Mechanism of the reactions of alcohols with o-benzynes

Article abstract of DOI:10.1021/ja502595m

We have studied reactions of secondary and primary alcohols with benzynes generated by the hexadehydro-Diels-Alder (HDDA) reaction. These alcohols undergo competitive addition vs dihydrogen transfer to produce aryl ethers vs reduced benzenoid products, respectively. During the latter process, an equivalent amount of oxidized ketone (or aldehyde) is formed. Using deuterium labeling studies, we determined that (i) it is the carbinol C-H and adjacent O-H hydrogen atoms that are transferred during this process and (ii) the mechanism is consistent with a hydride-like transfer of the C-H. Substrates bearing an internal trap attached to the reactive, HDDA-derived benzyne intermediate were used to probe the kinetic order of the alcohol trapping agent in the H₂-transfer as well as in the alcohol addition process. The H₂-transfer reaction is first order in alcohol. Our results are suggestive of a concerted H₂-transfer process, which is further supported by density functional theory (DFT) computational studies and results of a kinetic isotope effect experiment. In contrast, alcohol addition to the benzyne is second order in alcohol, a previously unrecognized phenomenon. Additional DFT studies were used to further probe the mechanistic aspects of the alcohol addition process.

Full text of DOI:10.1021/ja502595m

Article
pubs.acs.org/JACS
Mechanism of the Reactions of Alcohols with o‑Benzynes
Patrick H. Willoughby,†,§ Dawen Niu,‡,§ Tao Wang, Moriana K. Haj, Christopher J. Cramer,
and Thomas R. Hoye*
Department of Chemistry, Supercomputing Institute, and Chemical Theory Center, University of Minnesota, 207 Pleasant Street SE,
Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: We have studied reactions of secondary and primary alcohols
with benzynes generated by the hexadehydro-Diels−Alder (HDDA) reaction.
These alcohols undergo competitive addition vs dihydrogen transfer to
produce aryl ethers vs reduced benzenoid products, respectively. During the
latter process, an equivalent amount of oxidized ketone (or aldehyde) is
formed. Using deuterium labeling studies, we determined that (i) it is the
carbinol C−H and adjacent O−H hydrogen atoms that are transferred during
this process and (ii) the mechanism is consistent with a hydride-like transfer of
the C−H. Substrates bearing an internal trap attached to the reactive, HDDA-derived benzyne intermediate were used to probe
the kinetic order of the alcohol trapping agent in the H2-transfer as well as in the alcohol addition process. The H2-transfer
reaction is first order in alcohol. Our results are suggestive of a concerted H2-transfer process, which is further supported by
density functional theory (DFT) computational studies and results of a kinetic isotope effect experiment. In contrast, alcohol
addition to the benzyne is second order in alcohol, a previously unrecognized phenomenon. Additional DFT studies were used to
further probe the mechanistic aspects of the alcohol addition process.
noticeably contrasting behavior between secondary and primary
alcohols vis-a-vis that of tert-butanol. For example, the reaction
INTRODUCTION
■
̀
o-Benzyne (2),1 characterized by its inherently low-lying
LUMO,2 is among the most versatile and useful of all reactive
intermediates.3 Arynes are “trapped” by many different kinds of
nucleophilic species.4 It is perhaps surprising then that o-
benzyne generated by the tert-butoxide-promoted 1,2-elimi-
nation of bromobenzene (1, Figure 1a) cleanly gives the [4 +
2] furan cycloadduct 3 as the major product.5 That is, neither
the stoichiometric tert-butoxide reagent nor the byproduct t-
BuOH reacts with o-benzyne (2) under the basic conditions. In
contrast, Stiles and Miller reported that when 2 is generated by
thermal decomposition of benzenediazonium-2-carboxylate (4)
in the presence of tert-butanol and under neutral conditions,
the alcohol adds to give tert-butyl phenyl ether (5) as the major
event.6 Benzyne derivatives can be generated thermally by the
cycloisomerization of triynes, a reaction pathway first identified
by the groups of Johnson and Ueda.7 We recently reported that
this hexadehydro-Diels−Alder (HDDA) reaction, when
performed in tert-butanol solution, leads to the efficient
production of t-BuOAr ethers as shown for 6 to 8 via benzyne
7 (Figure 1b).8 This reaction (along with the related example of
9 to 11 via 10) proceeds with a high degree of regioselectivity,
which can be rationalized by the (computed) distorted
geometry of the benzyne intermediate(s); the nucleophilic
heteroatom adds to the aryne carbon having the larger internal
bond angle (cf. δ+ in 7 and 10).9
of triyne 9 in a solution of the secondary carbinol cyclohexanol
(12-hh) resulted in the isolation of the addition adduct 13 in
80% yield (Figure 2). However, we also observed the formation
of a small amount of the reduced benzenoid 14-hh (13:14-hh =
12:1 in neat cyclohexanol), the result of net addition of a
hydrogen atom to each of the benzyne carbon atoms. This
process was also recently noted in a report by Lee and co-
workers.10 To our surprise, when triyne 9 was heated in the
presence of only 1.6 equiv of cyclohexanol (12-hh), the
product ratio was substantially reversed, and 14-hh, the result
of H2-transfer, was formed to the near exclusion of 13 (13:14-
hh = 1:17 in 0.013 M cyclohexanol in CDCl3). A similar
dependency of the branching ratio between the dihydrogen
transfer (to give 14-hh) vs alcohol addition pathways on the
bulk concentration of the trapping alcohol was also observed
for both isopropanol and ethanol [see Graph S1 and Table S1
in the Supporting Information (SI)]. Together, these results
indicate that in the presence of higher concentrations of
trapping alcohol, relatively more addition product is formed,
whereas H2-transfer is strongly dominant at low alcohol
concentrations. These two reaction manifolds seemingly have
different kinetic profiles.
When the reaction between 9 and 12-hh (1.6 equiv) was
monitored directly by 1H NMR spectroscopy in CDCl3
solution, essentially equimolar amounts of 14-hh and cyclo-
hexanone (15) were observed, demonstrating that the
RESULTS AND DISCUSSION
■
In the course of exploring other alcohols that would participate
in an addition to HDDA-derived benzynes, we observed
Received: March 19, 2014
Published: September 4, 2014
© 2014 American Chemical Society
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Figure 3. Studies with various deuterium-labeled cyclohexanols. The
initial concentration of triyne 9 and alcohol 12-hh in CDCl3 for these
experiments was 0.010 and 0.015 M, respectively. (a) Results from the
use of tetradeuteroalcohol 12-d4 rule out the intermediacy of enol 16.
(b) The H2-transfer occurs with a high degree of regioselectivity.
dominant products observed. This experiment established that
generation of the enol 16 (and its subsequent tautomerization
to 15) was not operative, indicating instead that the OH and
carbinol methine hydrogen atoms in 12-hh were being
transferred. We therefore made and examined the behavior of
the complementary pair of monodeuterated cyclohexanols 12-
hd and 12-dh (Figure 3b). Each of these labeled alcohols
resulted in the formation of a monodeuterated benzenoid and
the all-protio cyclohexanone (15), as would be expected for a
redox process involving a simultaneous transfer of two
hydrogen atoms11 from a single encounter between the
benzyne and one molecule of the alcohol. Remarkably,
however, each of these monodeuteration reactions was highly
regioselective; that is, only 14-hd was observed using alcohol 12-
hd as the donor and only 14-dh when 12-dh was used.
The sense of regioselectivity observed in the formation of 14-
hd vs 14-dh can be explained by concerted H2-transfer from the
H−CO−H moiety in 14, in which addition involving a hydride-
like nucleophilic carbinol C−H is accompanied by a more
electrophilic O−H proton transfer. This view calls to mind the
Cannizzaro (or Oppenauer) class of C−H hydride transfer
reduction reactions. This model, involving concerted transfer of
both hydrogen atoms, accounts for the sense of the observed
regioselectivity. The hydride addition as portrayed in Figure 3b
for the reaction between benzyne 10 and the monodeuterated
cyclohexanol 12-dh delivers the deuterium atom to C3, the
more electrophilic benzyne carbon in 10 (cf. 10 to 11 in Figure
1b8).
Figure 1. Reactions of benzynes in the presence of tert-butanol. (a)
Different reactivities of o-benzyne (2) under basic5 vs neutral6
conditions. (b) HDDA-generated benzynes (7 and 10) also are
trapped by neutral tert-butanol.
Figure 2. Competitive H2-transfer vs addition processes for the
reaction of cyclohexanol (12-hh) with the HDDA-generated benzyne
10. The branching ratio for the pathways leading to product 13 vs 14-
hh/15 is dependent on the bulk concentration of 12-hh.
secondary alcohol was the source of the two hydrogen atoms
appearing in the benzenoid 14-hh. We have previously reported
that this same reduced product, 14-hh, arose when 9 was
heated in cyclooctane solution.11 In that study we showed that
concerted H2-transfer from the hydrocarbon to 10 (Figure 1)
gave equimolar amounts of 14-hh and (the oxidized)
cyclooctene.
To gain additional insight about the mechanism of the
alcohol/benzyne redox process, we turned to density functional
theory (DFT) computations. We first examined the H2-transfer
between methanol and o-benzyne (2), to give benzene and
formaldehyde, and located the transition-state (TS) structure
shown as 17‡ in Figure 4a. The computed overall free energy of
reaction (ΔGrxn) was = −70.8 kcal·mol−1 and the free energy of
activation (ΔG‡) was found to be 13.4 kcal·mol−1. The
geometry is indicative of a relatively early transition state for the
To identify the sites in cyclohexanol (12-hh) from which the
two hydrogen atoms were being transferred, we performed the
reaction using a series of deuterated cyclohexanol derivatives.
First, HDDA reaction of 9 in the presence of ca. 1.5 equiv of
2,2,6,6-tetradeuterocyclohexanol (12-d4) occurred without
1
observable (<5%, H NMR and GC/MS analysis) transfer of
deuterium (Figure 3a).12 That is, 14-hh and 15-d4 were the
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119°, respectively, in the benzyne acceptor, and they further
distort to 138° and 112° in the TS structure 19‡. The
computed ΔG‡ for the reaction via 19‡ was 11.1 kcal·mol−1.
This was lower by 3.7 kcal·mol−1 than the computed ΔG‡ for
the alternative mode of H2-transfer involving addition of C−H
to C4 (see SI).16
Encouraged by the supportive nature of these computations,
we proceeded to compute the expected kinetic isotope effect
(KIE) for the reaction of 9 with 12-dh (Figure 3b). The
truncated methyl-containing 19‡ was again used as the TS
structure for the process. Replacement of the proton on the
carbinol carbon with a deuteron gave rise to a computed KIE of
1.97 for the C−H transfer processes (see SI for additional
details). This value is consistent with an expected early
transition state for this H2-transfer reaction. We then measured
this KIE by heating triyne 9 with a mixture of 12-hh and 12-dh
1
and then analyzing the H NMR spectrum to determine the
ratio of 14-hh:14-dh. The experimental KIE was 2.0, a
̀
gratifying result vis-a-vis the computed value. This bolsters
the view that the redox transfer between 10 and 12-dh occurs
through a species like 19‡, as portrayed in Figure 4c.
We then examined the reactivity of a variety of alcohols (cf.
23a−k, Figure 5c) to learn their propensity to participate in the
H2-transfer process. The goal here was not to establish a
preparative method for making either a reduced benzenoid like
14-hh (cyclooctane is a better “reagent” for that task11) or any
of the ketones or aldehydes derived from 23 (a multitude of
oxidants is available for that task, of course). Instead, we hoped
to be able to gain further insights about mechanistic aspects of
this unusual redox reaction. In situ NMR analysis proved to be
a convenient method for this study. An example of such an
experiment is shown in Figure 5a. A CDCl3 solution of triyne
20 (0.02 M), which bears a methyl group in place of the n-
propyl substituent in triyne 9, was heated in the presence of
several equivalents of cyclooctanol at 85 °C. After 14 h this
Figure 4. Computed TS structure geometries and energies (gas-phase)
for H2-transfer from alcohols [DFT, M06-2X/6-311+G(d,p)].15 (a)
Methanol to o-benzyne (17‡); (b) cyclopentanol to o-benzyne to give
either cyclopentanone (18a‡) or its enol (1-hydroxycyclopentene;
18b‡) (the computed structure for each is given in the SI); and (c)
cyclohexanol to an actual HDDA benzyne (19‡). The ΔΔG‡ value of
−3.7 kcal·mol−1 corresponds to the two regioisomeric modes of H2-
transfer from 12 to the benzyne.
reaction, consistent with its high exothermicity. The process is
also considerably asynchronous, with C−H bond cleavage well
advanced over that of O−H. Interestingly, the initially
symmetrical o-benzyne (2) has a distorted geometry in TS
structure 17‡ (internal bond angles at Ca and Cb = 132° vs
118°, respectively), which we interpret as an accommodation of
a nucleophilic hydride-like transfer. The notion that aryne
polarizability plays an important role in contributing to the
immense versatility displayed in aryne trapping reactions4,13
perhaps merits broader consideration. Said differently, an aryne
represents one of the softest and most malleable of all carbon-
based electrophiles.14
We then used computation to explore the question of which
two hydrogen atoms were transferred from the alcohol donor
(i.e., the H−CO−H to give a ketone vs the H−CC−H to
produce an enol). Here we used cyclopentanol and benzyne to
locate the two relevant TS structures 18a‡ and 18b‡ (Figure
4b). These gave ΔG‡ values of 12.8 kcal·mol−1 vs 18.6 kcal·
mol−1, respectively. This (computed) preference for ketone vs
enol formation is consistent with the lack of deuterium
incorporation in the experiments presented in Figure 3a.
Finally, we computed the TS structure geometries for the
two regioisomeric modes of H2-transfer in which the carbinol
methine adds to C3 vs C4 in a benzyne like 10; to simplify this
computational analysis we replaced the n-propyl group in
benzyne 10 by a methyl substituent. The resulting most stable
TS structure is shown as 19‡ in Figure 4c. It depicts, again, an
asynchronous, hydride-like addition preferentially to C3 of the
now predistorted (and thereby predisposed) benzyne. The
internal angles at C3 and C4 were computed to be 136° and
1
reaction mixture was directly analyzed by H NMR spectros-
copy (Figure 5b), which showed the overall cleanliness of the
process. As was the case for triyne 9 when cyclized in the
presence of low bulk concentration of alcohols, this reaction
yielded the reduced benzenoid 21 as the dominant product
together with a small amount of the alcohol addition adduct 22.
Cyclooctanone was produced in an essentially equimolar
̀
amount vis-a-vis 21 as a result of this H2-transfer process [cf.
integration values of the resonances for Mea (δ = 2.47 ppm) vs
the C2 and C8 methylene protons (δ = 2.41 ppm) of
cyclooctanone].
Using this method of analysis, we observed that each of the
alcohols 23 shown in Figure 5c was capable of donating two
hydrogens to benzyne 10 (from triyne 9), albeit with different
levels of efficiency. The ratio of reduction to addition products
(given in parentheses in Figure 5c) varied with each alcohol.
Importantly, the amount of reduced arene 14 was always very
similar to that of the ketone derived from the corresponding
secondary alcohol donor. Inferences that can be taken from this
series of substrates include the following: (i) even highly
hindered alcohols like 23a−c readily donate dihydrogen, (ii)
the vicinal diol 23d did not show evidence of overoxidation or
oxidative cleavage, and the internal hydrogen bond appears to
inhibit the H2-addition process, (iii) the cyclopropylcarbinol
23e showed no signs of ring-opened products, which argues
against a stepwise radical mechanism initiated by benzylic
hydrogen atom abstraction (as well as stepwise hydride transfer
to generate a transient cyclopropyl carbenium ion), and is,
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To establish the effect of steric hindrance on the ability of an
alcohol to add to benzyne 10, we performed a series of three
competition experiments, each in 100% alcohol. Triyne 9 was
heated in the presence of equimolar mixtures of MeOH vs
EtOH, EtOH vs i-PrOH, and i-PrOH vs t-BuOH. The ratios of
the two possible alcohol addition products are shown in Figure
6. It is clear that increasing steric hindrance slows the rate of
Figure 6. Competition experiments to assess the relative ease of
addition of alcohols of differing steric bulk to the benzyne 10. An
authentic sample of each of the four alkoxyarene (ROAr) products was
prepared by heating 9 in the appropriate neat alcohol. The products
were obtained in the following yields after chromatographic
purification: R = Me (30%), R = Et (86%), R = i-Pr (83%), and R
= t-BuOH (11, Figure 1b, 62%).
addition. The extent of retardation grows exponentially in a way
that is reminiscent of the nonlinear change in A-values20 across
the series of Me (1.74 kcal mol−1), Et (1.78), i-Pr (2.21), and t-
Bu (>4) groups, a measure of steric size that also reflects
detailed conformational features of a system.
In order to gain additional mechanistic insights about both
the alcohol addition and redox reaction pathways, we have
studied kinetic aspects of the benzyne trapping events. It is
challenging to obtain fundamental mechanistic information of
this sort because aryne formation is the rate-limiting step for
virtually every preparatively useful method of generating and
trapping arynes. We have recently shown21 that a valuable
protocol for probing the kinetic order of a bimolecular benzyne
trapping process involves the design and use of a substrate that
contains a suitably reactive, competing intramolecular trap that
serves as an internal clock. By determining the ratio of products
arising from the intramolecular vs bimolecular capture of the
aryne as a function of concentration of the external trapping
agent, the kinetic order of that agent in the product-
determining reaction event can be deduced.
1
Figure 5. In situ H NMR analysis of a variety of alcohol dihydrogen
1
donors. (a,b) The H NMR spectrum of the product mixture arising
from the reaction of triyne 20 with cyclooctanol (in 5-fold excess) to
give products 21, 22, and cyclooctanone (ratio = 8:1:8). The vertical
scale for each of the three cutouts of the NMR spectrum is identical.
(c) Triyne 9 was heated [85 °C for 20 h (ca. 5 half-lives)] in the
presence of 10 equiv of each of the alcohols 23a−d/f−k (2 equiv of
23e was used) in CDCl3. The product mixture was analyzed by qNMR
analysis.19 The ratio of reduction to addition products is given in
parentheses below each substrate. The principal product derived from
each of alcohols 23a−k was identified as the corresponding ketone or
aldehyde (both but-3-ynal and 2,3-butadienal observed from 23i) by
1
analysis of the H NMR spectrum of the reaction mixture (see SI for
the spectrum from each experiment).
We selected the symmetrical tetrayne 24 as the first substrate
for these kinetic studies (Figure 7). When heated alone, 24
undergoes highly efficient conversion, via an intramolecular
Diels−Alder (IMDA) reaction of benzyne8 25, to 26 as the
instead, more consistent with a simultaneous transfer of two
hydrogens (cf. 17‡−19‡, Figure 4), (iv) primary alcohols (23f−
j) are also functional H2-donors, (v) allylic or propargylic
hydrogen atoms in substrates 23h or 23i, potential participants
in ene reactions with the benzyne,8,17 do not interfere with the
H2-transfer, (vi) the ease of the H2-transfer process correlates
qualitatively with the bond strength of the carbinol C−H that is
cleaved during the redox process, and (vii) accordingly, the
poorest H2-donor is methanol (23k), the carbinol with the
strongest C−H bond. Finally, the alcohol/aryne redox process
is not limited to benzynes produced by an HDDA reaction. We
1
only product observed in the crude reaction mixture by H
NMR spectroscopy (Figure 7a). Solutions (CDCl3) containing
eight different overall concentrations of 24 and isopropanol, but
always in a 1:70 starting molar ratio, were heated to 68 °C for
18 h (ca. 5 half-lives). Again 1H NMR spectroscopy was used to
analyze the product ratio in each crude reaction mixture
(Figure 7b,c). We were surprised to see that no aryne reduction
product, i.e., 28, was detected in this experiment. This is in
contrast to observations we made for the reaction between
isopropanol and benzyne 10, for which the H2-transfer process
outpaced alcohol addition at concentrations of isopropanol up
to 2 M (see Graph S1 and Table S1 in the SI). The character of
1
have observed (in situ H NMR analysis) that o-benzyne (2)
generated by the Kobayashi protocol (o-TMSC6H4OTf + CsF
in CD3CN)18 in the presence of cyclohexanol produces a
substantial amount of benzene (see SI).
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Figure 7. (a) Kinetic competition study involving the unimolecular
IMDA reaction in benzyne 25 (to form 26) as an internal clock
reaction vs various bimolecular trapping reactions with isopropanol [to
give addition products 27a and 27b]. Tetrayne 24 was heated in
CDCl3 at 68 °C for 18 h in the presence of the indicated bulk
concentration of isopropanol; the initial ratio of reactants was [i-
PrOH]bulk/[24]0 = 70 in each experiment. (b,c) Product ratios as a
function of the concentration of isopropanol ([i-PrOH]bulk). (d)
Possible hydrogen bond interaction influencing the reaction of an
alcohol with a benzyne bearing an adjacent benzyloxymethyl group.
Figure 8. (a) Analogous kinetic competition studies using the tetrayne
30. The initial ratio of reactants was [i-PrOH]bulk/[30]0 = 70. (b) The
change in product ratios as a function of the concentration of the
isopropanol monomer. (c) Log−log plot of the product ratio vs
concentration of isopropanol monomer. The kinetic order for the
addition reaction [to give product 32a (or 32b)] vs the H2-transfer
reaction (to give 33) was ca. two vs one, respectively.
To test the hypothesis that the ether oxygen in 24 is
pertinent to the results just described, we prepared the tetrayne
30 containing an all-carbon linker in place of the benzylic ether.
When a fully analogous set of experiments was carried out with
substrate 30 (CDCl3, isopropanol, Figure 8a), competition was
again observed between the intramolecular clock reaction to
give the IMDA adduct 31 and the formation of products
derived from engagement by isopropanol (32a/b and 33). In
contrast to the observations with ether 24, we found that (i)
the redox product 33 was now formed along with 31 and 32a/
b; and (ii) the addition products 32a and 32b were always
produced in the same ratio (ca. 10:1), regardless of the
isopropanol concentration. From the plot of ln(32a/31) vs
ln[i-PrOH]mono (cf. Figure 8c, red),21 we determined (see
Graph S3 in the SI for details) that the kinetic order of
isopropanol for the alcohol addition pathway was essentially 2.
Three mechanistic interpretations for the addition of an
alcohol to a benzyne, consistent with the second-order
dependency on alcohol, are shown in Scheme 1. For simplicity,
they are represented with o-benzyne (2) to give the alkyl
phenyl ether 40. In pathway i alcohol addition occurs by a
single encounter between a preformed alcohol dimer 34 and 2
via TS structure 35‡. In pathway ii dimer 34 adds to 2 to
produce a discrete intermediate 38, having one new C−O bond
by way of a TS structure like 36‡. Adduct 38 would then
proceed to 40 by an intramolecular proton shuttling event.
Assistance of intramolecular 1,3-proton migration by an
external hydroxyl-containing molecule has been invoked in
classical tautomerization reactions (e.g., enol ⇌ ketone and 2-
hydroxypyridine ⇌ 2-pyridone). In pathway iii initial rapid and
reversible addition of the first molecule of monomeric alcohol
gives zwitterion 39 by way of TS structure 37‡. This is followed
by a coordination with a second molecule of alcohol to
intersect with intermediate 38 invoked in pathway ii. It is
noteworthy that the results from our kinetic studies are
inconsistent with an intramolecular proton transfer that would
the benzyne intermediate is likely an important influence on
this branching ratio. It is also noteworthy that the ratio of the
two regioisomeric alcohol addition products 27a and 27b was
also dependent on the bulk concentration of isopropanol
(Figure 7b). That is, a relatively larger amount of 27b was
formed at higher [i-PrOH]bulk. This observation suggests that
different mechanisms are operating during the formation of the
two regioisomeric alcohol addition products 27a and 27b. We
speculated that the benzylic ether oxygen atom may be playing
a role via a hydrogen bonding phenomenon similar to that
shown in 29 (Figure 7d), which is influencing both (i) the
proximal addition leading to 27a as well as (ii) the lack of
formation of the reduced product 28.
From a log−log plot of the ratio of the major adduct vs the
clock reaction product (Figure 7c) against the bulk alcohol
concentration21 [i.e., ln(27a/26) vs ln[i-PrOH]bulk, see blue
data in Graph S2 in SI], we found that the kinetic order of
isopropanol in the formation of 27a was 1.1, i.e., essentially
first-order. However, if we adjust the value of the isopropanol
concentration for the amount of isopropanol dimer present in
solution, for which we assume an equilibrium value of 0.35,22
and use the resulting monomer concentration ([i-PrOH]mono),
this analysis (see red data in Graph S2 in the SI) leads to an
order of 1.4 for the kinetic dependence on isopropanol.
Discussion of why we view this adjustment to be a more proper
treatment as well as a mechanistic interpretation of the
noninteger nature of the alcohol dependency are presented
later, after the discussion of Figure 8. Because the ratio of the
two alcohol addition products 27b vs 27a increased at higher [i-
PrOH]bulk, we conclude that the formation of 27b has a
different (and, in fact, higher) order of dependence on the
monomeric alcohol (see below).
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a
MeOH through some TS structure 42‡. However, we were
unsuccessful in finding a fully converged TS structure (i.e., a
species having only one imaginary frequency) for this final step,
presumably owing to a very flat potential-energy surface along
the reaction coordinate and some numerical noise associated
with nonanalytic density functional integrals determined on
necessarily finite integration grids; such situations can defeat
optimization algorithms in their search for a stationary TS
structure. Instead, we approximately identified 42‡ (Figure 9)
by manually distorting the geometry of 38 in very small
increments toward that of the requisite product and computing
the energy with restrained internal coordinates (see SI for
details). The energy increased by only 0.3 kcal·mol−1 with
respect to 38 until a final small change (0.1° in one internal
angle) resulted in exergonic collapse to product upon geometry
optimization. This approach has been used to identify
approximate TS structures for processes for which optimization
algorithms fail to converge to stationary points.25
Scheme 1
An alternative reaction pathway involving dimer 34 (i.e., i;
blue) invokes its concerted addition to 2. The requisite TS
structure 35‡ shows the highest free energy (9.7 kcal·mol−1) for
the rate limiting step of any of the four pathways. In summary,
although it is prudent not to place excessive weight on the
merit of computed energetics for reactions having activation
barriers that vary by only a few kcal·mol−1, it is encouraging
that the results of this study are in concert with a lowest-energy
process that involves two molecules of methanol prior to its
rate-limiting event.
In contrast to the second order dependency on alcohol for
the addition process, we have observed that the molecularity for
the H2-transfer to produce the benzenoid 33 is approximately
one (1.2). The data are presented as a plot of ln(33/31) vs ln[i-
PrOH]mono in Figure 8c. This result is consistent with the TS
structures 17‡−19‡ discussed earlier (Figure 4). The first-order
nature of the H2-transfer is also consistent with the observation
that formation of the hydrogenation product is favored at lower
alcohol concentration and the addition product at higher
concentration (cf. Figure 2).26
Briefly let us return to the issue of the mixed-order
dependence observed for the addition of isopropanol to
benzyne 25 to give 27a (Figure 7a). As mentioned, using the
free monomer concentration of isopropanol and plotting
ln(27a/26) vs ln[i-PrOH]mono (see Graph S2 in the SI) leads
to the value of 1.4 for the kinetic order of isopropanol. We
suggest that the deviation of this value from a whole integer
may be indicative of two competing mechanisms for formation
of 27a. At high concentration of alcohol, the reaction is
dominated by a pathway analogous to one of those in Scheme
1. At low concentration, the hydrogen bonding effect of the
benzyl ether oxygen permits a pathway that is first-order in
alcohol, one that, in fact, supersedes the reduction event that
otherwise ensues for the other benzyne substrates.
a
Three possible mechanistic interpretations (pathways i−iii) that
would show second order dependence on alcohol concentration for
alcohol addition, portrayed here simply for ROH trapping of o-
benzyne (2). Pathway iv would show first order dependence on
[ROH].
convert 39 directly to 40 (pathway iv) because this would show
a simple first-order dependency on the alcohol concentration.
Additionally, any of these mechanisms could explain the
contrasting reactivity of neutral tert-butanol vs tert-butoxide
presented in Figure 1a.
We have examined the reaction pathways i−iv computation-
ally for the simple case of methanol (23k) addition to o-
benzyne (2) (Figure 9). For each of the four pathways, the level
of the highest energy TS structure and rate-determining step is
shown in color. The relative zero of free energy corresponds to
an isolated o-benzyne and a methanol dimer (all species in
Figure 9 include continuum methanol solvation). The stoichio-
metrically equivalent combination of o-benzyne and two
isolated methanol monomers was found to be 0.8 kcal·mol−1
higher in free energy.
The addition of methanol monomer (23k) to 2 to produce
the zwitterion 39 is a step common to both pathways iii and iv
(green/magenta). The associated TS structure 37‡ was found
to have a relative free energy of 8.3 kcal·mol−1. The subsequent,
low barrier, unimolecular proton transfer within 39 via 41‡ was
suggestive of rapid conversion to product 40 to complete
pathway iv, the reaction that would be first order in alcohol
concentration.23 Alternatively, we envision that 39 could
coordinate a second molecule of methanol24 to produce 38
by another presumably very low barrier process merely
involving hydrogen bond formation (a librational motion in
neat alcohol or a solvent-shell exchange reaction in a mixed
Finally, we mention some anecdotal information that is
relevant to and consistent with the mechanistic picture that has
emerged here for this alcohol addition process. Throughout our
studies of the HDDA reaction we have observed that the
dryness of the solvent system does not noticeably influence the
outcome of the reaction. Moreover, our attempts to directly
add water using mixed aqueous organic solvent systems (e.g.,
1,4-dioxane) have led to low amounts of the phenolic products.
It seems reasonable to think that water addition to a benzyne
would follow an analogous mechanism to that of alcohol
addition. A TS structure analogous to 35‡ or 36‡ (Scheme 1)
̀
solvent). Knowing the relative ease of that event vis-a-vis that
passing through 41‡ is somewhat moot, however, since (i)
irrespective of the barrier, a path to product having first-order
dependence on methanol would be available, and, more
importantly, (ii) TS structure 37‡ (green/magenta) is not
associated with the overall lowest energy pathway in Figure 9.
The most favored computed pathway is ii (red), the stepwise
addition of the methanol dimer (34) to 2. This proceeds
through the TS structure 36‡ having a relative free energy of 7.3
kcal·mol−1. The resulting adduct 38 was located as a minimum
and would be expected to proceed rapidly to product 40·
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Figure 9. DFT calculations were performed using M06-2X/6-311+G(d,p) and the SMD solvation model (MeOH). Standard state corrections (gas
phase to 1 M solution) were applied to all structures and the concentration of methanol was adjusted to 24.7 M (neat methanol). All values are of
the free energies in kcal·mol−1. Minima and TS structures of species in which one vs two methanol molecules have engaged o-benzyne (2) are shown
in panels (a) vs (b), respectively. The curved dashed lines represent low barrier processes in which a new hydrogen bond to methanol is being
formed to convert a species in panel (a) to one in panel (b). (c) A 3D view of the geometry of each of the five TS structures; the dashed lines in each
represent atom pairs between which bond order is increasing in the forward reaction direction.
but where R = H would then be operative. A relatively rarely
invoked fundamental difference between water and alcohols is
the relative strength of the O−H bond. The dissociation energy
of the water molecule is 119 kcal·mol−1, which stands in stark
contrast to the D(RO−H) = 104−107 kcal·mol−1 for virtually
all aliphatic alcohols.27 It follows, then, that a mechanism
involving multiple partial O−H bond cleavages, as is the case
for either 35‡ or 36‡, would be expected to be slower for water
than for an alcohol because of this difference in O−H bond
strengths.
the H2-transfer reaction proceeds via a Cannizzaro-type
mechanism in which the carbinol C−H adds to the benzyne
in hydride-like and the O−H in proton-like fashion. Through
kinetic studies we determined that this redox reaction is first
order in the alcohol H2-donor. This is consistent with the
notion of concerted, albeit asynchronous, transfer of
dihydrogen. In contrast, we have found that the formation of
ether product(s) from the addition of alcohol to benzynes is
second-order in alcohol. This previously unrecognized
mechanistic pathway has been investigated and supported by
DFT computations. Among other things it provides insight into
why water adds to benzynes only poorly, which happens to be a
significant practical advantage in the study and use of (HDDA-
derived) benzynes. The use of an internal clock reaction to
uncover kinetic information about the product-forming, post-
rate-determining steps in aryne trapping reactions21 is power-
fully demonstrated. The fundamental insights to emerge are
potentially valuable beyond the realm of aryne chemistry itself.
Finally, aspects of these studies highlight the importance of the
SUMMARY
■
We have explored various mechanistic aspects of the reactions
between benzynes and nontertiary alcohols. Competing
addition and H2-transfer processes are seen, the latter
constituting an unusual redox process. The branching ratio
between these pathways is dependent on the concentration of
trapping alcohol. Deuterium labeling studies in conjunction
with computational investigations have provided evidence that
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polarizability of arynes in response to their encounter with
various trapping agents, thereby contributing to the tremen-
dous versatility of arynes as reactive intermediates.
(8) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P.
Nature 2012, 490, 208−212.
ASSOCIATED CONTENT
* Supporting Information
■
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(12) We performed an entirely analogous experiment with 2,2,7,7-
tetradeuterocycloheptanol and observed entirely analogous results; no
deuterated benzenoid product 14 nor 2,2,7-trideuterocycloheptanone
was observed.
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chair-flipped form of the cyclohexanol for each of the two modes of
hydride-like addition to C3 and C4 (see SI for details).
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(22) (a) Alcohols are known to form aggregates in chlorinated
solvents.22b The enthalpy and entropy change associated with
dimerization of monomeric isopropanol in CCl4 has been
determined.22c Assuming that these values would be similar to those
for dimerization in CDCl3, we estimated the equilibrium constant for
the dimerization [i.e., i-PrOH(monomer) + i-PrOH(monomer) × i-
PrOH(dimer)] at 68 °C to be 0.35 (ΔG° = +0.95 kcal·mol−1); that is,
[i-PrOH]dimer = 0.35·{[i-PrOH]mono}2. (b) Pimentel, G. C.; McClellan,
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(23) (a) The possibility of a direct, single-step, O−H insertion
mechanism23b to produce anisole directly from methanol and o-
benzyne (not shown) was considered. Numerous attempts to locate a
TS structure were unsuccessful. (b) Im, G.-Y. J.; Bronner, S. M.;
Goetz, A. E.; Paton, R. S.; Cheong, P. H.-Y.; Houk, K. N.; Garg, N. K.
J. Am. Chem. Soc. 2010, 132, 17933−17944.
S
Experimental procedures for preparation of all new com-
pounds; characterization data for all new compounds;
description of computational methodologies; geometries and
energies of species shown in Figures 4 and 9; copies of 1H and
13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
hoye@umn.edu
■
Present Addresses
†Department of Chemistry, Ripon College, Ripon, Wisconsin
54971, United States.
‡Department of Chemistry, Massachusetts Institute of Tech-
nology, Cambridge, Massachusetts 02139, United States.
Author Contributions
§P.H.W. and D.N. contributed equally to the design, execution,
and interpretation of the experiments and results.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.H.W., T.W., D.N., and M.K.H. acknowledge the support of a
National Science Foundation Graduate Research Fellowship, a
Wayland E. Noland Fellowship, a University of Minnesota
Graduate School Doctoral Dissertation Fellowship, and a
Heisig-Gleysteen Fellowship, respectively. Suggestions and
interest from Professor Joseph D. Scanlon are acknowledged
with appreciation. Portions of this work were performed with
hardware and software resources available through the
University of Minnesota Supercomputing Institute (MSI).
Financial support for the research was provided by the General
Medical Institute of the National Institutes of Health
(GM65597).
REFERENCES
■
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(26) To provide direct comparison, we have computed the gas-phase
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monomeric methanol addition (pathway iv) reactions between
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methanol and o-benzyne at the M06-2X/6-311+G(d,p) level. The
ΔΔG‡ for the two processes is predicted to be 0.0 kcal·mol−1 (see SI
and cf. the data for entry 23k in Figure 5c). In addition, we have
compared these same two processes using a chloroform solvation
model (IEFPCM, M06-2X/aug-cc-pVTZ) to approximate the
competition reactions at low alcohol concentration, which were
always performed in CHCl3 or CDCl3. The solvated ΔΔG‡ is
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