Why are organotin hydride reductions of organic halides so frequently retarded? kinetic studies, analyses, and a few remedies

Article abstract of DOI:10.1021/jo502710a

Kinetic data for reduction of organic halides (RX) by tri-n-butylstannane (SnH) reveal a serious flaw in the current view of the kinetic radical chain: the tacit but unproven assumption that the speed of reaction is determined by the slowest propagation step. Our results show this is rarely true for reductive chains and that the observed rate is in fact controlled by unseen side-reactions of propagating R^? and Sn^? radicals with the solvent (notably, benzene!) or solvent impurities (e.g., trace benzophenone dryness indicator in THF) or, crucially, with allylic-CH and conjugated unsaturated groups in substrates and products. Most R^? and/or Sn^? radicals are therefore converted into relatively inert delocalized species A^? and/or B^? that inhibit the chain. Retardation in the degraded chain is given by a simple sum of terms, each being the ratio of the chain-transfer rate divided by the rate of chain-return. The model kinetic equation is linear and easy to ratify, interpret, and apply: to calculate retarding rate constants, optimize reaction conditions, and identify additives or "remedies" that repair the chain and accelerate reaction. The present work is thus expected to have a helpful impact on the practice and design of SnH radical chain based (and related) syntheses.

Full text of DOI:10.1021/jo502710a

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Why Are Organotin Hydride Reductions of Organic Halides So
Frequently Retarded? Kinetic Studies, Analyses, and a Few Remedies
†
,‡
K. U. Ingold and Vincent W. Bowry*
†National Research Council, Ottawa, Ontario K1A 0R6, Canada
‡James Cook University, Cairns 4878, Queensland, Australia
*
S Supporting Information
ABSTRACT: Kinetic data for reduction of organic halides (RX) by tri-n-
butylstannane (SnH) reveal a serious flaw in the current view of the kinetic
radical chain: the tacit but unproven assumption that the speed of reaction is
determined by the slowest propagation step. Our results show this is rarely true
for reductive chains and that the observed rate is in fact controlled by unseen
•
•
side-reactions of propagating R and Sn radicals with the solvent (notably,
benzene!) or solvent impurities (e.g., trace benzophenone dryness indicator in
THF) or, crucially, with allylic-CH and conjugated unsaturated groups in
•
•
•
substrates and products. Most R and/or Sn radicals are therefore converted into relatively inert delocalized species A and/or
•
B that inhibit the chain. Retardation in the degraded chain is given by a simple sum of terms, each being the ratio of the chain-
transfer rate divided by the rate of chain-return. The model kinetic equation is linear and easy to ratify, interpret, and apply: to
calculate retarding rate constants, optimize reaction conditions, and identify additives or “remedies” that repair the chain and
accelerate reaction. The present work is thus expected to have a helpful impact on the practice and design of SnH radical chain
based (and related) syntheses.
INTRODUCTION
and for two out of the three possible termination reactions
means that these processes are now among the best understood
two-step chain reactions”. Since that time, many more rate
constants for the propagation reactions 2 and 3 have been
■
Since its introduction in the 1960s, the “reduction of alkyl
halides by organotin hydrides” has been the most widely used
free-radical method in organic synthesis research. Reduction
takes place by the two-step free-radical chain shown in Scheme
1
2
4
measured using laser flash photolysis (LFP), kinetic
5
6
competition, radical “clocks”, and ESR methods.
Kinetic analysis of Scheme 1 for an alkyl bromide or iodide
1.
6
−1 −1
(
for which k ≫ k ≈ 10 M s ) yields the overall, SnH-
X
H
Scheme 1. Organotin Hydride Free-Radical Chain
7
limited, maximum, or “ideal” rate:
1
/2
v = d[RH]/dt = k [SnH](R /2k )
(6)
0
H
i
t
Reduction of an alkyl bromide under typical experimental
−
8
−1
conditions ([SnH] = 0.085 M, R = 4 × 10 M s , 2k ≈ 3 ×
i
t
9
−1 −1
1
0 M s ) would be expected to run to completion via a very
long chain (δ = v /R ≈ 20000) in just a few minutes. In
0
0
i
practice, the reductions of most halides are much slower than
the ideal rate of eq 6, often require large amounts of initiator,
and have chain lengths much shorter than predicted. Moreover,
•
it is reductions involving the most reactive R , with the largest
8
kH values, that tend to have the slowest reaction rates.
Herein we show that these “slow” reactions invariably involve
the formation of relatively unreactive radicals by the transfer of
•
•
some radical centers from the main chain (i.e., from Sn or R )
to create less reactive (often resonance-stabilized) radicals.
These may be unable to abstract hydrogen from the SnH (thus
breaking the chain and stopping the reaction), may abstract
hydrogen very slowly (thus retarding the reaction), or may
In Scheme 1, RX is most commonly an organic bromide or
2a−g
iodide and “SnH” is usually n-Bu SnH
or the less toxic
3
2h
(
Me Si) SiH (TMS SiH). The method offers a mild, versatile,
3
3
3
2
and selective method for constructing organic molecules.
The mechanism and kinetics shown in Scheme 1 have been
extensively studied: As early as 1968 it was stated: “The
evaluation of the rate constants for both propagation reactions
3
Received: November 30, 2014
Published: December 29, 2014
©
2014 American Chemical Society
1321
DOI: 10.1021/jo502710a
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The Journal of Organic Chemistry
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3
undergo a reversal of transfer (which will also retard the
reaction). Notably, chain-breaking radicals include cyclo-
hexadienyls, and these may be formed by addition of the
indicated, as expected, similar propagation rate constants (k
H
≈
6
−1 −1
1−2 × 10 M s ); see Table 1.
•
propagating R radical to an arene, including benzene solvent!
Table 1. Reduction Rates and Calculated Propagation Rate
Constants in Cyclohexane (315 K)
Such inhibition of the reaction is most dramatic with aryl and
vinyl halides but can also occur with alkyl halides, particularly at
the very low SnH concentrations often employed in syntheses. The
overall rate is struck from a balance between the transfer of
radical centers from the main chain (to form radicals of low
reactivity) and the return of these low reactivity radical centers
to the main chain. When return to the main chain can be
hastened or catalyzed there is a consequent improvement in the
reaction rate and product selectivity.
a,b
4
kH (10 M s−1
5
−1
halide, R−X
kobs (10− s−1
)
)
c
CH
CH
−I
3
90
40 (110)
c
(CH ) CH −Br
40 (±4)
38 (±4)
32 (±3)
55
14 (30)
3
2 5 2
c
c-C
t-Bu−Br
Br−CH
Br−CH(CH
Br−C(CH
Br−CH(CO
H
11−Br
13 (22)
6
c
10 (25)
CO
Et
)CO
CO Et
Et)
18
d
2
2
Et
50
16 (44)
3
2
3
d
In the pioneering kinetic study, Carlsson and Ingold used
3
)
2
2
8 (±1)
65
3 (2)
the rotating-sector method to obtain the propagation and
2
2
18
a
termination rate constants for the SnH reduction of alkyl
SnH/RX/BONNOB = 80:300:2.2 mM; stannane decay rate, k
=
obs
9
b
1/2
halides under nitrogen in cyclohexane at 25 °C. In this and
[[ln(1 + α)]/t]av (±SD), α = (SnBr/SnCl) . kH = kobs/(R /2k )
gc i t
8 9
−
−1 −1
related studies, it has been noted that SnH reduction rates can
vary erratically from adventitious factors such as traces of
peroxides and olefins in organic halides and the presence of
(eqs 7, 9, and 10 with R
i
= 4 × 10 M/s and 2k
= 4 × 10 M s ).
t
c
d
Reference 4a. Reference 13.
1
0
oxygen, O (which can initiate, accelerate, or retard a reaction
2
3
Reduction of methyl iodide was 80% complete by the first
sampling and was thus roughly 4-fold faster than that for the
alkyl bromides. Replacement of the Bu
depending on conditions ). Scatter was minimized in this early
study by excluding oxygen and unwanted light and by using3
2h
SnH with TMS
SiH
3
3
materials freshly purified by distillation and alumina filtration.
•
afforded 5-fold slower reduction, indicating k
= 3 ×
at 298 K). All these
heptyl /TMS3SiH
5
−1 −1
2h
5
−1 −1
1
0 M
s
at 315 K (cf. 4 × 10 M
results are in fair agreement with literature values (given in
parentheses in Table 1) and indicate that reasonable absolute
s
RESULTS
3,4
■
1
. Reduction of Organic Halides in Cyclohexane. In the
present work, reactions were thermally initiated using either di-
tert-butyl hyponitrite (BONNOB: iNNi, i = t-BuO ) or azo-
bismethylvaleronitrile (AMVN: i = BuMe(CN)C ), where
values for k can be calculated from observed reaction rates in
H
•
•
cyclohexane solvent.
•
i‑
•
Likewise, reductions of α-ester-substituted bromides
BrCH CO Et, BrCMeHCO Et, and BrCH(CO Et) were all
11
the initiation rates are given by eqs 7 and 8:
2
2
2
2
2
(
14.9−28.1/2.3RT)
faster than the alkyl bromides, indicating that the α-ester group
increases these radicals’ reactivity toward the SnH. These
results are consistent with those reported by Newcomb et al.
R = 10
[BONNOB]/s
[AMVN]/s
(7)
(8)
i
(15.4−29.7/2.3RT)
R = 10
13
i
using the LFP-calibrated “clock” PTOC ester method. The
•
faster reactions of electron-deficient R radicals with SnH are
In a typical experiment, a mixture of 1-bromoheptane (290
mM) and the azo-initiator (2.2 mM BONNOB) in cyclohexane
was warmed (42 °C) in an argon-sparged ampule, and the
reaction initiated by injection of neat deoxygenated n-Bu SnH
85 mM). Samples were removed at intervals and added to 10
volumes of CCl . The CCl induces a fast, spontaneous reaction
that consumes all of the remaining SnH, converting it into
Bu SnCl. This allows the reaction to be monitored using the tin
halide product ratio: α = (SnBr/SnCl) . This reduction was
usually attributed to favorable polar effects in the transition
δ+
•
δ−
state, Sn ...H ...R . The slower reduction rate for tertiary
species Br−CMe CO Et (Table 1) may result from the
2
2
3
diminished polar effect and greater radical stabilization in
(
•
CMe CO Et.
2
2
4
4
•
2•
Benzyl bromide (R = PhCH ) was reduced ∼20-fold more
4 −1
slowly than 1-bromoheptane: kobs = 1.8 × 10− s ,
corresponding to kHPhCH2 = 5 ± 1 × 10 M s . This value
is in good agreement with Franz et al.’s kHPhCH2
3
•
4
−1 −1
gc
4
2%, 73%, and 93% complete after 120, 240, and 480 s,
•
1
4
=
corresponding to an average reaction rate constant, k = 4.4 ±
obs
(8.65−5.58/2.3RT)
4
−1 −1
.4 × 10−3 s , an initial reaction velocity, v = 3.8 × 10 M/s,
−1
−4
10
= 6.3 × 10 M
s
(315 K). The reduction
0
−
4
−8
rates (v ) of other benzylic and allylic halides (RX) were then
RX
and a kinetic chain length, δ = v/R = 3.8 × 10 M/s/4 × 10
M/s = 9500. The propagation rate constant (k ) can now be
calculated from eq 6 using eq 7 for the initiation rate and by
assuming a diffusion-controlled termination rate constant, i.e.,
i
measured relative to that of benzyl bromide under matched
conditions using the formula
H
11
4
−1 −1
kH = (v/vPhCH2Br)× 6.3 × 10 M
s
(11)
9
−1 −1
2
k ≈ 2.6 × 10 M
s
(T/298 K)/(η/cP)
(9)
t
The reduction rates for allyl and crotyl bromides (Table 2)
or 4 × 10 M s−1 for cyclohexane at 315 K. The foregoing
9
−1
12
were ∼8-fold slower than for benzyl bromide, indicating that
these allylic radicals were 8-fold less reactive than the 1°- and
data for the hept-1-yl radical indicate
•
3
−1 −1
2
°-benzylic radicals (kHallylic ≈ 4−8 × 10 M s ).
k = (2k /R )1/2k = 1.5 × 10 M
6
−1 −1
s
H
t
i
obs
(10)
The reactions of 2-cyclohexenyl bromide, 2-cyclopentenyl
bromide, and BrCHPh were very slow, each taking 4 h to
2
This value for kH is approximately half the LFP value for a
primary alkyl radical (3 × 10 M
to the range found in the original rotating sector study for hex-
-yl (0.7−1.4 × 10 M
cyclohexyl and tert-butyl bromides under matched conditions
6
−1 −1
4a
produce a 2% conversion, which is ca. 100-fold slower than
s
at 315 K) but it is close
•
3
benzyl bromide (kH2°‑allylic• ≈ kHPh2CH ≈ 5 ± 2 × 10 M s ).
This is close to the lower limit of reactivity suitable for the
present overall rate method, with the chain lengths being only
2
−1 −1
•
6
−1 −1
1
s
at 298 K). Reductions of
1
322
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Table 2. Reduction of Benzylic and Allylic Halides in
Cyclohexane Solvent (315 K)
By comparison, reductions in the aromatic solvents: PhH,
a
PhCl, PhCF PhCH , and PhCMe (i.e., in the “traditional”
3
3
3
solvents used for free-radical syntheses) were up to 50-fold
slower, depending on the SnH and initiator concentrations.
This large “solvent effect” is due to side reactions of
propagating radicals with the solvent and/or substrate (in the
case, e.g., of ArBr or ArI) and is examined below following a
brief account of the relevant chain-transfer kinetic equations.
kH (10 M s−1
3
−1
)
halide, R−X
100vRX/vPhCH2Br
b
c
PhCH −Br
100
63
2
d
Ph(Me)CH−Br
Ph CH−Br
40 ± 3
25
0.7
8
1.1
2
CH CHCH −Br
14 ± 2
11 ± 1
0.9
2
2
CH CHCHCH −Br
7
3
2
3
. Chain-Breaking Chain Transfer. The origins of the
2
-cyclohexenyl−Br
-cyclopentenyl−Br
0.5
present investigations were some unexpectedly slow SnH
2
1.1
0.6
21
reductions during synthetic studies in the Beckwith group.
a
b
c
Relative rates in matched ampules. vPhCH2Cl ≈ vPhCH2Br
.
The
Aryl bromide, 1−Br, and the alkyl iodide, 2−I (and related
species), proved extraordinarily difficult to reduce and required
large amounts of initiator and long heating times (Scheme 2).
d
benchmark value. ± 1SD.
•
∼
3−5. An even slower R + SnH reaction has been calibrated
1
6
(7.65−7.8/2.3RT)
−1 −1
by a different method: k = 10
or 180 M
s
at
H
Scheme 2
•
3
15 K for SnH = Et SnH and the “clock” radical R = c-
3
•
C H Ph C .
3
5
2
The remarkably good linear correlation between log(k •
)
R /SnH
and the R−H bond dissociation enthalpy D(R−H) for
1
7
15
nonpolar radicals will be examined later. Suffice it to note
here that for the reduction to be a chain process, the H atom
•
transfer to R from SnH must be faster than radical/radical
−1
Rates of halogen abstraction from these compounds by the
Sn radical were measured by competition kinetics (Exper-
imental Section) and, despite the very long reaction times, were
normal”:
termination, i.e., k [SnH] > 15 s (vide infra). This may not
H
•
•
be the case for nonpolar R radicals for which D(R−H) ≤ 82
−
1
−1
kcal/mol. (For D(R−H) = 82 kcal/mol, k ∼ 500 M s ).
H
“
Thus, 2°- and 3°-allylic radicals do not carry the chain in the
18
6
−1 −1
dilute SnH solutions often used for radical synthesis, while
bis-allylic radicals would be chain-terminating at any [SnH]
•
•
k
k
≈ 1.7k
≈ 1.3k
= 2 × 10 M
s
Sn /1−Br
Sn /PhCH2Cl
(12)
(13)
9
−1 −1
(
see below, arene addition).
. Reduction Rates in Common Solvents. The azo-
•
•
= 2 × 10 M
s
Sn /2−I
Sn /PhCH2Br
2
•
It soon became clear that after 1 underwent intramolecular
initiated SnH reduction of 1-bromoheptane was not retarded in
the solvents cyclohexane, n-hexane, ethyl acetate, tert-butyl
arene addition, it produced a resonance-stabilized radical that
was incapable of propagating the chain. Treatment of 1−Br
under standard conditions produced only ∼1% reduction after
19
acetate, tert-butyl alcohol, or THF (see Table 3). The rate
2
h, indicating a chain length δ = 1−2 (i.e., no “chain”)
Table 3. Reduction Rates of 1-Bromoheptane in Common
a
(Scheme 3).
Solvents and Derived k (315 K)
H
kobs (10 s−1)
4
kH (10 M s−1
5
−1
)
solvent
Scheme 3
cyclohexane
n-hexane
40 (±4)
26 (±2)
28
14
13
15
15
16
11
ethyl acetate
tert-butyl acetate
tert-BuOH
THF
34 (±2)
80
24 (±4)
b
b
Me CO
9/36
3/15
2
benzene
8 (±1)
3
a
Per Table 1 (η315K from CRC Handbook of Chemistry & Physics; CRC
b
This phenomenon was investigated further. The addition of
−Br to an ongoing reduction of 1-bromoheptane greatly
retarded the reaction and the rate became approximately first
Press: Boca Raton, FL, 2005. Value for RX = 1-iodoheptane.
1
order in R and in [bromoheptane] but was zero order in
[SnH]!
i
was somewhat slower in acetone probably because of a reaction
of the Sn radical with this solvent, since the rate of reduction of
the much more reactive 1-iodoheptane was the same in acetone
as in the other nonaromatic solvents (see footnote b in Table
•
The kinetics of this situation are modeled in Scheme 4. It is
•
•
proposed 1−Br acts as a chain-breaking trap for Sn (not R ).
•
Each time a propagating Sn radical reacts with 1−Br, a radical
3).
chain is terminated. For long (v ≫ R ) but strongly retarded (v
i
0
The k values calculated using eqs 9 and 10, i.e., adjusted for
≫ v) chains, the chain length (δ) can be approximated by eq
H
the effect of solvent viscosity on radical/radical termination rate
constants, show even smaller kinetic solvent effects than those
seen in the raw reaction rate data (see Table 3), which assume a
14, which is derived from a simple kinetic competition between
propagation and termination. The rate constant ratio k1‑Br/k
RBr
calculated from the chain length, viz., k1‑Br/kheptyl‑Br = δobs−
1
2
0
constant R . The k value for the hept-1-yl radical is therefore
[RBr]/[1−Br] ≈ 0.08, is in good agreement with the ratio
i
H
4
6
rather insensitive to solvent polarity and to chain-transfer to
these solvents.
derived from the known absolute rate constants (1.8 × 10 /3
7
× 10 = 0.06). This supports the premise that abstraction of Br
1
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•
Scheme 4. Chain Length Kinetic Model: Sn Type
retarded and require a more general treatment that includes
second-order termination (vide infra).
4
. Kinetic Model. Reduction of an organic halide in a
•
mixture containing species that transfer some radical centers ( )
from the main chain to lower reactivity radicals (R + A → A
and Sn + B → B ) is represented in Scheme 7, in which
•
•
•
•
Scheme 7. Chain-Transfer Degraded-Chain Reduction
from 1−Br invariably leads to the termination of one
bromoheptane reduction chain.
Iodide, 2−I, behaved similarly but was vastly more active as a
chain terminator than 1−Br because alkyl iodides are more
•
3
reactive toward Sn than aryl bromides (k ∼ 10 × k ∼ 2
1−Br
2
−I
9
−1 −1
×
10 M s ) (Scheme 5).
Scheme 5
transfer can be via atom-abstraction or radical-addition. An
example of “B” would be a halide (e.g., 1−Br) that reacts with
•
•
the Sn radical to produce a slow- or nonpropagating “B ”
•
radical (e.g., 1’ ); an example of “A” would be an arene that
adds a propagating R radical to produce a slow- or
nonpropagating “A ” radical (the adduct RArH ).
•
•
•
22
Indeed, 2−I acted as a true inhibitor of alkyl bromide
reductions. The addition of just 50 μM 2−I to 7 M 1-
bromoheptane containing SnH and initiator produced an
inhibition period that lasted until the 2−I had been consumed
In these analyses, it is assumed that all radical−radical
23
reactions, including those involving resonance-stabilized
24
radicals, will be diffusion controlled with rate constants
25
given by eq 9. This simplifies the kinetics greatly compared to
(
∼30 min by GC); thereafter, the reaction resumed its pre-2−I
polymerization and autoxidation radical chains (where 2k can
t
reduction rate.
vary over a wide range). Thus, it follows from the normal
It had by now become clear that the slow reactions seen in
aromatic solvents resulted from chain-breaking chain transfer
• 2
steady-state assumption, R = 2k [ ] , that a uniform pseudo-
i
t
first-order radical-center termination rate constant can be
assigned to these systems:
•
via intermolecular R radical addition to the solvent. While the
chain-transfer from R• to benzene yields only a trace of
addition products (∼0.1%), its effect on the chain redefines the
reduction kinetics as per Scheme 6 (see the Supporting
Information for reversible addition).
•
1/2
•
r = 2k [ ] = (2k R ) = R /[ ]
(18)
t
t
i
i
−1
This is usually in the range 10−30 s (for a radical-center
•
turnover time, τ = [ ]/R ≈ 0.06 s).
(•)
i
•
4.1. Reduction without Chain Transfer. Steady-state
analysis of the main chain in Scheme 7 yields the maximum
or ideal stannane-limited reaction rate:
Scheme 6. Chain Length Kinetic Model: R Type
•
1/2
v = k [SnH][R ] = k [SnH](R /2k )
0
H
H
i
t
or which the chain length, δ , is given by
0
δ = v /R = k [SnH]/r
A more complete analysis yields the rate equation
(19)
0
0
i
H
26
v0
v
kH[SnH] + r
kX[RX]
=
1 +
(20)
(21)
⎛
⎝
⎞
k [RX]k [SnH]
X
H
1/2
v = ⎜
⎟(R /2k )
i
t
k [RX] + k [SnH] + r ⎠
X
H
To illustrate, if there is one chain-breaking reaction with
solvent per thousand R + SnH reactions (0.1%), the observed
The bracketed term in eq 21 is typically within a few percent
of unity for an alkyl bromide RX, and r is insignificant. The
point at which the chain collapses (from dilution or from low
reactivity) is where r ceases to be insignificant. Thus, e.g., bis-
•
chain length (v/R ) cannot be greater than 1000. Thus, if the
i
“
ideal” chain length is, e.g., 10000, the observed rate will be
only 10% of the ideal rate. Such reactions are not strongly
18
−1 −1
benzylic or 2°-allylic radicals (k ∼ 500 M s ) are expected
H
1
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The Journal of Organic Chemistry
Featured Article
to terminate rather than propagate if [SnH] is less than ∼10
As an example, a test mixture of anthracene (38 mM), 1-
bromoheptane (280 mM), SnH (80 mM), and BONNOB (3
mM (500 M−
1
s
−1
× 0.01 M = 5 s ), which leads to
−1
−
8
unsatisfactory yields and annoying mixtures of products.
mM, R = 6.0 × 10 M/s) reacted with first-order kinetics, kobs
i
26
−4 −1
4
.2. Reduction with Chain Transfer. Similarly, Scheme 7
= 2.2 × 10 s , and had a chain length, δ ≈ 250, versus an
affords eq 22 for the ideal rate/observed rate ratio (cf. eq 20).
unretarded (no anthracene) chain length, δ ≈ 9,000. These
0
heptyl•
This contains two rate-retarding chain-transfer (C-T) terms:
results give the chain-transfer constant k /k or C
=
A
H
An
•
−3
one for transfer of radical centers from R to A and one for
(80/38)(1/250−1/9000) = 8 × 10 . Hence, the rate constant
for addition of the hept-1-yl radical to anthracene is
= 0.008 × (5 × 10 ) M
s . This is consistent with the rate constant Fischer calculated
•
transfer from Sn to B. Equation 22 is linear, and it is therefore
315 K
6
−1 −1
4
−1
•
readily applied to various limiting scenarios and can be used to
identify reaction mechanisms via simple kinetic tests.
k
s
= 4 × 10 M
heptyl +An
−
1
29
315K
4
•
from Szwarc’s methyl affinity data, viz., k
= 18 × 10
Me +An
ideal rate
obsd rate
= v
0
−1 −1
M
s , considering methyl/heptyl radical reactivity differ-
v
ences. Other polyaromatics are also likely to be strong A-type
retarders of SnH reductions of alkyl halides.
The rate retarding effect of benzene solvent (10 M), on the
other hand, was mild for alkyl halides, e.g.,
kH[SnH] + r
kX[RX]
kA[A]
[SnH] + k−A + r
=
1 +
+
kA
•
kH[SnH]
kX[RX] kB
kB[B]
[SnH] + k−B + r
•
+
heptyl
•
k /k = C
(22)
A
H
PhH
=
=
(0.08 M/10 M)(1/1930 − 1/9500)
4 × 10
Chain transfer changes the radical mixture from one
•
•
comprising R and Sn radicals to one dominated by sluggish
−6
•
•
A (and/or B ) species (see the Discussion). The A and B
expressions in eq 22 represent the reduction in relative reaction
rate, and hence increase in reaction time, induced by the
presence, or addition, of the chain-transfer agent. The fact that
chain transfer is much slower than propagation means that the
Rate retardation increased markedly with increasing thermody-
namic reactivity of the R radical.
Reactions of aryl and vinyl radicals in benzene were severely
retarded. The 315 K chain transfer constants for various
solvents with various radicals run under matched conditions are
given in Table 4. Benzyl bromide and tert-butyl iodide
reduction rates were unaffected by benzene.
•
•
resulting retardation is more sensitive to R reactivity than is
•
propagation. Accordingly, the more active the R radical the
slower will be the reaction. This is clearly evident from the
chain-lengths for reductions in aromatic solvents, which we
6
now examine in more detail.
Table 4. Chain-Transfer Constants (× 10 ) for Some
a
•
5
. Chain Breaking R /Arene Addition. Anthracene (An)
Aromatic Solvents (315 K)
is a highly reactive arene that can add benzyl, methyl, and other
b
radical
PhH
PhCH3
PhCF3
PhCl
•
radicals to form adducts (An ) that terminate chains cleanly to
•
27
1°-alkyl
4
2
7
8
13
6
produce the expected nonoxidized dimers (An2). It was
chosen as a model for arene addition chain transfer (Scheme 8).
•
2
°-alkyl
c
•
CH3
10
•
C H
37
85
3
5
Scheme 8. Chain Length Model for A = Anthracene
•
Me CCH
230
400
2
•
2
Ph
600
1100
a
Equation 24 with δ and δ0 data tabulated in the Supporting
b
Information. RX: 1-bromoheptane; bromocyclohexane; t-BuI; CH I;
C H I; Me CCHI and PhI. Blank = not measured.
3
c
3
5
2
Substituted benzenes are more reactive toward radical
•
•
Setting r ≫ k [SnH] (no-reinitiation) and generalizing to R
additions. This reflects the corresponding activation of double
bonds to radical addition by alkyl and halogen substituents.
Approximate rate constants for addition to benzene can be
obtained by multiplying the chain transfer constants by the
A
trapping agents that behave in a manner similar to anthracene
by replacing An by A allows eq 22 to be written in terms of the
kinetic chain length (δ is the ideal chain length, v /R ):
0
0
i
relevant k ; i.e.:
H
⎛
⎜
⎞
1
δ
kA [A]
1
δ0
≈
⎟
+
⎝ k ⎠ SnH
H
(23)
This has a strong similarity to the Mayo equation for (mean
physical) chain length in polymer chemistry. The first term
on the right of eq 23 represents first-order (radical-molecule)
28
decay of the propagating radical (rate α R ), while the second
i
term arises from second-order (radical/radical) decay (rate α
√
Ri). For the purpose of calculating chain-transfer constants
(
C = k /k ) from observed rate data; eq 23 may be rearranged
A
A
H
to eq 24.
6. Sn• Addition Reactions. These can occur with
⎛
⎞
⎟
kA
=
[SnH] 1
⎜
1
−
unsaturated groups, particularly carbonyl groups (the usual
kH
[A] ⎝ δ
δ ⎠
•
0
(24)
“
B” in Scheme 7). Carbonyls can react with Sn to form
1
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•
•
stannyloxyalkyl radicals (SnOC RR′ = B ) that may sometimes
be reduced by the SnH to yield SnOCHRR′ (BH), a
and enthalpic grounds because ring rotation must be “frozen” in
the transition state for the former ketone, but not for the latter.
Acetophenone and methyl benzoate also retarded the SnH +
33
34
3536
hydrostannated ketone, aldehyde, or ester (Scheme 9).
1
-bromooctane reaction but with observed rates that were half-
order in initiator and (almost) zero order in SnH. This suggests
Scheme 9
that these two carbonyls (unlike benzophenone and
•
fluorenone) trap Sn reversibly. Reinitiation via β-scission
(
rate constant, k , in Scheme 7 and eq 22) yields the initial
−B
rate retardation expression.
v /v − 1 = (k /k )k [B]/k [RX]
0
H
X
B
−B
=
(k /k )K [B]/[RX]
H X B
•
(26)
(27)
Alternatively, such B may undergo β-scission to reform B
•
and release the Sn radical to continue the chain. This back-
reaction (rate constant, k ) means that even very rapid Sn
addition to carbonyls may yield insignificant amounts of the
BH.
Benzophenone and fluorenone were chosen because their
adduct radicals would, for thermodynamic reasons, be unlikely
The value of (k /k )K can be calculated from
H X B
•
−B
(
k /k )K = (v /v − 1) [B]/[RX]
H
X
B
0
obs
Taking k /k ≈ 0.10 for a 1-bromoalkane, the observed
H
X
retarding effects of methyl benzoate and acetophenone gave
Scheme 12:
3
7,38
to propagate or undergo β-scission at 315 K.
Addition of a
small amount of either compound strongly retarded the SnH +
Scheme 12
7
−1
1
-bromooctane reaction (kRBr [RBr] ≈ 1 × 10 s ) in
cyclohexane, but only fluorenone blocked the 1-iodooctane
reaction (k [RI] ≈ 1 × 10 s ). The retarded rates were first-
8
−1
RI
order in initiator, zero-order in SnH, and first-order in the
substrate halide RX.
Scheme 10. Chain-Length Model for B = Fluorenone
In these two cases, rate retardation arises because the Sn•
radical is reversibly adsorbed onto the CO group, which
•
39
diminishes [Sn ]. Esters are less reactive to addition than
ketones because of mesomeric ground-state stabilization.
Notably, these two retarded rates were proportional to
kx[RX], implying that the overall reaction rates might be
accelerated up to 10-fold by using iodides rather than bromides
4
0
(
see below, Figure 1).
. Retardation by Alkenes: Abstraction of Allylic
7
•
The kinetic competition of Scheme 10 indicates a chain-
Hydrogen by R . The SnH + 1-bromooctane reaction was
length, δ = k [RX]/k [B]. More precisely, eq 22 with r ≫ k
strongly retarded in 1-hexene and was fully suppressed in
X
B
−A
•
+
k [SnH] gives the chain-transfer constant,
A
⎛
⎞
⎟
kB
kX
[RX] 1
[B] ⎝ δ
1
C =
=
⎜
−
B
δ ⎠
0
(25)
where δ and δ are the observed chain lengths with and without
0
the retarder. The observed chain-transfer constants for 1-
bromo- and 1-iodooctane with fluorenone (C = 5.4 and 0.2)
B
8
−1 −1
•
give k
= 2 × 10 M s , in complete agreement
with the LFP value. Similarly, benzophenone yields
Sn +fluorenone
4b
6
−1 −1
•
k
= 7 × 10 M
s
(Scheme 11). •
Sn +Ph2CO
The lower rate constant for addition of Sn to benzophe-
none, compared with fluorenone, is expected on both entropic
Scheme 11
Figure 1. Simplified degraded chain, examples: radical centers flow
•
•
•
•
from R (or Sn ) to A forming delocalized A (or B ) diminishing
•
•
[
R ]
and retarding reduction. Use of RI diminishes [Sn ] and
steady‑state
•
its radical flow to B ∼10-fold, restoring the reduction rate v.
1
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,2i
1
cyclohexene (Table 5). Indeed, the addition of as little as 20
mM cyclohexene to the usual reactant mixture lowered the
radical synthesis for close on half a century,
but little
quantitative attention has been paid to its radical chain kinetics
under typical laboratory conditions. This is surprising because
most reported reduction rates are one or more orders of
magnitude slower than those predicted from the propagation
rate constants and from those measured for simple organic
halides in a nonaromatic solvent. The sheer size of these
discrepancies has long cried out for explanation.
One source of sluggish reaction rates, radical addition to
arenes, was identified by the Beckwith group while examining
the synthetically promising but extremely slow reductions of
−Br and 2−I for which the rates were up to 5,000 times
slower than calculated because intramolecular cyclization onto
an arene group produced highly stabilized radicals that could
not continue the chain (e.g., Schemes 4). It was soon realized
that this rate-retarding effect extended to intermolecular SnH/
RX radical reactions, particularly in aromatic solvents (see
Scheme 6).
a
Table 5. Alkene-Retarded Reduction
b
c
d
alkene (M)
[SnH]
Ri
v0 /v
kA/kA•
43
3
1
1
1
-hexene (8.4)
-hexene (8.4)
-hexene (8.4)
0.08
0.16
0.08
0.08
0.08
0.08
5
5
6
0.05
0.04
e
e
3
5
11
5
0.055
44
c-hexene (0.020)
c-hexene (0.020)
4.6
18
e
11
11
5
20
e
1,4-CHD (0.02)
30−40
f
1
a
Relative observed initial rates in matched runs (300 mM Oct-Br)
b
c
−8
d
−4
e
without/with the alkene. M. 10 M/s. v = 3.5 × 10 M/s. v = 5
0
0
−4
f
×
10 M/s. For 1,4-cyclohexadiene, C = k /k = (R /v)obs[SnH]/
A A H i
−2
[
A] ≈ 2−3 × 10 .
initial rate by 80%, while the same quantity of 1,4-cyclo-
hexadiene lowered the rate by 97%.
Kinetic measurements showed that the SnH dehalogenations
of 1−Br and 2−I were not chain reactions under standard
•
These retarding effects must be due to reactions of R (not
•
44−46
Sn ) radicals since substantially the same results were found
conditions
and that the addition of small amounts of 1−Br
with 1-iodo-octane. Moreover, adding an olefin (CH 
2
or 2−I to a SnH + alkyl halide reaction strongly retarded its
rate. Indeed, the more reactive iodide (2−I) completely
suppressed the reduction of neat 1-bromoheptane until all of
CHCMe CH OH) with no allylic C−Hs had only a small
2
2
rate-retarding effect.
The retarded rates were consistent with the kinetic equation
for the abstraction-degraded chain
•
the 2−I had been consumed by Sn -radicals generated from
SnH by the initiator radicals. The kinetics of these retarded
coreductions were consistent with the breaking of the radical
chains (Scheme 4).
v /v − 1 = k [A]/k
•
[SnH]
(28)
0
A
A
•
•
which yielded k /k (Table 5). Substitution with k from
A
A
A
Likewise, radical addition to arenes, e.g., benzene solvent or
•
•
•
•
Table 2 (k
and k
) then affords kA,
c‑hex‑2‑enyl /SnH
the H-abstraction rate constants for the alkenes:
H3CHCHCH2 /SnH
when the substrate is aromatic, R + ArH → RArH (Scheme
), transfers some radical centers from the main (fast) chain to
slower chains (or nonchains) and retards the reaction (as
6
≈ 400 M−1
−1
k1
‐octyl /c‐hexene
•
≈ 9000 and k
1‐octyl /1‐hexene
•
s
•
•
represented by the A/A loop in Scheme 4). The RArH
radicals may then terminate with each other either directly or
Thus, the 300-fold difference in the retarding effect of
cyclohexene versus that of 1-hexene comprises a ∼20-fold faster
chain transfer and a ∼15-fold slower chain return. Retardation
is even greater with 1,4-CHD because the chain transfer is ∼10-
44−46
revert or transfer their radical centers onto the initiator,
26
depending on reaction conditions. In the kinetics experi-
•
ments, addition of R to an aromatic solvent is a very minor
•
45
fold faster again and the A radical terminates. Confirming this
(but rate-retarding) side reaction. In homolytic arylation, it is
•
picture, our observed chain constant (C = k /k ∼ 0.02−0.03)
reduction of the R radical that is the undesired side reaction. In
either case, an optimal chain is desired for optimal yields (cf.
Remedies, below).
A
A
H
•
41
is consistent with that for the R = hex-5-enyl radical clock:
5
−1 −1
6
−1 −1
•
•
CA = k
0
/k
= 2 × 10 M s /5 × 10 M
s
=
R /1,4‑CHD R /SnH
4
2
.04 (323 K). The situation for the tested species is summed
Benzene has been the most widely used solvent for free-
radical syntheses because of its chemical compatibility, stability,
low polarity, negligible H-donor reactivity, and low radical-
addition reactivity. However, despite its popularity among free-
radical synthetic chemists, there was plenty of prior evidence
from polymer chemistry that, as a solvent, benzene retards the
rates of organic-radical chain reactions and that it does so by
up in Scheme 13.
Scheme 13. Rate Effect of Allylic CHs
47
introducing kinetically first-order chain termination. The
•
addition of various R radicals to benzene solvent strongly
retards the SnH reductions of aryl, vinyl, and cyclopropyl
halides, and it even retards the reductions of 1°- and 2°-alkyl
bromides and iodides, especially in dilute SnH solutions (Table
29
4
). Unsurprisingly, given their greater methyl affinities,
substituted benzenes retard more than benzene (in the order:
chlorobenzene > CF C H > toluene > benzene). However,
3
6
5
aromatic solvents did not affect the rates of SnH reactions
•
•
Substrates containing these or related groups are expected to
suffer a large degree of autoinhibition.
involving tertiary (tert-butyl ) and delocalized (benzyl )
48
radicals.
Clearly, aromatic solvents should be avoided for SnH
reactions that involve aryl or vinyl radicals, and even 1°- and
2°-alkyl radicals, if low [SnH] is required to effect the desired
transformation. The standard procedure for working at low
DISCUSSION
■
Tributyltin hydride reduction of organic halides has been the
most frequently used and well-developed method of free-
2
1
327
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The Journal of Organic Chemistry
SnH] is to slowly add the SnH to a dilute reaction mixture in
benzene via a motorized syringe pump. The SnH concentration
reaches a steady state defined by the addition rate, P, the chain-
transfer constant, C, the initiation rate, and the benzene
concentration:
Featured Article
•
[
This “chain return” process replaces the reduction by RArH
of AIBN with a chain-propagating pathway. This repair of the
reaction chain eliminates the need for heroic amounts of
4
5
2
6
“initiator” and (in cyclizations) reduces the ipso-addition
radicals that may otherwise form dimers.
51a
Curran and Keller have devised another neat remedy using
[SnH]
≈ C (P/R )× 10 M
steady‐state
.
i
(29)
51
oxygen to rearomatize arene adduct radicals. The radical
center is returned to the main chain via the hydroperoxyl
radical, HOO :
Thus, benzene solvent might raise [SnH]steady‑state by a factor
of 10 over that in an unreactive solvent: i.e., eq 29 with P = 3 ×
•
−6
−6
−8
10
M/s, C = 3 × 10 , and R = 3 × 10 M/s gives
i
[SnH]steady‑state = 3 mM for benzene versus the 0.3 mM
calculated for a nonaromatic solvent. This situation is much
49
worse for aryl and other σ-radicals.
The reduction of aryl halides is, of course, strongly self-
•
•
retarded: Ar + ArX → Ar−ArX (terminating). Under the
standard conditions, iodobenzene reacted ∼40 times more
slowly than did 1-bromoheptane in cyclohexane solvent.
This procedure worked well for cyclizations and arene
26
26
additions, especially with iodide precursors, iodine as initiator,
Since the chain length is proportional to the mole ratio SnH/
ArX, the reduction of aryl halides might be optimized by
keeping the SnH in a large excess and, naturally, by using a
nonarene solvent.
and the silane, TMS SiH.
3
Another potential remedy is suggested by the studies of
52
Larauffie et al. In a series of intricate label-crossover
experiments they established that a conjugated terminal olefin
•
More generally, our findings indicate most substrates and
products of any synthetic interest will contain chain-transfer
groups that retard the SnH chain. These include allylic CHs,
is a more active bimolecular trap (H -acceptor) for the labile
•
44
hydrogen in the adduct (RArH ) than is the AIBN initiator.
•
Inclusion of an even better H -trap, the electron deficient olefin
M, as a “sacrificial” bimolecular oxidant afforded near-
quantitative yields of both the oxidized arylation product,
2
6
conjugated double bonds, and aryl or bis-aryl CO groups.
Regardless of whether the transfer is from the organic or the
stannyl radical, via abstraction or addition, the result is the
transfer of most radical centers into a pool of “slow” or dead-
end species, such as delocalized radicals A or B . The result is a
slower reaction and a longer reaction time, as quantified by eq
53
RAr, and reduced M (MH = PhCH CH(CN) ) (Scheme
2
2
2
14).
•
•
Scheme 14
22. The effect of chain transfer is depicted in Figure 1, where
relative areas represent relative radical concentrations (totaling
•
[
] = √(R /2k ) ∼ 15 nM), down-arrows are chain transfer or
i
t
termination, up-arrows are chain return, and horizontal arrows
represent propagation in the main chain (i.e., v and v =
0
−
d[RX]/dt).
Steady-state radical concentrations are determined by relative
reactivities, with the most highly reactive radicals being present
at the lowest concentrations. Thus, in spite of benzene’s low
Product analysis showed that one H came from the arene
and one from the SnH, i.e.
53
−
1
−1
•
reactivity toward alkyl radicals (k
≈ 15 M s ),
RCH2 +PhH
•
•
RArH + M → MH + RAr
(36)
around 80% of the C-centered radicals in the 1-heptyl bromide
SnH reaction in solvent benzene are delocalized radicals and
only 20% are heptyl . When R is an aryl radical, Ar , the ratio
of terminating A (ArPhH ) to propagating R (Ar ) radicals
climbs to 90 or 95%, with the rate falling to just 5−10% of its
value in cyclohexane solvent. (ArX, being aromatic, will be
both substrate and product inhibited).
+
•
•
MH + SnH → MH + Sn
Thus, a third way to convert chain-blocking arene-adduct A
(37)
•
•
•
2
•
•
•
•
•
radicals into propagating species may be to add an electron-
26
•
deficient unsaturated compound as a RArH oxidant:
•
•
A + M + SnH → → A(−H) + MH + Sn
(38)
2
However, the “plumbing” of Figure 1 means that increasing
•
•
the flow of radical centers back from A or B to the main chain
A nonterminal M is indicated, but even a simple monomer
•
•
will increase [R ] and [Sn ], thus accelerating the reaction.
like methyl acrylate might work.
•
18a
Known and Potential Remedies for Slow Tin Hydride
As for remedies for allylic A radicals, Crich et al. have
shown that catalytic PhSeH can accelerate reactions and
eliminate dimers in SnH reductions that are retarded or blocked
by allylic species.
50
Reactions. Crich et al. have developed a clever remedy by
the addition of PhSeH (or a source thereof). This compound is
a highly reactive H atom donor, which enhances the desired
chain as shown below:
A• + PhSeH + SnH → → AH + PhSeHcat + Sn•
cat
(39)
•
50d
For benzylic A radicals, Ford et al. have shown PhSeH
improves the kinetics and yields in the radical-chain hydro-
•
stannation of styrenes, Sn + CH C(X)Ph → SnCH −
2
2
•
•
C (X)Ph (A ).
Alternatively, if “trickier” to implement, a well-judged flux of
oxygen (O ) could serve to convert allylic or other delocalized
2
1
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The Journal of Organic Chemistry
Featured Article
A• radicals into fast-propagating organic peroxyl radicals
halides). These factors were minimized by using freshly purified,
alumina-filtered, and argon-sparged solvents and reagents and by
excluding oxygen and light. Typically, a cyclohexane solution of RX
and the initiator was degassed using a slow stream of argon delivered
via a fine glass capillary inside a syringe needle inserted through the
septum of a small glass ampule warmed to 42 ± 1 °C. Vacuum distilled
SnH (0.2−0.5 equiv) was then injected (and rapidly mixed by the
argon stream). Samples from the reaction mixture were quenched by
•
(
AOO ), returning radical centers to the chain and hastening
the overall reduction.
•
•
A + O + SnH → → AOOH + Sn
(40)
2
•
•
•
The problem here is that i , R , and Sn radicals all undergo
diffusion-controlled reactions with O2. Even so, from eq 22
5
4
addition to 10 volumes of argon-sparged CCl , warmed for a few
(
Scheme 7) we calculate substantial rate acceleration at low O
4
2
−4
•
•
minutes (or for up to 2 h for strongly retarded reactions), and analyzed
by capillary GC (25 m × 0.32 mm BP1 column and FID). Reaction
rates were calculated from the product ratio α = (SnBr/SnCl)gc (the
chloride being formed from reaction of the remaining SnH with the
concentrations ([O ] < 10 M) from the removal of A
provided, that is, the formation of the retarding SnOO
radical is minimized by using an iodide rather than bromide
substrate.
2
5
5
2
6
CCl ). This afforded the observed first-order reaction rate constant
4
Iodides also minimize retardation by carbonyls, since, unlike
(
kobs = [ln(1 + α)]/t) and initial reaction velocity, (v) = −(d[SnH]/
0
•
•
R radicals, Sn radicals do not abstract hydrogen but they can
dt) = [SnH] [ln(1 + α)]/t, which was averaged over eligible time
0
0
undergo rate-retarding reversible additions (see Figure 1). That
said, the benefit of reversibility is that even fast addition does
not preclude high yields from slower irreversible reactions. For
points. The initiator BONNOB has a half-life of 25 h at 42 °C, so Ri
was taken to be constant for reaction periods of up to 6 h. GC product
ratios were reproducible to ±4% (1 SD) and repeat reactions exhibited
a further ±5% superposed random variation.
Competition Kinetics. Competition kinetics were used to
determine the halogen-atom abstraction rate constants for 1−Br and
instance, addition to the activated carbonyl in 1−Br (forming
•
Sn1Br ) would likely be faster than the bromine abstraction (k
Br
6
−1 −1
=
2 × 10 M s ) and yet products arise only from the
bromine abstraction (via 1 ). Build-up of adduct Sn1Br may
2
−I. Where the stannane is consumed by a large excess of a mixture of
•
•
halides RX and R′Y (X ≠ Y), the pseudo-first-order rate equation k /k
X
Y
slow the reduction rate but does not divert the reaction because
≈
(SnX/SnY) (R’Y/RX) gave reasonably accurate rate ratios (where
gc 0
it undergoes β-scission more rapidly than it reacts with the
the use of stannyl halide yield ratios obviated the need to quantify the
injection-port-labile rearranging halides). Thus, a freeze−pump−thaw
degassed cyclohexane solution of 1−Br (100 mM), benzyl chloride
•
SnH: k ≫ k
[SnH] (Scheme 15).
β
Sn1Br /SnH
(100 mM), SnH (20 mM), and BONNOB (8 mM) was warmed to 42
Scheme 15
°
C for 15 h in a sealed glass ampule and then analyzed, and the relative
rate constants were calculated from the yield ratio k1‑Br/kPhCH2Cl
≈
(
SnBr/SnCl)gc = 1.7 ± 0.2. Likewise, for 2−I with benzyl bromide as
the competitor: k /k
measurement for 2-I (0.10 M) in 1-bromoheptane solvent (8.0 M)
afforded a confirming rate constant: k
M
≈ (SnI/SnBr) = 1.3 ± 0.2. Another
2‑I PhCH2Br
gc
9
•
•
≈ 81 x k
= 2 × 10
Sn /2I
Sn /1‑HepBr
−1
−1
s .
The chain-transfer kinetic analysis demonstrated here is
readily adapted to nonstannyl reagents, as well as to the
optimization of mixed reagents like triethylsilane + thiol/
ASSOCIATED CONTENT
Supporting Information
■
2
6,56
*
S
selenol.
Kinetic derivations; radical-flow figures; reversible benzene
•
CONCLUSION
The rates of SnH reductions of RX under laboratory conditions
addition; 1-hexene + Sn reversible addition equilibrium data;
■
arene addition mechanism; selenol-assisted arene cyclization
mechanism; O -assisted arene addition; kinetic competition
are frequently determined by chain-transfer side reactions of
2
•
•
equations; Table showing 1-Br/bromoheptane coreduction.
This material is available free of charge via the Internet at
http://pubs.acs.org.
the Sn or R radical with solvent, substrate, and product. These
side processes can lead to much slower overall reactions and
greatly extended reaction times. Such retarded reactions can be
accelerated, and reaction times therefore reduced, by catalyzing
the transfer of less reactive, and even unreactive, radical centers
back to the main chain. Chain transfer in the industrially
AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: vincent.bowry@jcu.edu.au.
57
58
important fields of polymer and autoxidation chemistry has
been the subject of intense research interest, whereas SnH
reductions have been restricted (thanks to the perceived
toxicity of organotin compounds) to small-scale work in
Present Address
James Cook University, McGregor Road, Smithfield QLD
4787, Australia.
†
2
research laboratories. Nonetheless, organostannane radical
chain reduction is a powerful synthetic tool that continues to be
developed and published at an undiminished rate. It is hoped
that the findings and ideas presented here, including the use of
faster nontoxic solvents in place of benzene, and strategies to
either minimize or utilize chain transfer will help to further
refine experimental procedures.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. John Storey for providing precursors and
products for 1−Br and Dr. David Harman for 2−I.
EXPERIMENTAL SECTION
■
Reduction Velocity (v). The rates of tri-n-butylstannane (SnH)
reductions can be erratic owing to the effects of residual oxygen,
reagent, and solvent impurities (notably radical-generating peroxide
impurities in ethers and rate-retarding olefin impurities in organic
DEDICATION
■
In grateful memory of Professor Athel Beckwith for initating
and supporting this investigation.
1
329
DOI: 10.1021/jo502710a
J. Org. Chem. 2015, 80, 1321−1331

The Journal of Organic Chemistry
Featured Article
1
780. Similarly, for hydroaromatic radicals, see: (c) Manka, M. J.;
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(
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(
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8
2
603. For TMS SiH, see: (h) Chatgilialoglu, C. Acc. Chem. Res. 1992,
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1
(
5, 188. For a stimulating overview, see: (i) Zard, S. Z. Radical
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=
2
(
(
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1
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levels.
•
(
23) For Bu Sn radicals, see ref 3 and: Shaw, W. J.;
3
Kandandarachchi, P.; Franz, J. A.; Autrey, T. Organometallics 2004,
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2
(
(
(
(
(
25) Fischer, H.; Paul, H. Acc. Chem. Res. 1987, 20, 200.
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27) Radical 9/10-addition to An is more exothermic and less
(
reversible than addition to a monoarene: (a) Beckwith, A. L. J.;
Waters, W. A. J. Chem. Soc. 1956, 1108. (b) Beckwith, A. L. J.; Waters,
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C.; Waters, W. A. J. Chem. Soc. 1958, 171.
(
(
1
(
(
28) That is, for mean polymer chain-length in monomer M, with
(
P) and without (P ) chain-transfer agent S: 1/P = C[S]/[M] + 1/P ;
of temperature during the UV photolysis of the initiator α,α-azo-bis-
cyclohexylnitrile. While conditions at the center of the reaction cell
remain adiabatic (i.e., for 10−15 s after the start of photolysis), the rate
of temperature increase is proportional to the reaction rate. The light
was then turned off for 10 min for thermal re-equilibration. Initiation
rates were measured using inhibition by galvinoxyl, and termination
rate constants were determined by the rotating sector kinetic method.
The rates of heat evolution and the enthalpies of overall reaction were
measured by conventional methods and this allowed propagation rate
constants k and k to be measured.
0
0
chain-transfer constant C = k /k : Mayo, F. R. J. Am. Chem. Soc. 1943,
S
p
6
5, 2324.
29) Methyl affinities are rate constants for addition measured
relative to the hydrogen abstraction from isooctane at 65 °C:
a) Leavitt, F.; Levy, M.; Szwarc, M.; Stannett, V. J. Am. Chem. Soc.
955, 77, 5493. (b) Zytowski, T.; Fischer, H. J. Am. Chem. Soc. 1997,
119, 12869.
(
(
1
(
(
30) Scaiano, J. C.; Stewart, L. C. J. Am. Chem. Soc. 1983, 105, 3609.
•
31) This work; noting, however, that it is based on a k
Me2CCH /SnH
H
X
4
c
•
value that may well contain a contribution from k
(
106, 4877.
(33) (a) Degueil-Castaing, M.; Rahm, A.; Dahan, N. J. Org. Chem.
1986, 51, 1672. α,β-Unsaturated ketones: (b) Hays, D. S.; Scholl, M.;
Fu, G. C. J. Org. Chem. 1996, 61, 6751.
(34) (a) Enholm, E. J.; Prasad, G. Tetrahedron Lett. 1989, 30, 4939.
(b) Zelechonok, Y.; Silverman, R. B. J. Org. Chem. 1992, 57, 5785.
(35) Chopa, A. B.; Koll, L. C.; Savini, M. C.; Podesta, J. C.;
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(36) Pereyre, M.; Quintard, J. P. Pure Appl. Chem. 1981, 53, 2401.
(37) Even so, the “salmon red” SnOC Ph
scission above 340 K: Tomaszewski, M. J.; Warkentin, J. J. Chem. Soc.,
Chem. Commun. 1993, 1407.
(38) Alberti, A.; Hudson, A. J. Organomet. Chem. 1979, 164, 219.
(39) Equation 26 indicates v α [RX][SnH] . Reinitiation via stannane
reduction of the B radical would be first order in the stannane and can
be ruled out.
.
(
(
1
(
10) For O acceleration of homolytic arylation, see the Discussion.
Me2CCHCO2 /SnH
2
32) Johnston, L. J.; Scaiano, J.; Ingold, K. U. J. Am. Chem. Soc. 1984,
11) 2.3RT/kcal/mol. See: Bowry, V. W.; Ingold, K. U. J. Org. Chem.
995, 60, 5456.
12) For discussion, see: Beckwith, A. L. J.; Bowry, V. W.; Ingold, K.
U. J. Am. Chem. Soc. 1992, 114, 4983.
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S. U. J. Am. Chem. Soc. 1995, 117, 3674.
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1, 19.
15) Ingold, K. U.; DiLabio, G. A.; Bowry, V. W. Unpublished results.
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Tronche, C.; Newcomb, M. J. Am. Chem. Soc. 2000, 122, 2988.
17) In brief, all published k data for nonpolar radicals lie within 0.4
(
(
5
(
(
•
radical does undergo β-
2
(
H
−
1 −1
log units of the line log(k /M s ) = −13.34 + 0.20(D(R−H)/kcal
H
−
1
15
mol ) <r> = 0.989. Congruent with this trend, the 3.3 kcal/mol
weaker R−H bond in propene compared to toluene, D(benzyl−H) −
0
•
D(allyl−H) = 3.3 kcal/mol, indicates a 5-fold lower k for allyl than
for benzyl (observed k
H
benzyl•
allyl•
/k
≈ 8). Similarly, the 8.4 kcal/mol
H
H
•
weaker R−H bond in cyclohexene than in toluene indicates a 50-fold
(40) See the Supporting Information on the Sn + olefin reaction.
benzyl•
c‑hex‑2‑enyl•
slower rate (observed k
/k
≈ 100). Relative D(R−H)
data derived from: Lin, C. Y.; Peh, J.; Coote, M. L. J. Org. Chem. 2011,
6, 1715.
18) The 3-toluylcyclohex-2-en-1-yl radical (a 3°/2°-allylic radical)
gave about a 6:4 dimer/reduced product ratio in the presence of 20
(41) Newcomb, M.; Park, S. U. J. Am. Chem. Soc. 1986, 108, 4132.
(42) (a) Hawari, J.; Engel, P.; Griller, D. Int. J. Chem. Kinetics 1985,
17, 1215. (b) Chatgilialoglu, C.; Ingold, K.; Scaiano, J. J. Am. Chem.
Soc. 1982, 104, 5119.
(43) Reviewed in: Newcomb, M. Tetrahedron 1993, 49, 1151 See also
ref 6a..
(44) Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann, E.;
Parr, J.; Storey, J. M. D. Angew. Chem. Int. Edit 2004, 43, 95.
(45) Increasing the initiator concentration [i N ] up to 1000-fold
H
H
7
(
−1
−1 −1
mM SnH, from which k [SnH] ≈ 10 s or k ≈ 500 M
s
(similar
H
H
to k (cyclohex-2-enyl)); see: (a) Crich, D.; Mo, X.-S. J. Am. Chem. Soc.
H
1
998, 120, 8298. None of the reduced product can arise from
disproportionation since “pairs of allylic radicals react exclusively by
combination”; see: (b) Klein, R.; Kelley, R. D. J. Phys. Chem. 1975, 79,
2
2
46
(for 1−Br or 2−I) leads to stannane-mediated homolytic arylation as
1
330
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The Journal of Organic Chemistry
Featured Article
4
6
discussed in ref 44. Under the usual synthesis conditions the
2
6
arylation is likely a nonchain radical reaction of overall stoichiometry
(
1/ε)i N + SnH + RX + ArH
2
2
→
2iH + SnX + RAr + (1/ε)N2
where ε is the initiator efficiency (∼0.7).
(
46) First report: (a) Narasimhan, N.; Aidhen, I. S. Tetrahedron Lett.
988, 29, 2987. Reviewed in: (b) Bowman, W. R.; Storey, J. M. D.
Chem. Soc. Rev. 2007, 36, 1803.
47) In an early precedent, chain-transfer to benzene solvent was
1
(
•
attributed to addition of a polymer radical to benzene (M + PhH →
M PhH ) followed by H -transfer to monomer, starting a new chain
M PhH + M → M Ph + HM ) (a) Mayo, F. R. J. Am. Chem. Soc.
x
•
•
x
•
•
(
x x 1
1
943, 65, 2324. (b) Florey, P. J. Principles of Polymer Chemistry;
Cornell University Press: Ithaca, 1953; p 143. Rate-retarding arene
addition has also been observed in the kinetic chain of t-butyl
hypochlorite chlorination of alkyl arenes: (c) Carlsson, D. J.; Ingold, K.
U. J. Am. Chem. Soc. 1967, 89, 4891.
(
48) Addition of these radicals is likely to be too reversible to have
26
any kinetic effect.
(
49) (a) Vinyl: Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am.
Chem. Soc. 1988, 110, 5900. (b) Lee, E.; Ko, S. B.; Jung, K. W.; Chang,
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9
(
(
022.
50) (a) Crich, D.; Hwang, J.-T. J. Org. Chem. 1998, 63, 2765.
b) Crich, D.; Patel, M. Tetrahedron 2006, 62, 7824. (c) Crich, D.;
Grant, D.; Krishnamurthy, V.; Patel, M. Acc. Chem. Res. 2007, 40, 453.
d) Ford, L.; Wille, U.; Schiesser, C. H. Helv. Chim. Acta 2006, 89,
306.
51) (a) Curran, D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128,
3706. For a metal-free O -driven homolytic arene addition, see:
(
2
(
1
2
(
2
b) Hofmann, J.; Jasch, H.; Heinrich, M. R. J. Org. Chem. 2014, 79,
314. For O /SnH acceleration with allylic radicals, see “21” in:
2
(
c) Nakamura, E.; Imanishi, Y.; Machii, D. J. Org. Chem. 1994, 59,
178.
52) Larraufie, M.-H.; Courillon, C.; Ollivier, C.; Laco
M.; Fensterbank, L. J. Am. Chem. Soc. 2010, 132, 4381.
8
(
̂
te, E.; Malacria,
•
•
(
53) See ref 52 for the H /D -addition regiochemistry.
(
54) A limiting flux of O should intercept the least active radicals in
2
the degraded chain. Thus, the reaction system used by Curran is less
•
liable to O inhibition, since an aryl R is less likely to be intercepted
2
•
by O before addition /cyclization onto ArH than is an alkyl R .
55) The SnOO radical is likely ∼100-fold less reactive to SnH than
is the alkyl ROO ; cf.: Howard, J. A.; Tait, J. C.; Tong, S. B. Can. J.
2
•
(
•
Chem. 1979, 57, 2761.
(
(
56) Cai, Y.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 2 2002, 1858.
57) First defined: (a) Flory, P. J. J. Am. Chem. Soc. 1937, 59, 241.
kinetics: (b) Jenkins, A. D. Trans. Faraday Soc. 1958, 54, 1885−1895.
(
c) Burnett, G.; Loan, L. Trans. Faraday Soc. 1955, 51, 214. chain
transfer in ‘living radical’ polymerization, is reviewed in: (d) Moad, G.;
Rizzardo, E.; Thang, S. H. Polymer 2008, 49, 1079. and (e) Rizzardo,
E.; Solomon, D. H. Aust. J. Chem. 2012, 65, 945.
(
58) (a) Mahoney, L. R. Angew. Chem., Int. Ed. Engl. 1969, 8, 547.
(
b) Ingold, K. U. Chem. Rev. 1961, 61, 563. (c) Valgimigli, L.; Pratt, D.
A. In Encyclopedia of Radicals in Chemistry, Biology and Materials; John
Wiley & Sons, Ltd: Chichester, UK, 2012. (d) Ingold, K. U.; Pratt, D.
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1
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