Protodecarboxylation of a carboxylic acid 1 is a fundamental
functional group transformation in organic chemistry that
which is readily prepared (in situ) from acid chlorides 4 and 1-
formally involves the extrusion of a molecule of carbon dioxide
hydroxypyridine-2(1H)-thione sodium salt 5, or through the
(CO2) from a carboxylic acid residue, furnishing the
prior reaction of carboxylic acids 1 and 1-hydroxypyridine-
corresponding hydrocarbon 2.1 While the R-group can in
2(1H)-thione 6 in the presence of a dehydrating agent (Scheme
principle be any organic moiety, including alkyl, vinyl, alkynyl,
and aryl, only carboxylic acids that contain a neighboring
2).9 Under the influence of visible light and heat, Barton esters
3 undergo rapid homolytic decomposition furnishing the
stabilizing group, such as a β-keto group, are capable of
corresponding alkyl acyloxy radicals 7, which decarboxylate
rapidly10 to produce the corresponding alkyl radicals 8, and in
undergoing decarboxylation under moderate reaction con-
ditions (Scheme 1).2
turn the reduction product 2 upon interception with a suitable
H-donor. Alternatively, in the absence of a competitive H-
donor the radical 8 can react with the Barton ester 3 to produce
the 2-pyridylsulfide 9, a process known as self-trapping.
Effective H-donors are typically characterized by a relatively
low H-donor bond dissociation enthalpy (BDE), and they give
rise to stabilized conjugate radicals that can effectively
participate in chain propagation, as exemplified by established
H-donors such as tributyltin hydride (TBTH),11 thiophenol
(TP),12 tris(trimethylsilyl)silane (TTMS),11 and tert-butylthiol
(TBT).13−15 Table 1 lists the best available BDEs and hydrogen
atom transfer (HAT) rate constants for these benchmark H-
Protodecarboxylations of alkyl carboxylic acids (1, R = alkyl)
through the Barton radical decarboxylation protocol in the
presence of a suitable hydrogen atom donor (H-donor), also
referred to as reductive decarboxylations, are an important
Scheme 1. Protodecarboxylation of Carboxylic Acids
Received: May 8, 2013
Published: June 3, 2013
© 2013 American Chemical Society
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Scheme 2. Barton Reductive Decarboxylation Process
highlights the inadequacy of this analysis. Additionally, chlorine
atom transfer (CAT) has been shown to be competitive,
especially with tertiary alkyl radicals, thereby introducing an
added dimension to this observed reactivity of chloroform.
In the present work, we have employed electronic structure
and direct dynamics calculations, and additional experimental
(including deuterium kinetic isotope effects) studies to examine
how chloroform might act as a H-donor in Barton reductive
decarboxylation reactions and to better define the scope of the
reaction. The results show that HAT from chloroform occurs
directly with primary, secondary, and tertiary alkyl radicals
under kinetic control and is aided by polar and tunneling
effects. With unstrained tertiary carboxylic acids, significant
chlorination via direct chlorine atom transfer from chloroform
is shown to be competitive.
Table 1. Bond Dissociation Enthalpies (BDEs) and
Hydrogen Atom Transfer (HAT) Rate Constants with Alkyl
Radicals and Some Benchmark H-Donors
16
H-donor BDE HAT rate constants (kH, M−1 s−1
)
for
H-donor
(kcal/mol)
primary alkyl radicals at 25 °C
Bu3Sn−H
PhS−H
(Me3Si)3Si−H
tert-BuS−H
7811
2.2 × 106
8012
9 × 107
8411
8813−15
3.9 × 105
6 × 106
donors. The use of these H-donors, however, is disadvantaged
by their cost, availability, malodorous nature, toxicity, or
difficulties associated with product purification. As such, there is
an ongoing need for effective H-donors that are inexpensive,
readily available, easily handled, and readily removed from the
final reaction products.
We have reported recently on chloroform’s effectiveness as a
H-donor in the Barton reductive decarboxylation reactions of
various primary, secondary, and tertiary (including strained
bridgehead) alkyl carboxylic acids (Scheme 3).17 Table 2
In the next section we describe the methods to compute the
Gibbs free energy and the rate constants. Sections 3 and 4 show
the results and the discussion respectively.
COMPUTATIONAL METHODS
■
The thermodynamic data associated with hydrogen and chlorine atom
transfer reactions were computed at the G3(MP2)-RAD level of
theory20 in conjunction with MPW1K/6-31+G(d,p) geometries and
frequencies. The electronic structure model chemistries were chosen
on the basis of a previous assessment study.21 Scale factors22 have been
applied to the harmonic frequencies in all calculations. To obtain free
energies in solution, solvation free energies (at 333 K) were calculated
using the SMD23 model at the M06−2X/6-31+G(d,p)24 level of
theory (which the models were parametrized for) and using
chloroform as the solvent on solution phase optimized geometries.
The solvation free energies were then combined with the gas phase
free energies, taking into account the appropriate standard state
corrections, to arrive at the solution phase reaction barriers and free
energies with a standard state of 1 mol L−1. The SMD model has been
parametrized to predict solvation free energies at 298 K, and we have
assumed that the solvation contributions to the reaction and activation
Gibbs free energies are the same at 298 and 333 K.
Scheme 3. Products Arising from the Homolytic
Decomposition of Barton Esters in Chloroform
provides a summary of experimental data from both this work
and our earlier work that demonstrates this utility. For primary
and strained bridgehead carboxylic acids (entries 1−3, 7, and 8)
the yields of reduced products 2 are comparable to, if not better
than, those obtained using classical H-donor sources such as
TBTH and TP. With secondary and tertiary carboxylic acids
(entries 4, 5, and 6), however, significant quantities of the
corresponding chlorides 10 and the 2-pyridiylsulfides 9 were
also produced. This process has since been developed as an
Organic Syntheses procedure.18
The reaction rate constants for hydrogen and chlorine atom transfer
were based on the following rate law: R = kH/Cl[CHCl3][R•], where
the rate constants kH/Cl were evaluated using variational transition state
theory with multidimensional tunneling (VTST/MT).25 The varia-
tional effects were incorporated by canonical variational transition-
state theory (CVT), in which the flux is minimized for a canonical
ensemble. Tunneling was incorporated using the microcanonically
optimized multidimensional tunneling (μOMT) method,26 which
optimizes microcanonically (at every energy) the largest probability
between the small curvature tunneling (SCT) probability27,28 and the
large curvature tunneling (LCT) probability,29 the latter evaluated
with the LCG429 version of multi-dimensional large curvature
While the data presented in Table 2 demonstrate chloro-
form’s hitherto unrecognized synthetic utility as a H-donor,
especially for primary and strained bridgehead radicals, it
provides little insight into this reactivity, especially when
considered through the simple perspective of C−H BDE alone,
which for chloroform is 93.8
comparison with the BDEs of H-donors listed in Table 1
0.6 kcal mol−1.19 Simple
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a
Table 2. Examples of Barton Reductive Decarboxylations in Chloroform
a
b
c
1
Data taken from ref 17. Isolated yields. Identified and quantified by H NMR and/or GCMS where yields were small (<1).
tunneling, interpolated in two dimensions.30 A detailed description of
these procedures is provided in the Supporting Information.
symmetry number is three with the exception of the chlorine atom
transfer reaction by the methyl radical where it is nine.34
All electronic structure calculations were performed using the
Gaussian 0935 and Molpro 2009.136 programs and the rate constants
were computed with the program GAUSSRATE,37 which is an
interface between POLYRATE37 and Gaussian09.
All of the dynamics calculations were computed using the direct
dynamics method where all the electronic structure calculations were
performed using M06−2X24 including the solvation effects of the
chloroform by the SMD23 continuum solvation model. The basis set
used was 6-31+G(d,p) except for the larger radicals, i.e. cyclohexyl,
adamantyl, and cubyl, where the smaller 6-31G(d) basis set was used
instead. The MEP was followed in nonredundant curvilinear (internal)
coordinates by using the Page−McIver31 algorithm, and the RODS32
algorithm was used to maximize the value of the vibrationally adiabatic
potential at each point along the MEP optimizing the orientation of
the dividing surface. A converged MEP was obtained with a step size of
0.005 Å, scale mass μ = 1 amu, and Hessian calculations every nine
steps. All frequencies were scaled by a factor of 0.967 when the 6-
31+G(d,p) is used and a factor of 0.963 where the 6-31G(d) is used.33
All the rate constants have been computed taking into account that the
RESULTS
■
To understand the role played by the chloroform in Barton
reductive decarboxylation, we studied the hydrogen atom
transfer (HAT), deuterium atom transfer (DAT), and chlorine
atom transfer (CAT) reactions between chloroform and
different radicals. That includes methyl and ethyl as primary
radicals; isopropyl and cyclohexyl as secondary radicals; and
tert-butyl and adamantyl as tertiary radicals and cubyl as a
tertiary strained bridgehead radical. It should be noted that
cyclohexyl and adamantyl radicals are models of the
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Table 3. Computed Standard-State Gibbs Free Energies of Activation (in kcal·mol−1) at the Generalized Transition State and
Gibbs Free Energies of Reaction (in kcal·mol−1) for the Hydrogen Atom and Chlorine Atom Transfer Reaction between
a
Chloroform and Various Alkyl Radicals at 333 K in Chloroform Solution
bc
,
bc
,
d
d
R•
methyl
ΔG‡H,CVT,
°
ΔG
°
ΔGH
ΔGCl
‡,CVT,
CI
14.48 (13.86)
15.31 (14.44)
15.93 (15.27)
16.23 (15.82)
14.02 (12.95)
10.68 (10.24)
9.51 (9.31)
19.47 (19.33)
19.59 (19.42)
18.61 (18.46)
15.94 (15.81)
17.18 (17.07)
13.17 (13.13)
14.14 (14.09)
−7.86 (−8.49)
−3.26 (−3.94)
−0.32 (−0.72)
0.86 (1.43)
−10.71 (−11.04)
−9.51 (−11.22)
−10.15 (−10.86)
−10.34 (−10.65)
−12.19 (−12.20)
−16.59 (−16.09)
−18.84 (−18.50)
ethyl
isopropyl
tert-butyl
cyclohexyl
adamantyl
cubyl
−0.91 (−1.25)
−3.25 (−2.17)
−8.30 (−7.61)
8.89
2-pyridinethiol
20.90 (20.78)
a
b
The standard-state concentration is taken as 1 M. Values in parentheses correspond to the phenomenological free energy of activation, which
c
includes both variational and tunneling effects (i.e., ΔGphen = ΔG‡,CVT,° − RT ln κ). Computed at the M06−2X/6-31+G(d,p) level of theory using
the SMD continuum solvation model. For the cyclohexyl, adamantyl, and cubyl radicals, the 6-31G(d) basis set was used instead. Computed using
d
G3(MP2)-RAD model chemistry in conjunction with solvation free energies from the SMD solvent model. Values in parentheses were computed by
M06−2X/6-31+G(d,p) using the SMD continuum solvation model. The results are in very good agreement with G3(MP2)-RAD; therefore the
former was used in the direct dynamics calculations for reasons of cost.
Table 4. Computed VTST/μOMT Rate Constants (in M−1 s−1) and Barrier Heights (in kcal·mol−1) for the Hydrogen Atom and
Chlorine Atom Transfer Reaction between Chloroform and Various Alkyl Radicals at 333 K in Chloroform Solution
a
a
R•
methyl
kH
kD
kCl
ΔV‡(HAT)
ΔV‡(CAT)
5.72 × 103
2.40 × 103
6.81 × 102
2.98 × 102
2.29 × 104
1.37 × 106
5.55 × 106
1.64 × 10−1
3.31 × 103
5.08 × 102
8.25 × 102
1.73 × 102
5.72 × 103
3.34 × 105
1.55 × 106
1.48 × 100
1.29 × 100
5.50 × 100
3.04 × 102
4.52 × 101
1.74 × 104
4.03 × 103
7.31
7.81
8.01
7.59
6.79
4.71
4.07
15.07
10.39
9.16
8.02
6.81
6.89
4.11
5.66
ethyl
isopropyl
tert-butyl
cyclohexyl
adamantyl
cubyl
2-pyridinethiol
a
ΔV‡ is the barrier height in the vibrationally adiabatic potential (VaG); see eq 5 in the Supporting Information.
experimentally studied systems, 4-carbomethoxycyclohexyl, 4-
carbomethoxycubyl respectively. The competing HAT reaction
between 2-pyridinethiol and chloroform is also examined. Table
3 shows the Gibbs free energy of activation and reaction for
HAT and CAT for various systems at 333 K, where the effect of
chloroform as solvent was included. The rate constants for all
the reactions described before computed with VTST/μOMT in
solution are shown in Table 4, while Table 5 lists the μOMT
transmission coefficients. For all of the studied reactions, we
found that the differences between μOMT and SCT trans-
mission coefficients are very small (see Supporting Informa-
tion).
DISCUSSION
■
Direct versus Indirect HAT. Mechanistically, the first
event in the Barton reductive decarboxylation process involves
the homolytic decomposition of the thiohydroxamic ester 3 to
generate the alkyl acyloxy radical 7 and the 2-pyridinethiyl
radical 11 (Scheme 4). The acyloxy radical 7 then undergoes
rapid decarboxylation10 to generate the corresponding alkyl
radical 8 and CO2. Pathway A invokes direct HAT from
chloroform to the alkyl radical 8, producing the reduction
product 2 and the trichloromethyl radical 12, which in turn can
Scheme 4. Possible HAT (Pathways A and B) and
Propagation Pathways for the Barton Reductive
Decarboxylation Reaction with Chloroform as the H-Donor
Table 5. Microcanonical Optimized Multidimensional
Tunneling (μOMT) Transmission Coefficients for HAT,
DAT, and CAT between Chloroform and Various Alkyl
Radicals at 333 K in Chloroform Solution
R•
methyl
HAT
DAT
CAT
2.55
3.77
2.71
1.86
5.08
1.96
1.35
1.20
3.92
4.10
2.54
1.49
4.02
2.50
2.09
1.25
1.29
1.25
1.22
1.19
1.07
1.08
ethyl
isopropyl
tert-butyl
cyclohexyl
adamantyl
cubyl
2-pyridinethiol
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function as a chain carrier by reaction with the thiohydroxamic
ester 3, thereby furnishing trichloromethyl sulfide 14 and a new
alkyl radical 8. Another mechanistic possibility leading to the
same overall outcome (Pathway B) requires a rapid HAT from
chloroform to the connate 2-pyridinethiyl radical 11, generating
2-pyridinethiol 13 and 12. The pyridinethiol 13 would then be
expected to react rapidly with 8 to furnish the reduction
product 2, and regenerate 11, consistent with the well-known
ability of thiophenol to function as an effective H-donor to alkyl
radicals.38
follows that HAT must take place directly from CHCl3 to the
alky radical 8 (pathway A, Scheme 4).
Self-Trapping. In competition with direct HAT from
chloroform, however, are two other processes: (i) CAT leading
to chlorination and (ii) self-trapping wherein the alkyl radical 8
reacts with the thiohydroxamic ester 3 to generate the
corresponding alkyl 2-pyridyl sulfide 9 (Scheme 6).
Scheme 6. Competitive CAT and Self-Trapping Reactions
In order to probe the involvement of 2-pyridinethiyl radical
11 in these processes (Pathway B), the reaction of 2,2′-
dipyridyl disulfide 15 and chloroform under various reaction
conditions was investigated. The participation of 11 in these
reactions would be expected to lead to the production of the
trichloromethyl sulfide 14 which is a stable, isolable compound
(Scheme 5).39 Irradiation of 15 with a tungsten lamp in
Scheme 5. Reactions of 2,2′-Dipyridyl Disulfide (15) with
Chloroform
Newcomb and Kaplan have previously determined the rate
constant for the reaction of n-octyl radical with its precursor
thiohydroxamic ester 3 (R = n-octyl) to be 2.8 × 106 M−1 s−1 at
60 °C,42 which effectively imposes a minimum reactivity for any
H-donor to effectively compete with self-trapping. This is the
fate of all alkyl thiohydroxamic esters when decomposed
homolytically in the absence of a competitive radical trap.43,44
In the present case the suppression of significant amounts of
alkyl 2-pyridyl sulfides 9 can be attributed to the high relative
concentration of chloroform ([CHCl3] = 12.4 M) and the
maintenance of a constant but sufficiently low “steady state” in
situ concentration of thiohydroxamic ester 3, through the slow
dropwise addition of the acid chloride 4 to an equivalent of 1-
hydroxypyridine-2(1H)-thione sodium salt 5 in chloroform.
This experimental regimen can be reliably employed to
effectively control the relative concentrations of both the
thiohydroxamic ester 3 and the alkyl radical 8, thereby
channelling the reaction of the latter toward HAT (and
CAT) from chloroform rather than self-trapping with 3
(Schemes 4 and 6).
The only reported rate constant for the abstraction of a
hydrogen atom from chloroform by an n-alkyl radical comes
from the early work of Tuan and Gaumann who studied the
radiolysis of liquid binary mixtures of n-hexane and chloro-
form.45 This study produced a rate constant, kH, for the HAT
from chloroform to n-hexyl of 4.8 × 103 M−1 s−1 at −10 °C.
Using the ethyl radical as a model for the n-hexyl system, our
calculations predict a 9.5-fold increase in rate going from −10
to 60 °C (see Supporting Information). Applying this
correction to the −10 °C experimental value yields a kH of
4.6 × 104 M−1 s−1 for HAT from chloroform to n-hexyl at 60
°C. When combined with the molar concentration of
chloroform (12.4 M), an effective rate constant, kH, of ca. 5.7
× 105 M−1 s−1 is obtained, which becomes competitive with
self-trapping (2.8 × 106 M−1 s−1 at 60 °C). This preference for
HAT over self-trapping is further enhanced through controlled
low concentrations of thiohydroxamic ester 3, thereby
providing an explanation for the experimental observations.
chloroform, and under reflux for several hours, however, did
not produce any observable 2-pyridylsulfide 14. Similarly, UV
irradiation (254 nm)40 of a solution of 15 in chloroform using a
Rayonet Reactor at room temperature for 30 min provided no
evidence of 14. These experiments show that HAT from
chloroform to the 2-pyridinethiyl radical 11 is not occurring
under these conditions.
Pathway B was also studied computationally. The HAT
reaction between chloroform and 2-pyridinethiyl radical 11 to
generate trichloromethyl radical 12 and 2-pyridinethiol 13 in
chloroform solution at 60 °C (or 333 K, i.e. the boiling point of
chloroform) was found to be 8.9 kcal/mol endothermic and to
proceed with a calculated rate constant for HAT of about 0.2
M−1 s−1 thereby indicating that Pathway B is not likely to be
important due to the very slow formation of 2-pyridinethiol 13.
For comparison, the direct HAT reaction between chloro-
form and a series of alkyl radicals was also investigated
theoretically, as detailed in Tables 3 and 4. The calculations
indicate that these reactions are generally exergonic (ΔGH < 0),
occurring with rate constants (kH) ranging from 102 to 106 M−1
s−1 at 333 K. For the tert-butyl radical, experimental values for
kH (2.54 × 102 M−1 s−1) and kCl (1.84 × 102 M−1 s−1) at 310 K
have been determined41 and are in good agreement with the
corresponding calculated values at this temperature of 1.42 ×
102 and 1.17 × 102 M−1 s−1, respectively. Accordingly, the
combination of these experimental and theoretical studies
effectively rules out the involvement of 2-pyridinethiyl radical
11 as a catalyst in these reactions (pathway B, Scheme 4). It
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Chlorine Atom Transfer (CAT) and Polar Effects. As
noted in Table 2, significant chlorination (as high as 50%
relative to reduction) has been observed in a number of
systems, especially with the strain-free tertiary carboxylic acids.
To better understand the interplay between HAT and CAT
observed in the present work, the thermal rate constants and
Gibbs free energies of reaction for the CAT reaction between
chloroform and various acyclic and cyclic alkyl radicals were
also studied (see Tables 3 and 4 above).
r4 which correspond to the ratio of the Cl3C−H (r1), R−H (r2),
H2ClC−Cl (r3), and R−Cl (r4) bond lengths (in angstroms) in
the HAT and CAT transition states relative to that in the
reactants or products. The relative values of r1 and r2 and those
of r3 and r4 provide a measure of the position of the transition
state. Accordingly, the steady decrease in r2 and concurrent
increase in r1 with the increasing degree of alkylation signifies a
more product-like transition state as the thermodynamic
preference for HAT decreases.
Surprisingly, theoretical calculations predict chlorination to
This raises the question as to why HAT transition states are
more stabilized relative to their CAT counterparts. An
explanation for the origin of this effect is related to the
concept of matched polarities in hydrogen atom transfer
reactions47−49 and may be explained using qualitative concepts
from valence bond theory and the curve-crossing model.50−54
In valence bond theory, the HAT and CAT transition states can
be represented as resonance hybrids of the contributing
resonance structures depicted in Scheme 8. Since the transition
state lies in the part of the reaction coordinate where the
reactant and product configurations are of similar energy, the
electronic description of the transition state may be described
by a resonance hybrid of the two covalent contributors.
Additionally, in the HAT reaction, the trichloromethyl radical
12 is also a better electron acceptor (electron affinity = 2.16 eV
compared to <0 eV for an alkyl radical).55 Consequently, an
ionic configuration (Cl3C− H• R+; see Scheme 8) is expected to
make a significant contribution to the stability of the transition
state, and the size of this resonance effect increases with the
electron-donating potential of the alkyl radical. This presum-
ably accounts for the stability of the HAT transition state and
explains why the barrier to HAT is relatively insensitive to the
stability of the carbon centered radical. This resonance effect is
also sometimes referred to as a polar effect47−49 or charge-shift
bonding.56−58
In this context, the polar effect is also likely to be more
pronounced if the transferring atom is electron withdrawing, as
would be the case in CAT from chloroform. This is reflected in
the thermodynamics for CAT where the strengthening of the
R−Cl bond counteracts the increase in the reactant radical
stability as reflected in the nearly constant ΔGCl in the
progression from the methyl to tert-butyl radical.59−61
However, Shaik and co-workers have showed earlier that the
ionic contributors associated with a series of halogen transfer
identity reactions are accompanied by a significantly higher
Pauli repulsion compared to their HAT counterpart.62 This
might explain why the CAT transition states are less stabilized
relative to their HAT counterparts. Nonetheless, for strain-free
secondary and tertiary alkyl radicals, CAT becomes competitive
be the thermodynamically preferred pathway (ΔGH − ΔGCl
≫
0), irrespective of the alkyl radical, and predict that this
preference increases in progressing from methyl to tert-butyl
radicals. This is due to a steady decrease in the thermodynamic
driving force for HAT, in contrast to the Gibbs reaction energy
for CAT (ΔGCl), which remains relatively constant. For the
cyclic radicals there is also a strong thermodynamic preference
for CAT over HAT. In contrast to the thermodynamics, the
calculated rate coefficients reveal that HAT is faster than CAT
for the unstrained radicals and remains competitive with CAT
for the strained radicals, despite the overwhelming thermody-
namic preference for CAT, mainly because the Gibbs free
energies of activation are lower for HAT than for CAT. The
collective results thus suggest that the HAT reaction occurs
under kinetic control. Clearly, tunneling would favor HAT over
CAT; however as discussed in the next section, the size of this
effect, though significant, is not sufficient to explain the
predominance of the rates of HAT over CAT.
The steady decrease in thermodynamic driving force for
HAT is directly related to the increase in radical stability with
the increasing degree of alkylation.46 Accordingly, the contra-
thermodynamic behavior of the HAT reactions might indicate
that the transition state is early or more reactant-like; however,
inspection of the transition state geometries reveals that there is
a growing preference for a late transition state for the HAT
reaction in the progression from the methyl to tert-butyl radical.
Shown in Scheme 7 are selected geometrical ratios r1, r2, r3, and
Scheme 7. Ratios of C−H (r1), R−H (r2), C−Cl (r3), and R−
Cl (r4) Bond Lengths (in angstroms) in the HAT and CAT
Transition States Relative to That in the Reactants and
Products
Scheme 8. Resonance Contributors for the HAT and CAT Transition States
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Table 6. Contributions in Ratios of the Rates Constants for HAT, DAT, and CAT Reactions between Chloroform and Various
Alkyl Radicals at 333 K in Chloroform Solution
kH/kD
kH/kCl
kD/kCl
μOMT
tun
μOMT
tun
μOMT
tun
R•
ηint
ηvar
η
ηtot
ηint
ηvar
η
ηtot
ηint
ηvar
η
ηtot
methyl
5.31
5.14
0.80
4.95
5.06
5.04
5.49
0.50
1.00
0.96
0.28
1.01
1.04
1.01
0.65
0.92
1.06
1.24
1.26
0.78
0.65
1.73
4.73
0.82
1.72
6.41
4.09
3.58
2162.79
642.86
104.24
2.46
0.88
0.99
0.55
0.26
1.13
1.19
1.03
2.04
2.92
2.15
1.52
4.26
1.83
1.26
3861.79
1864.49
123.77
0.98
406.98
125.00
129.55
0.50
1.75
0.99
0.57
0.94
1.12
1.15
1.02
3.14
3.17
2.02
1.22
3.38
2.35
1.94
2231.71
393.93
150.05
0.57
ethyl
isopropyl
tert-butyl
cyclohexyl
adamantyl
a
105.20
36.00
506.67
78.55
20.79
7.14
79.07
19.20
a
cubyl
1060.75
1374.63
193.15
383.58
a
Models of the experimentally studied systems, 4-carbomethoxycyclohexyl, and 4-carbomethoxycubyl respectively.
with HAT as indicated by the experimental product
distributions in Table 2 (entries 5 and 6).
on the basis of vibrational contributions alone. Thus one would
expect significant reductions in HAT versus CAT product
ratios for the reactions in deuterated chloroform (CDCl3).
Although the calculated deuterium atom transfer (DAT) versus
CAT ratios presented in Table 6 are consistent with this
expectation, this is largely due to quasiclassical kinetic isotope
effects rather than tunneling. Indeed, the calculated trans-
mission coefficients for DAT are relatively similar to those for
HAT, and actually slightly larger for the smaller alkyl radicals.
This effect is unusual but not unprecedented67−72 and can be
explained by noting that the tunneling depends not only on the
masses but also on the height and width of the barrier. Indeed,
further analysis (see Supporting Information) confirms that the
barrier width for DAT is narrower than that for HAT which is
the critical factor with regard to determining the transmission
coefficient. The larger barrier width associated with HAT is
attributed to the higher frequencies associated with the bending
modes that involve the transferred atom. For the larger alkyl
radicals, the HAT transmission coefficient is higher than that
for DAT (consistent with expectation) and this is presumably
because the contribution of these bending modes diminishes.
To provide some experimental support for our calculations,
we repeated our experiments using CDCl3 but otherwise
identical conditions for a representative set of alkyl carboxylic
acids and the resulting product ratios are included in Table 7
below. As shown, the rate of deuterium transfer is significantly
slower and this generally resulted in an approximately 10-fold
reduction in the product ratio of reduction to chlorination, in
qualitative agreement with our calculations on model systems.
Thus, the combined theoretical calculations and experimental
results suggest that Barton reductive decarboxylation reaction
Finally, it is also worth noting that the calculated rates of
HAT and CAT are higher for cyclic alkyl radicals compared
with their acyclic counterparts. For example, the rates of HAT
and CAT between chloroform and the cyclohexyl radical are an
order of magnitude higher than that of the isopropyl radical.
This observation may be understood in terms of the geometry
about the radical carbon center in the reactant and the
transition state. Carbon-centered radicals generally adopt very
near planar geometries whereas their geometry is significantly
pyramidal in the transition state. As such, cyclic alkyl radicals
are generally strained, and this is manifested in the increased
exergonicity and rates of the HAT and CAT reactions,
compared to their acyclic analogues as shown in Table 3.
Quantum Mechanical Tunneling. It is well-known that
quantum mechanical tunneling effects can play an important
role in reactions involving the transfer of light atoms63 (e.g.,
hydrogen atom), and this could also directly affect the patterns
of reduction versus chlorination observed in the present work.
Indeed, earlier work has provided evidence for tunneling effects
in hydrogen abstraction reactions between the adamantyl
radical and various hydrocarbon solvents.64−66 Thus, to better
delineate the contribution of tunneling in the observed product
distributions, the transmission coefficients for HAT and CAT
reactions were computed using multidimensional tunneling
methods (see Table 5 above), and the ratios of rate coefficients
(at 333 K) for HAT versus DAT, HAT versus CAT, and DAT
versus CAT are shown in Table 6. The contributions to these
ratios (ηtot) from classical effects (ηint), variational effects (ηvar.),
and tunnelling (ημtuOnMT) are also shown.
The data in Tables 5 and 6 confirm that tunneling typically
contributes to a 2-fold increase in the rate of HAT relative to
CAT. Even when the classical contribution to the ratio kH/kCl is
lower than 1, like in the case of the tert-butyl radical, tunnelling
makes an important contribution to the increase in the HAT
rate constant with respect to the CAT rate constant. Indeed for
the tert-butyl and adamantyl radicals, where the barrier height
of the reaction of HAT is higher than the barrier for CAT (see
Table 4), tunnelling is greater for the HAT mainly because the
mass of the particle that is being transferred is smaller. As
shown in Table 6 the ratios are in qualitative agreement with
the product branching ratios observed experimentally where
chlorination becomes increasingly competitive with reduction
from unstrained primary to tertiary radicals.
Table 7. Experimental kH/kCl and kD/kCl Determined Using
CHCl3 and CDCl3, Respectively
a
c
cd
,
e
R•
kH/kCl
kH/kCl
kD/kCl
kH/kD
b
palmityl
>86
79.4
7.8
0.6
98
7.4
0.5
0.1
9.4
10.7
15.6
6
4-carbomethoxycyclohexyl
adamantyl
15
2
b
4-carbomethoxycubyl
>82
10.4
a
b
Based on data from Table 2. These values represent lower bounds of
kH/kCl because the yield reported for the reduced product is after
c
purification and thus include losses. This work: H/D to Cl product
d
ratios determined by GC/MS on crude reaction mixtures. The kD/kCl
ratios are an average of 2 runs. Higher proportions of the
corresponding 2-pyridylsulfides (9a, d, e, and g) were produced in
these reactions, consistent with a slower overall transfer of D. No
In light of this, the transfer of a heavier deuterium atom is
normally expected to attenuate the effects of tunneling and lead
to reductions in the hydrogen (or in this case deuterium)
transfer rate, over and above the kinetic isotope effects expected
e
attempt was made to isolate the products in these reactions. Obtained
from data in columns 2 and 3.
6683
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The Journal of Organic Chemistry
Article
mmol) and one drop of N,N-dimethyl formamide, and the reaction
was stirred at rt under argon. The formation of the acid chloride was
monitored by IR. The crude reaction mixture (Note: excess oxalyl
chloride and HCl can be removed prior to addition to the under
reduced pressure and the resulting residue redissolved in chloroform)
was then added dropwise to a suspension of 1-hydroxypyridine-2(1H)-
thione, Na salt (179 mg, 1.5 mmol), and 4-N,N-dimethylamino-
pyridine (1 mg, 0.1 mmol) in chloroform (5 mL), with concomitant
irradiation from a tungsten lamp (240 V, 500 W). The reaction
mixture took on a bright yellow appearance, and CO2 evolution
became evident. After 15 min to 1 h the bright yellow coloration had
faded. Heating and irradiation were then discontinued. The reaction
mixture was partitioned between CH2Cl2 or CHCl3 (20 mL) and 1 N
HCl (20 mL), and the organic layer was then further washed with 1 N
HCl (2 × 20 mL) and brine (20 mL), dried over MgSO4, and
concentrated. Purification by column chromatography (SiO2) yielded
the desired products. For the more volatile substrates, the solvent was
removed in vacuo from the reaction mixture and the resulting residue
partitioned between Et2O (20 mL) and 1 N HCl (20 mL). The
organic layer was then further washed with 1 N HCl (2 × 20 mL) and
brine (20 mL), dried over MgSO4, and concentrated. Purification by
column chromatography (SiO2) yielded the desired products.
occurs under kinetic control predominantly due to favorable
polar effects and is aided by quantum mechanical tunneling.
CONCLUSION
■
We have shown through a combination of mechanistic and
theoretical studies that the chloroform-assisted, Barton
reductive decarboxylation process involves direct HAT from
chloroform to alkyl radicals. Our theoretical calculations predict
that, while CAT is the thermodynamically preferred process,
HAT proceeds via a lower free energy barrier due to favorable
polar effects. These effects, in combination with quantum
mechanical tunneling (as confirmed by kinetic isotope studies),
confirm that the chloroform-assisted Barton reductive decar-
boxylation process proceeds under kinetic control.
The present reaction protocol has also been carefully
designed to exploit concentration effects to minimize the
formation of side products associated with self-trapping. The
end result is that the nature of the alkyl radical is critical to the
experimental outcome, with primary alkyl and strained
bridgehead systems delivering optimal conversions of proto-
decarboxylation products. CAT becomes competitive for strain-
free tertiary alkyl radicals as a result of increased resonance
interaction with the ionic configuration.
The collective results highlight the limitations associated with
the sole use of BDEs in screening for suitable H-donors, as was
also recently noted for the selection of chain carrier agents.61 It
is envisaged that the mechanistic insight developed through this
work will provide users of the Barton decarboxylation
procedure the ability to design optimized synthetic outcomes.
Finally, this process avoids the common toxic or miasmic
conditions normally associated with the H-donors (viz. TBTH,
TBT, and TP) typically used in Barton reductive decarbox-
ylation reactions and as such should find wide application in
both academic and industrial laboratories.
Pentadecane (2a). Purification by column chromatography (SiO2,
pentane) yielded 2a (182 mg, 86%) as a colorless oil; νmax/cm−1 (film)
1
2921, 2853, 1465; H NMR (400 MHz, CDCl3) δH 1.25 (26H, br s),
0.87 (6H, t, J = 6.85 Hz); 13C NMR (100 MHz, CDCl3) δC 31.9 (2 ×
CH2), 29.7 (5 × CH2), 29.7 (2 × CH2), 29.4 (2 × CH2), 22.7 (2 ×
CH2), 14.1 (2 × CH3); m/z LRMS (EI): 212.4 ([M]+).
5-Ethylbenzo[d][1,3]dioxole (2b). Purification by column
chromatography (SiO2, (1:10) Et2O/Pet) yielded 2b (116 mg, 77%)
as a colorless oil and 9b (10 mg; 4%) as pale yellow residue.
2b: νmax/cm−1 (film) 2965, 2875, 1503, 1486, 1232, 1037; 1H NMR
(500 MHz, CDCl3)δH 6.73 (1H, d, J = 7.9 Hz), 6.70 (1H, dd, J = 1.7,
0.4 Hz), 6.65 (1H, dd, J = 7.9, 1.7 Hz), 5.92 (2H, s), 2.58 (2H, q, J =
7.6 Hz), 1.20 (2H, t, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δC
147.5, 145.4, 138.2, 120.4, 108.4, 108.1, 100.7, 28.6, 15.9; m/z LRMS
(EI): 150 (50% [M]), 135 (100%).
9b: Collection of HRMS or elemental analysis of this compound
was not possible due to its limited stability. νmax/cm−1 (film) 2889,
1
EXPERIMENTAL SECTION
1577, 1501, 1487 1414; H NMR (400 MHz, CDCl3) δH 8.43 (1H,
■
1H and 13C NMR spectra were recorded in deuteriochloroform
(CDCl3) unless otherwise stated. Coupling constants are given in Hz,
and chemical shifts are expressed as δ values in ppm. Low resolution
electrospray ionization mass spectrometry measurements (LRESIMS)
were recorded in positive ionization mode using a high capacity 3D
ion trap instrument. High resolution electrospray ionization
(HRESIMS) accurate mass measurements were recorded in positive
mode on a quadrupole−time of flight instrument. Accurate mass
measurements were carried out with external calibration using sodium
formate as the reference calibrant. H/D to Cl product ratio analyses
were undertaken using a GCMS. The GC was coupled to a quadrupole
mass spectrometer operating in electron ionization (EI) mode at 70
eV. The GC separation was performed using a fused silica column (30
m × 0.25 mm i.d., 0.25 mm film thickness; 5% phenylmethylpolysilox-
ane). The oven temperature was programmed as follows: 50 °C (hold
4 min); 10 °C/min to 280 °C (hold 3 min). The total running time
was 30 min. Ultrahigh purity helium was used as the carrier gas at a
constant flow of 0.7 mL/min. The interface and ion source
temperatures were set to 250 and 180 °C, respectively. A solvent
delay of 4 min was used to prevent damage in the ion source filament.
Column chromatography was undertaken on silica gel (flash silica gel
230−400 mesh), with distilled solvents. Analytical high performance
liquid chromatography was performed using a C18 5 μm column.
Chloroform and D-chloroform were distilled from a phosphorus
pentoxide still and stored over 3A molecular sieves under an
atmosphere of nitrogen. Melting points were determined on a melting
point apparatus and are uncorrected.
ddd, J = 4.9, 1.9, 0.9 Hz), 7.44 (1H, ddd, J = 8.0, 7.4, 1.9 Hz), 7.15
(1H, dt, J = 8.0, 0.9 Hz), 6.95 (1H, ddd, J = 7.4, 4.9, 0.9 Hz), 6.76−
6.68 (3H, m), 5.91 (2H, s), 3.36 (2H, dd, J = 8.5, 6.9 Hz), 2.91 (2H,
dd, J = 8.5, 6.9 Hz); 13C NMR (100 MHz, CDCl3) δC 158.8, 149.5,
147.5, 146.0, 135.7, 134.4, 122.3, 121.5, 119.2, 109.1, 108.1, 100.8,
35.5, 31.6; m/z LRMS (ES+): 282.1 (100% [MNa]+); HRMS (ES+):
Found [MNa]+ 282.0557, C14H13NNaO2S requires 282.05779.
24-Norcholane-3,7,12-trione (2c). Purification by column
chromatography (SiO2, (1:2) EtOAc/Petrol) yielded 2c (243 mg,
68%) as colorless crystals; [α]D = 14.5 (c = 0.94, CHCl3); mp >250 °C
1
(hexanes); νmax/cm−1 (film) 2920, 2868, 1712, 1182; H NMR (500
MHz, CDCl3) δH 2.91−2.84 (2H, m), 2.82 (1H, t, J = 10.5 Hz), 2.36−
1.90 (12H, m), 1.81 (1H, dt, J = 11.3, 7.1 Hz), 1.58 (1H, td, J = 14.4,
4.6 Hz), 1.50−1.40 (1H, m), 1.37 (3H, s), 1.31−1.05 (4H, m), 1.04
(3H, s), 0.83 (3H, t, J = 7.3 Hz), 0.79 (3H, d, J = 6.5 Hz); 13C NMR
(100 MHz, CDCl3) δC 212.1, 209.1, 208.8, 56.9, 51.8, 49.0, 46.8, 45.6,
45.5, 45.0, 42.8, 38.7, 37.4, 36.5, 36.0, 35.3, 27.8, 27.7, 25.2, 21.9, 18.4,
11.8, 10.8; m/z LRMS (ES+): 381.2 (100% [MNa]+); 298.3 (100%);
HRMS (ES+): Found [MNa]+ 381.2388, C23H34NaO3 requires
381.2400.
Methyl Cyclohexanecarboxylate (2d) (2 mmol scale).
Purification by column chromatography (SiO2, (1:10) Et2O/pentane)
yielded 2d (203 mg, 77%) as a colorless oil, methyl 4-chlorocyclo-
hexanecarboxylate (10d) (17 mg, 5%, mixture of diastereoisomers) as
a colorless oil, and methyl 4-(pyridin-2-ylthio)cyclohexanecarboxylate
(9d) (15 mg; 3%, mixture of diastereoisomers) as a pale yellow
residue.
2d: νmax/cm−1 (film) 2931, 2856, 1732, 1168; 1H NMR (400 MHz,
CDCl3) δH 3.65 (3H, s), 2.30 (1H, tt, J = 11.3, 3.7 Hz), 1.94−1.84
(2H, m), 1.79−1.69 (2H, m), 1.63 (1H, m), 1.51−1.36 (1H, m),
General Method for the Barton Reductive Decarboxylation
in Chloroform. To a solution/suspension of the appropriate acid (1
mmol) in chloroform (5 mL) were added oxalyl chloride (94 μL, 1.2
6684
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The Journal of Organic Chemistry
Article
1.33−1.16 (3H, m); 13C NMR (100 MHz, CDCl3) δC 176.6, 51.4,
43.1, 29.0 (2 × CH2), 25.7, 25.4 (2 × CH2); m/z LRMS (ES+): 165.1
(100% [MNa]+).
7,7-Dimethylbicyclo[2.2.1]heptan-2-one (2g). Purification by
column chromatography (SiO2, petrol) yielded 2g (119 mg, 86%) as a
colorless solid.
2g: νmax/cm−1 (film) 2899, 2848, 1450; 1H NMR (400 MHz,
CDCl3) δH 2.43−2.33 (1H, m), 2.07−1.93 (4H, m), 1.76 (1H, d, J =
18.3 Hz), 1.49−1.33 (2H, m), 1.02 (6H, s); 13C NMR (100 MHz,
CDCl3) δC 218.6, 58.3, 45.4, 44.2, 43.4, 27.6, 22.7, 21.7, 20.7; m/z
LRMS (ES)+: 161.1 ([MNa]+).
10d: νmax/cm−1 (film) 2951, 1730, 1436, 1219; 1H NMR (400
MHz, CDCl3) (2:1 mixture of two diastereoisomers) δH 4.34−4.25
(1H, m, major), 3.90−3.80 (1H, m, minor), 3.67 (3H, s, major), 3.65
(3H, s, minor), 2.42−2.27 (1H, m, major +1H, m, minor), 2.26−1.48
(8H, m, major +8H, m, minor); 13C NMR (100 MHz, CDCl3) δC
175.4, 175.3, 58.5 (2 × CH2 minor), 58.4 (2 × CH2 major), 51.7 (2 ×
CH2 major, CH2 minor), 41.4, 35.7, 33.3 (CH3 major + minor), 29.7,
28.1, 23.7; m/z LRMS (ES+): 199.1 (100% [MNa]+).
Methyl Cubanecarboxylate (2h). Purification by column
chromatography (SiO2, (1:8) Et2O/Petrol) yielded 2h (132 mg,
82%) as colorless crystals; mp 51.2−52.9 °C (hexanes) [ref 7; mp
1
51.8−52.5 °C]; νmax/cm−1 (film) 2987, 1722, 1319, 1221; H NMR
9d: Collection of HRMS or elemental analysis of this compound
(400 MHz, CDCl3) δH 4.27−4.18 (3H, m), 4.04−3.93 (4H, m), 3.67
(3H, s); 13C NMR (100 MHz, CDCl3) δC 172.8, 55.7, 51.4, 49.5 (3 ×
CH), 47.8, 45.2 (3 × CH); m/z LRMS (ES+): 185.0 (100% [MNa]+).
General Procedure for Barton Reductive Decarboxylations
in Chloroform and D-Chloroform. To a solution/suspension of the
appropriate acid (2 mmol) in chloroform (10 mL) were added oxalyl
chloride (260 μL, 380 mg, 3 mmol) and one drop of N,N-
dimethylformamide, and the reaction was stirred at rt under nitrogen
until gas evolution ceased, then concentrated under reduced pressure
using a rotary evaporator (diaphragm pump pressure; bath temper-
ature set to 40 °C), and then released to nitrogen. The crude acid
chloride was then dissolved in either dry chloroform or D-chloroform
(10 mL) and added dropwise over ∼10 min to a suspension of 1-
hydroxypyridine-2(1H)-thione, Na salt (450 mg, 3 mmol), and 4-N,N-
dimethylaminopyridine (5 mg, 0.04 mmol) in either dry chloroform or
D-chloroform (10 mL), with concomitant irradiation from a tungsten
lamp (240 V, 150 W). The reaction mixture took on a bright yellow
appearance, and CO2 evolution became evident. After 1 h of heating
and irradiation were discontinued and the reaction mixture cooled to
rt, it was diluted with dichloromethane (30 mL), washed with
saturated aqueous NaHCO3 solution (50 mL), and dried over MgSO4.
This solution was analyzed by by GCMS.
1
was not possible due to its limited stability. H NMR (400 MHz,
CDCl3) (5:4 mixture of two diastereoisomers) δH 8.39 (1H, dddd, J =
4.8, 2.7, 1.9, 0.9 Hz, major + minor), 7.43 (1H, dddd, J = 8.0, 7.4, 3.5,
1.9 Hz, major + minor), 7.12 (1H, ddt, J = 8.0, 3.5, 0.9 Hz, major +
minor), 6.93 (1H, dddd, J = 7.4, 4.8, 3.5, 0.9 Hz, major + minor),
4.18−4.09 (1H, m, minor), 3.77−3.67 (1H, m, major), 3.66 (3H, s,
major), 3.65 (3H, s, minor), 2.43 (2H, tt, J = 8.7, 4.2 Hz, major), 2.32
(2H, tt, J = 11.9, 3.6 Hz, minor), 2.24−2.17 (2H, m, major), 2.09−
1.99 (2H, m, minor), 1.99−1.73 (8H, m, major + minor), 1.68−1.55
(2H, m, major), 1.43 (2H, m, minor); 13C NMR (100 MHz, CDCl3)
δC 175.9, 175.6, 158.8, 158.7, 149.6, 149.5, 135.9, 135.8, 123.0, 122.9,
119.4, 119.4, 51.6 (2 × CH3), 42.4, 41.8, 41.4, 41.0, 32.2 (2 × CH2),
30.3 (2 × CH2), 29.0 (2 × CH2), 25.7 (2 × CH2).
Adamantane (2e). Purification by column chromatography (SiO2,
pentane) yielded 2e and 1-chloroadamantane (10e) as a 2:1 mixture
(69% combined yield) as a colorless solid and 2-(adamantan-1-
ylthio)pyridine (9e) (26 mg, 11%) as a pale yellow residue.
2e: νmax/cm−1 (film) 2899, 2848, 1450; 1H NMR (300 MHz,
CDCl3) δH 1.86 (4H, br s), 1.74 (12H, t, J = 3.4 Hz); 13C NMR (75
MHz, CDCl3) δC 37.7 (6 × CH2), 28.3 (4 × CH); m/z LRMS (EI):
136.3 ([M]+).
10e: 1H NMR (400 MHz, CDCl3) (δH 2.12 (9H, br s), 1.66 (6H, br
s); 13C NMR (100 MHz, CDCl3) δC 68.9, 47.8 (2 × CH2), 35.6 (4 ×
CH2), 31.7 (3 × CH).
Reaction of 2,2′-Dipyridyl Disulfide 14 with Chloroform
under Irradiation and Heating (Pathway B). A solution of 2,2′-
dipyridyl disulfide 14 (2.2g, 1 mmol) in chloroform (10 mL) was
purged with nitrogen for several minutes and then irradiated (and
heated under reflux) with either a tungsten or low pressure Hg vapor
lamp (Rayonet Reactor). The progress of the reaction was monitored
by TLC. Even after prolonged treatment (10 h), only starting material
was present. 1H NMR of the crude sample after simple solvent
removal and after aqueous workup showed 2,2′-dipyridyl disulfide 14
with some baseline peaks indicating formation of some degradation
products. No loss in mass of starting material recovered after workup
occurred.
9e: νmax/cm−1 (film) 2908, 2851, 1575, 1450; 1H NMR (300 MHz,
CDCl3) δH 8.51 (1H, ddd, J = 4.9, 2.0, 0.9 Hz), 7.54−7.48 (1H, m),
7.36 (1H, dt, J = 7.6, 1.0 Hz), 7.09 (1H, ddd, J = 7.6, 4.9, 1.0 Hz), 2.06
(6H, br d, J = 2.9 Hz), 2.02 (3H, br s), 1.67 (6H, t, J = 3.0 Hz); 13C
NMR (100 MHz, CDCl3) δC 156.8, 149.6, 136.0, 129.0, 121.3, 50.0,
43.6 (2 × CH2), 36.3 (4 × CH2), 30.1 (3 × CH); m/z LRMS (ES+):
246.1 (100% [MH]+); HRMS (ES+): Found [MH]+ 246.1318,
C15H20NS requires 246.1311.
Hexadecylcyclohexane (2f). Purification by column chromatog-
raphy (SiO2, petrol) yielded 2f and 1-chloro-1-hexadecylcyclohexane
(10f) as a 2:1 mixture (72% combined yield) as a colorless oil, and
further elution (10:1 petrol/Et2O) yielded 2-((1-hexadecylcyclohexyl)-
thio)pyridine (9f) (25 mg, 6%) as a pale yellow residue.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, discussion of computational results,
including Cartesian coordinates of all studied species in gas
phase, and 1H and 13C spectra for all isolated compounds listed
in Table 2 are provided in the Supporting Information. This
material is available free of charge via the Internet at http://
pubs.acs.org.
2f: νmax/cm−1 (film) 2920, 2851, 1449; 1H NMR (400 MHz,
CDCl3) δH 1.72−1.58 (3 H, m), 1.33−1.04 (38H, m), 0.86 (3H, t, J =
6.9 Hz); 13C NMR (100 MHz, CDCl3) δC 37.7, 37.6, 33.5 (2 × CH2),
31.9, 30.0, 29.7 (8 × CH2), 29.6, 29.4, 26.9, 26.8, 26.5 (2 × CH2), 22.7,
14.1; m/z LRMS (EI): 308.6 (100% [M]).
10f: νmax/cm−1 (film) 2922, 2853, 1462; 1H NMR (400 MHz,
CDCl3) δH 1.92 (2 H, br d, J = 14.6 Hz), 1.78−1.58 (5H, m), 1.57−
1.42 (6H, m), 1.34−1.08 (27H, m), 0.86 (3H, t, J = 6.9 Hz); 13C
NMR (100 MHz, CDCl3) δC 39.7 (2 × CH2), 33.5, 31.9, 29.8, 29.7 (8
× CH2), 29.6, 29.5, 29.4, 25.5, 23.7, 22.7, 22.4 (2 × CH2), 14.1; m/z
LRMS (EI): 306.6 (100% [M−Cl]).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: John.Tsanaktsidis@csiro.au; mcoote@rsc.anu.edu.au;
c.williams3@uq.edu.au; Paul.Savage@csiro.au; truhlar@umn.
edu.
9f: Collection of HRMS or elemental analysis of this compound was
1
not possible due to its limited stability. H NMR (300 MHz, CDCl3)
Notes
δH 8.46 (1H, ddd, J = 4.9, 2.0, 1.0 Hz), 7.46 (1H, ddd, J = 7.9, 7.4, 2.0
Hz), 7.31 (1H, dt, J = 7.9, 1.0 Hz), 7.03 (1H, ddd, J = 7.4, 4.9, 1.0 Hz),
2.07−1.92 (2H, m), 1.75−1.38 (34H, m), 1.22 (28H, br d, J = 10.3
Hz), 0.86 (3H, t, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3) δC 158.3,
149.5, 135.8, 128.0, 120.7, 56.5, 36.6 (2 × CH2), 31.9, 30.0, 29.7−29.6
(10 × CH2), 29.4, 26.0, 23.7, 22.7, 22.3 (2 × CH2), 14.1.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Australian National University, CSIRO, and the
University of Queensland for financial support. M.L.C.
■
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gratefully acknowledges generous allocations of supercomput-
ing time on the National Facility of the Australian National
Computational Infrastructure, support from the Australian
Research Council (ARC) under its Centres of Excellence
Scheme, and receipt of an ARC Future Fellowship. This work is
also supported in part by the National Science Foundation of
the U.S.A. C.M.W. gratefully acknowledges generous support
from the Australian Research Council (ARC), and receipt of an
ARC Future Fellowship.
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