C-H functionalization of sp3centers with aluminum: A computational and mechanistic study of the baddeley reaction of decalin

Article abstract of DOI:10.1021/ja5062246

Decalin undergoes reaction with aluminum trichloride and acetyl chloride to form a tricyclic enol ether in good yield, as first reported by Baddeley. This eye-catching transformation, which may be considered to be an aliphatic Friedel-Crafts reaction, has not previously been studied mechanistically. Here we report experimental and computational studies to elucidate the mechanism of this reaction. We give supporting evidence for the proposition that, in the absence of unsaturation, an acylium ion acts as a hydride acceptor, forming a tertiary carbocation. Loss of a proton introduces an alkene, which reacts with a further acylium ion. A concerted 1,2-hydride shift/oxonium formation, followed by elimination, leads to formation of the observed product.

Full text of DOI:10.1021/ja5062246

Article
pubs.acs.org/JACS
C−H Functionalization of sp3 Centers with Aluminum: A
Computational and Mechanistic Study of the Baddeley Reaction of
Decalin
Catherine L. Lyall,† Makoto Sato,‡ Mario Uosis-Martin,† Syeda Farina Asghar,†,§ Matthew D. Jones,†
Ian H. Williams,*,† and Simon E. Lewis*,†
†Department of Chemistry, University of Bath, Bath, U.K. BA2 7AY
‡Department of Chemistry, Rikkyo University, Toshima-ku, Tokyo 171-8501, Japan
§Department of Chemistry, University of Azad Jammu & Kashmir, Muzaffarabad, 13100 Azad Jammu & Kashmir, Pakistan
S
* Supporting Information
ABSTRACT: Decalin undergoes reaction with aluminum
trichloride and acetyl chloride to form a tricyclic enol ether
in good yield, as first reported by Baddeley. This eye-catching
transformation, which may be considered to be an aliphatic
Friedel−Crafts reaction, has not previously been studied
mechanistically. Here we report experimental and computa-
tional studies to elucidate the mechanism of this reaction. We
give supporting evidence for the proposition that, in the
absence of unsaturation, an acylium ion acts as a hydride
acceptor, forming a tertiary carbocation. Loss of a proton
introduces an alkene, which reacts with a further acylium ion. A concerted 1,2-hydride shift/oxonium formation, followed by
elimination, leads to formation of the observed product.
successfully. However, use of expensive catalysts/reagents is
not practicable in this case, as the C−H functionalization of a
saturated hydrocarbon will most likely be the first step of a
synthetic sequence, and therefore will likely be carried out on a
large scale. As such, the cost of the reagents for C−H
functionalization and also of the substrate itself are paramount
if the transformation is to be synthetically useful.
A standout example of a transformation in this second
category is the work of Baddeley et al. on the reaction of decalin
with aluminum trichloride and acetyl chloride.8 Using an excess
of AlCl3, multiple products are observed8a,c (Scheme 1a), but
using an excess of AcCl (at a lower temperature) leads cleanly
to formation of tricyclic enol ether 68b−f (Scheme 1b).
This transformation can be considered to be an aliphatic
Friedel−Crafts acylation, which is not without precedent: such
reactions have been reported for other simple, unfunctionalized
alkanes.9 (It should be noted that Friedel−Crafts acylations of
several alkenes are also known.10) The products arising from
these transformations have been deployed for synthesis, and the
area has been reviewed.11 Most recently, we have demonstrated
the applicability of the Baddeley reaction to a range of
bicycloalkyls and bicyclo[x.y.0]alkanes (Scheme 2).12
INTRODUCTION
■
The Friedel−Crafts reaction1 is one of the first aromatic
transformations students encounter, often in their preuniversity
education. It can be considered the archetypal C−H
functionalization reaction and is ubiquitous in organic syn-
thesis.2 It remains a focus of much current research, with
particular activity devoted to the development of asymmetric
variants.3
C−H functionalization more broadly is a rapidly expanding
field4 because, unlike traditional functional group interconver-
sions, C−H activation is a conceptually distinct approach
wherein functionality is introduced at locations where none was
present beforehand. Such methodology permits the use of
entirely new strategies to effect complex molecule synthesis.5
Uses of C−H functionalization in synthesis can be
subcategorized as either reactions performed on substrates
with extensive existing functionality or reactions carried out on
substrates having little or no functionality whatsoever. In the
first category, the presence of pre-existing functionality
necessitates that the C−H functionalization methodology
used displays wide functional group tolerance; regio- and
chemoselectivity are also prerequisites. Thus, not all reported
methodologies are applicable.6 “Late stage” C−H functionaliza-
tions of this type most typically employ expensive or hard-to-
access transition metal-based catalysts,7 although the value of
the final products so accessed justifies this approach.5c On the
other hand, in the second category, the lack of functionality
allows for a wider range of methodologies to be used
Of these various examples, the transformation of decalin is
particularly appealing in the context of C−H functionalization
for several reasons. The product is formed in acceptable yield
Received: June 20, 2014
© XXXX American Chemical Society
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Scheme 1. C−H Functionalization of Decalin with
Aluminum Trichloride and Acetyl Chloride
Scheme 3. Additional Byproducts Identified from the
Baddeley Reaction
Additionally, hydroxyketone 15, previously reported to be
formed from 6 upon treatment with sulfuric acid, was identified
as another product of the reaction.8b,13e However, as seen by
Baddeley,5b 15 is observed to equilibrate with 6 upon heating.
Another side-product was identified as 1-chloroethyl acetate 16,
which is formed from acetaldehyde (vide infra).
Mechanistic Proposals. The original proposal by Baddeley
Scheme 2. Selected Applications of the Baddeley Reaction
and co-workers8b involved the dehydrogenation of decalin to
Δ
9,10-octalin 17, followed by formation of a tricyclic oxonium
intermediate (18, Scheme 4). This intermediate, possessing two
Scheme 4. Mechanisms Proposed in the Literature for the
Baddeley Reaction
(30−46%),8c and the substrate and reagents are of very low
cost. In addition, enol ether 6 boils at a temperature
significantly different from those of unreacted decalin (which
comprises most of the mass balance) and any byproducts.
Therefore, large-scale purification of 6 by distillation is possible;
we have prepared it on a ∼100 g scale. The enol ether is
especially valuable as a building block for synthesis by virtue of
the fact that it has been selectively functionalized at C1 and
C10there is a dearth of other methods in the literature for
accessing this substitution pattern of decalin in a concise
fashion. Indeed, 6 has seen diverse uses, from synthesis of
potential antiviral agents to natural products.13 More generally,
functionalized decalins are crucial building blocks for
terpenoid14 and steroid15 natural products and are also of key
importance in the fragrance industry.16 Other examples of the
functionalization of decalin with AlCl3 include the use of
benzenesulfonyl chloride to form several monosubstituted
chlorodecalins.17
sp2 hybridized atoms in a four-membered ring, would be rather
strained. Over 30 years later, Santelli and co-workers9m were
the first to posit a mechanism that did not include such a
strained intermediate, instead invoking a carbocation inter-
mediate 20, which cyclizes by means of a [1,2]-hydride shift
(Scheme 4).
Our mechanistic proposal (Scheme 5), which we have
disclosed previously,12 is a variant of the proposals in Scheme 4.
The acylating agent initially acts as a hydride sink (such
reactivity is precedented11), because, at the outset of the
reaction, there is no unsaturation present. Thus, hydride
abstraction leads to the formation of a tertiary cation at the ring
RESULTS AND DISCUSSION
■
Experimental Aspects. Upon replication of the Baddeley
reaction, in addition to the originally reported products (enol
ether 6 and trans-decalin), we were also able to isolate and
identify additional products (Scheme 3). The chloroketone 14
is known to be formed from 6 upon treatment with
hydrochloric acid, and we have found that it is in fact also
formed as a minor product in the Baddeley reaction itself.8b
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the 1H NMR spectrum (Figure 1, shown in red), a comparable
shift to similar compounds in the literature.19 Such deshielding
Scheme 5. Our Mechanistic Proposal for the Baddeley
Reaction
Figure 1. 1H NMR spectrum of the Baddeley reaction prior to
workup, with chlorotrimethylsilane standard (400 MHz, 273 K,
CD2Cl2).
of Ha can only be accounted for by its proximity to the
positively charged oxygen in 19. In contrast, in neutral species
21, Ha would not be so far downfield, and no other proton
environment would be so deshielded. Thus, we have excluded
Santelli’s proposal. Additionally, we have excluded Baddeley’s
proposal on the basis of computational data (vide infra).
Hydride Abstraction. In the original report, Baddeley made
no comment on the isomeric composition of the decalin
starting material, save that it was of technical grade. Such a
grade would be expected to consist of a mixture of the cis and
trans isomers. It has previously been reported that cis-decalin
was the only reactive isomer, as trans-decalin was recovered
unreacted.9m (Also of note, functionalization of decalin with
AlCl3 and benzenesulfonyl chloride proceeded only with cis-
decalin.17) However, in our hands the Baddeley reaction of
pure trans-decalin did in fact yield some enol ether, 6, albeit in a
poorer yield, 0.9%, as well as the chloroketone 14 in 3.6% yield.
The trans-decalin recovered from this reaction, depleted of any
trace of cis-decalin that may have been present, was resubmitted
to the reaction conditions, and the same result was obtained.
Pure cis-decalin gave the enol ether, 6, in 27% yield and
recovered starting material in 31% yield (10% of 14 was also
isolated). Crucially, the recovered decalin was entirely the trans
isomer. Thus, it can be concluded that, when performing the
Baddeley reaction on a mixture of decalin isomers, although cis-
decalin is undisputedly more reactive, the recovered trans-
decalin is both unreacted trans-decalin and isomerized cis-
decalin. Indeed, under other reaction conditions it has been
shown that AlCl3 alone can isomerize cis-decalin into trans-
decalin.20
junction, 22. Deprotonation gives Δ9,10-octalin 17. Another
equivalent of acylium ion is then able to react with the newly
formed unsaturation, affording acyl cation 23. Discounting
formation of a 4-membered ring, we propose instead the [1,2]-
hydride shift and attack of the oxygen at the position α- to the
ring junction, as per Santelli’s proposal. Crucially, these two
events may be concerted or stepwise. The concerted process is
represented by the direct transformation of 23 into 19 (red and
blue arrows). Alternatively, a stepwise process can also be
envisaged whereby a [1,2]-hydride shift of 23 gives isomeric
cation 24 (red arrow only), followed by nucleophilic attack of
the carbonyl oxygen as a separate step (green arrow) to give 19.
The stepwise process may seem less likely, given that it involves
the transformation of a tertiary cation (23) into a secondary
one (24). However, it should be noted that in 24 the positive
charge is further from the electron-withdrawing carbonyl and
the ring junction carbon is no longer planar, thus allowing for
alteration of the conformation of the bicyclic system. Thus, this
mechanism was not dismissed out of hand, and a key aspect of
this current work was to determine whether this process is
indeed concerted (vide infra). Finally only on workup does the
final deprotonation of 19 occur to give enol ether 6. Overall,
our proposal varies from Santelli’s in that 23 and 19 comprise
an sp2 carbon (Santelli proposes the same carbon to be sp3 with
a bond to a chlorine, cf. 20 and 21).
We justify the variance from Santelli’s proposal as follows.
Various studies have confirmed the formation of free acylium
ion from AcCl/AlCl3 under various conditions.18 For this
reason, we have invoked a free acylium ion as the reactive
species that reacts with Δ9,10-octalin 17. The product of this
reaction would be 23 (i.e., with an sp2 carbonyl carbon and no
chlorine incorporated), not 20. It is conceivable that 20 could
then be formed from 23, but this would necessitate
intermolecular transfer of a chloride anion from the highly
stable [AlCl4]− anion, as opposed to intramolecular direct
cyclization of 23 to 19. More conclusively, in situ reaction
monitoring by NMR spectroscopy unambiguously shows the
presence of cyclized oxonium 19 prior to workup: the
diagnostic proton Ha (Scheme 5) resonates at 6.08 ppm in
Experimental investigations to determine the mechanism of
the reaction initially focused on the hydride abstraction from
the tertiary position of decalin. Reacting AlCl3with a mixture of
cis- and trans-decalin in 1,2-dichloroethane yielded pure trans-
decalin, indicating AlCl3 is capable of acting as a hydride
abstractor toward cis-decalin under our reaction conditions.
However, it should be considered that, in the Baddeley
reaction, the optimized conditions employ 1.5 and 2.4 equiv of
AlCl3 and AcCl, respectively, premixed. In reacting these
reagents together prior to addition of the decalin, the formation
of the “ate” complex inhibits the ability of AlCl3 to act as a
hydride abstractor, as [AlCl3] is very low.
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Reaction of AcCl with AlCl3 also generates the acylium
cation (Ac+), which could plausibly be considered as the
hydride abstractor; such a reaction would yield acetaldehyde
(cf. Scheme 5). However, in fact no acetaldehyde is observed
(in 1H and 13C NMR spectra of the unpurified products). This
could be attributed to its volatility, but we also entertained the
possibility that the acetaldehyde formed in the reaction
undergoes further transformation. To probe this, we subjected
acetaldehyde to reaction conditions comparable to those
present in the original reaction mixture after acetaldehyde
had been formed (i.e., 1 equiv of AlCl3 and AcCl have already
been consumed), but omitting the decalin. As shown in Scheme
6, this led to formation of 1-chloroethyl acetate 16, which we
in the aliphatic region of the proton NMR spectra, it was not
possible to observe directly the consumption of cis-decalin. In
lieu of this, it was possible to follow the growth of resonances
representing both the cyclized oxonium, 19 (an effective
surrogate for the final product 6), and also the 1-chloroethyl
1
acetate byproduct, 16. A representative H NMR spectrum
recorded is reproduced in Figure 1, with the species of interest
and their relevant protons highlighted next to their key
diagnostic resonances.
The initial rates of reaction could be determined for various
concentrations of cis-decalin and of the preformed AlCl3·AcCl
complex. In all reactions the ratio of AcCl to AlCl3 was
maintained at 1.6:1.0 (as per Baddeley’s original procedure)
because alteration of this ratio has been shown to result in
product variation (vide supra, Scheme 1a). Figure 2 shows plots
Scheme 6. Control Reaction: Formation of 1-Chloroethyl
Acetate 16
had previously observed in the crude reaction mixture (cf.
Scheme 3). Thus, the ultimate fate of at least some of the
abstracted hydrides is to be incorporated into 16. This pathway
also accounts for the consumption to up to 1 equiv of AcCl in a
nonproductive fashion and somewhat rationalizes the fact that
the yield for the reaction never approaches quantitative.
(Because 2 equiv of AcCl are needed for formation of 6, and
because only 2.4 equiv of AcCl are in fact used, it is the case
that formation of >0.4 equiv of 16 would leave insufficient AcCl
for quantitative formation of 6.) It follows that an increase in
the equivalents of AcCl could lead to an increase in conversion
to product; we have observed this indeed to be the case (Figure
S10, Supporting Information). It should be noted that the
reaction of acetaldehyde and AcCl to form 1-chloroethyl
acetate has been reported before, mediated by zinc chloride in
substoichiometric quantities.21
Performing the Baddeley reaction with decanoyl chloride
instead of AcCl led to the observation of the nonvolatile
aldehyde decanal 27 in the 1H NMR spectrum of the distillate,
as well as peaks indicative of enol ether 25 and chloroester 26
(Scheme 7). From these investigations it is inferred that Ac+ is
both abstracting and retaining the hydride originating from the
decalin ring junction.
Figure 2. (A) Concentration of cyclized oxonium, 19, vs time with
varying initial concentrations of cis-decalin. (B) Concentration of
cyclized oxonium, 19, vs time with varying initial concentrations of
1.6AcCl·1.0AlCl3.
of concentration of cyclized oxonium 19 against time for the
initial period of the reaction. The observed rate law may be
expressed as eq 1, which, upon taking logarithms of both sides,
yields eq 2. According to the method of initial rates, the kinetic
order x with respect to decalin is obtained as the slope of a plot
(see Supporting information) of ln(rate0) against the natural
logarithm of the initial decalin concentration for a constant
value of the initial AlCl3·AcCl complex concentration; the initial
rates, rate0, are the slopes of the plots shown in Figure 2A.
Similarly, the kinetic order y with respect to the AlCl3·AcCl
complex is obtained as the slope of a plot of ln(rate0) against
the natural logarithm of the initial AlCl3·AcCl complex
concentration for a constant value of the initial decalin
concentration; the initial rates are the slopes of the plots
shown in Figure 2B.
Scheme 7. Use of a Long-Chain Acyl Chloride Allows Direct
Observation of the Aldehyde By-product 27
x
y
rate0 ∝ [decalin]0 [1.6AcCl·1.0AlCl3]0
Kinetic Experiments. With the intention of establishing the
order of reaction in both cis-decalin and the acylating complex,
a set of reactions were undertaken by varying the starting
concentrations of cis-decalin and subsequently the starting
concentrations of the AlCl3·AcCl complex. These reactions
were performed in an NMR tube at 273 K with a trimethylsilyl
chloride standard. Unfortunately, due to the overlapping peaks
(1)
ln(rate ) = xln([decalin]0) + y ln([1.6AcCl·1.0AlCl3]0)
0
(2)
+ c
The experimentally determined order of reaction in cis-decalin
was 0.9 0.1, indicative of the reaction being first order in cis-
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decalin. The experimentally determined order of reaction in the
AlCl3·AcCl mixture was 1.3 0.1. This result is indicative of
the reaction being greater than first order in the ionic complex
generated from AcCl and AlCl3, which can be explained by the
possibility of more than one rate-limiting step.
The experimentally observed difference in reactivity between
cis-decalin and trans-decalin implies that the initial hydride
abstraction is at least partly rate-limiting. If it were wholly rate-
limiting, the reaction would obey first-order kinetics with
respect to the AlCl3·AcCl mixture. However, a noninteger order
>1 suggests another step in the reaction mechanism is also
partially determining the reaction rate, and this step involves
another molecule of acylating reagent. The other step involving
an additional molecule of acylating reagent is nucleophilic
attack on an acylium ion by the Δ9,10 -octalin, 17, affording 23.
Computational results discussed later show that this is likely to
be the case.
Intermediacy of Octalin. The focus of our experimental
investigations then turned toward the proposed alkene
intermediate, Δ9,10-octalin 17. Subsequent to abstraction of a
hydride from the tertiary position of 1, two pathways for
deprotonation can be envisaged: loss of a proton from the other
tertiary position, giving 17, or from an adjacent secondary
position, giving the isomeric Δ1,9-octalin. Our previous studies
have determined that formation of 17 is favored.12
It follows from our proposed mechanism that subjecting 17
to the Baddeley reaction conditions would furnish the same
products as seen in the reaction of decalin itself. As the hydride
abstraction step would not occur, fewer equivalents of AcCl and
AlCl3 would be required. We found that reaction of 17 (readily
prepared by literature procedures22,23) with 1 equiv of AlCl3
and AcCl formed 6 in 32% yield as well as 14 in 5% yield
(Scheme 8). This finding is strongly supportive of the
intermediacy of 17 in the formation of 6 from decalin 1.
discussion, it is only necessary to consider relative energies
within the encounter complexes in solution.
The first phase of the reaction (hydride transfer and proton
transfer), which consumes the first equivalent of Ac+, is shown
in black on the left-hand side of Figure 3. The second phase
(addition and cyclization), which consumes the second
equivalent of Ac+, is shown in blue on the right-hand side of
Figure 3. Note that, relative to octalin (D2 +conformation; see
Supporting Information) + Ac+ + AcH2 + 2AlCl4 , the
−
transition structures (TS) TS-HT (+ Ac+ + 2AlCl4 ) and TS-
−
+
−
CYC (+ AcH2 + 2AlCl4 ) have essentially the same Gibbs
energy, suggesting that at 298.15 K and 1 atm both would be
kinetically significant.
Hydride Abstraction and Alkene Formation. The MP2/6-
31+G* Gibbs energy profiles for hydride abstraction in CH2Cl2
by Ac+ from cis-decalin (black) and trans-decalin (red) are
shown in Figure 4. Although, of course, the lowest energy
chair/chair conformer of trans-decalin is ∼14 kJ mol−1 lower
than that of cis-decalin, the transition structure cis-TS-HT for
hydride transfer from the latter is ∼5 kJ mol−1 lower than that
from trans-decalin, trans-TS-HT, and the resulting difference of
19 kJ mol−1 between the Gibbs energy barriers (54 and 73 kJ
mol−1, respectively) corresponds to a factor of about 5000 in
relative reactivity at 0 °C.
The imaginary frequency corresponding to the transition
vector (“reaction-coordinate vibrational mode”) is i472 and
i414 cm−1, respectively, in the cis- and trans-TSs, and the atomic
displacements in this normal coordinate are dominated by
hydride transfer and the angle bending associated with
rehybridization of the donor and acceptor carbons, Cd and
Ca. The angle CdH′Ca is much less bent (176°) in the trans-TS
than in the cis-TS (155°), probably owing to greater steric
interactions, and the Pauling bond order24 for the breaking
CdH′ bond in the trans-TS is slightly lower (0.45 vs 0.50) than
that in the cis-TS. The sum of the breaking CdH′ and making
H′Ca bond lengths in each TS is entirely typical of hydride-
transfer reactions.25
Scheme 8. Experimental Evidence Supporting the
Intermediacy of 17
The complex between AcH and decalinyl cation 22 is a stable
intermediate that has several readily interconvertible con-
formers. Relative rotation of these components is a prerequisite
for proton transfer via transition structure TS-PT for formation
+
of Δ9,10-octalin 17 and AcH2 . The potential energy surface for
proton transfer is very flat: the Gibbs energy of the transition
structure for deprotonation of the lower-energy C2-symmetric
decalinyl cation is apparently also lower than that of either the
reactant or product complex that precede and follow it,
respectively, along the proton transfer reaction path,26 and it is
∼10 kJ mol−1 lower than the TS for deprotonation of the Cs-
symmetric conformer.
Computational. Gibbs Energy Profile. Figure 3 shows the
overall Gibbs energy profile for the Baddeley reaction of cis-
decalin. Relative energies (kJ mol−1, sums of single-point MP2/
cc-PVTZ electronic and optimized MP2/6-31+G* thermal free
energies with solvation treated by the polarized continuum
model (PCM); see Supporting Information for details) are
shown with respect to (separated) Δ9,10-octalin 17 and
We have also investigated proton transfer from the decalinyl
−
cation to AlCl4 as base and have located the corresponding
reaction paths and TSs (see Supporting Information).
However, with the method of calculation employed, the
relative basicity of AcH is found to be ∼18 kJ mol−1 greater
+
protonated acetaldehyde (AcH2 ), which are the common
products of reaction of both isomers of decalin. With this
−
method of calculation (at 298.15 K, 1 atm), formation of Ac+
than that of AlCl4 , meaning that formation of octalin + AlCl4H
−
and AlCl4 from AcCl and AlCl3 is favorable by 89 kJ mol−1
is endoergic. Whichever species serves as the base, deprotona-
tion is in no way rate-limiting.
and 2 equiv of Ac+ are required to complete the full reaction.
Addition, Cyclization, and Enol Ether Formation. There
are two low-energy conformers of Δ9,10-octalin 17: the C2h-
symmetric conformer is 3 kJ mol−1 higher than the D2
conformer, and there is a Gibbs energy barrier of 23 kJ
mol−1 for conversion of the former to the latter. Similarly, the
complex of Ac+ with the D2 octalin conformer is ∼4 kJ mol−1
The starting point (left-hand end) of the profile therefore
involves cis-decalin + 2Ac+ + 2AlCl4 , and the finishing point
−
−
(right-hand end) involves PC-CYC (19) + AcH2+ + 2AlCl4 .
Note that the acid−base neutralization AcH2+ + AlCl4− → AcH
+ AlCl3 + HCl is unfavorable by 74 kJ mol−1 with the MP2/cc-
pVTZ//MP2/6-31+G* method. For the purposes of this
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Figure 3. MP2/cc-pVTZ//MP2/6-31+G* Gibbs energy profiles in PCM CH2Cl2 for overall reaction from cis-decalin. Relative energies are in kJ
mol−1. Boxed red numbers correspond to species in Scheme 5.
separated components; more significantly, the TS for its
formation is lower: 39 vs 44 kJ mol−1.
The acyl moiety in the C2h octalin-derived adduct PC-AD
(23) adopts an orientation that is essentially symmetrical with
respect to both fused chair-cyclohexyl rings, but the lowest-
energy pathway for cyclization begins with a conformational
change of one of these rings (right-hand side as shown in
Figure 5) from chair to twist-boat in the reactant complex RC-
CYC, which is another local minimum. Figure 5 shows both the
relative Gibbs energies (black) for RC-CYC, TS-CYC, and the
protonated enol ether product PC-CYC (19) and the potential
energy profiles (blue) along the forward and reverse segments
of the intrinsic reaction coordinate (IRC) path in each direction
from the TS. The structural changes occurring along the entire
IRC path show that the transformation, although concerted, is
highly asynchronous. The initial phase from RC-CYC toward
TC-CYC (bottom-left of Figure 5; note the expanded energy
scale) continues the conformational change in the right-hand
ring (as drawn) toward a half-chair conformation in which
carbon atoms 1, 9, 10, and 4 are almost coplanar. Then the
hydride shift from C4 (donor) to C10 (acceptor) occurs, trans
to the acyl group, which does not participate in the motion. At
the start of this intramolecular hydride transfer, both the bond
angle C10C4H′ and the dihedral angle between these atoms
and C9 are essentially 90°. In TS-CYC the C4H′ and H′C10
bond lengths (respectively, 1.54 and 1.20 Å) are again entirely
typical of an asymmetric hydride transfer, and the angle
C4H′C10 is only 59°; the distance between the oxygen atom
and C1 diminishes very little from its value in RC-CYC and
corresponds to a Pauling bond order of only ∼0.1 in the TS.
The imaginary frequency corresponding to the transition vector
is i388 cm−1, and the atomic displacements in this normal
coordinate are dominated by hydride transfer and the angle
bending associated with rehybridization of the donor and
acceptor carbons. Once the TS is passed, then the final phase of
the transformation takes place: the O···C4 distance becomes
shorter and the ring conformation changes toward the slightly
distorted chair found in the cyclized product PC-CYC.
Figure 4. MP2/cc-pVTZ//MP2/6-31+G* Gibbs energy profiles in
PCM CH2Cl2 for hydride abstraction from cis- and trans-decalin. Bond
lengths are in Å, and angles in degrees. Energies are relative to
separated CH3CHOH+ and octalin 17.
lower than that with the C2h conformer, but each complex lies
at least 30 kJ mol−1 above the separated reactants. The
reactivity of the octalin intermediate should not depend on
whether it was formed under the experimental conditions from
either cis- or trans-decalin.
Addition of Ac+ to octalin 17 gives a covalent adduct 23 (
PC-CYC) that then undergoes cyclization accompanied by a
[1,2]-hydride shift. The adduct derived from the C2h octalin
conformer has a slightly longer CC bond (1.57 vs 1.54 Å)
between the two species than the D2 conformer, but it also has
a lower Gibbs energy (23 vs 28 kJ mol−1) relative to the
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finding only TS-CYC, which interconnects RC-CYC with PC-
CYC; it seems that 18 is a cul de sac in the mechanistic scheme.
With respect to the octalin intermediate 17, the lowest Gibbs
energy barriers for the forward reaction (56 kJ mol−1 to enol
ether 6) and the reverse reaction (55 kJ mol−1 to decalin 1)
involve similar Gibbs energy barriers. Although each of these
calculated energy barriers may be subject to an uncertainty of
perhaps several kJ mol−1, nonetheless this computational
observation implies that under experimental conditions the
initial hydride abstraction from decalin may not be entirely rate-
limiting. Cyclization of the octalin−acylium adduct is at least
partially rate-limiting and offers a potential branching point in
the mechanism in competition with formation of the 1-
chloroethyl acetate byproduct. This computational result is in
agreement with the kinetic data presented above.
CONCLUSIONS
■
We have presented a mechanism for the Baddeley reaction that
is supported by both experimental and computational data. Key
characteristics of this mechanism are (a) the rate difference for
cis- and trans-decalin, (b) the hydride-abstracting ability of the
acylium ion, (c) the intermediacy of unsaturated species 17,
and (d) the concerted nature of the cyclization/[1,2]-hydride
shift. Mechanistic elucidation of this so-called aliphatic Friedel−
Crafts reaction allows for rational selection of other saturated
hydrocarbon substrates and prediction of the products that
would be formed. Such transformations would serve to add
significant value by providing rapid access to complex polycyclic
oxygenated architectures, and we have already reported several
such transformations.12 Additional studies focusing on employ-
ing the Baddeley reaction in natural product target synthesis are
ongoing and will be disclosed in due course.
Figure 5. MP2/cc-pVTZ//MP2/6-31+G* Gibbs energy profile
(black) in PCM CH2Cl2 for cyclization of acylium−octalin adduct
with concerted hydride shift, together with MP2/6-31+G* intrinsic
reaction coordinate energy profiles (blue; note the different energy
scales for the forward and reverse segments). Bond lengths are in Å,
and angles in degrees. Energies are relative to separated CH3CHOH+
and octalin 17.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Gibbs energy for the transition structure TS-CYC
shown in Figure 5 is 56 kJ mol−1 relative to octalin + Ac+; this
species is derived from the C2h octalin conformer. Other TSs
derived from the D2 conformer are all much higher in energy
(ΔG‡ = 68, 75, and 85 kJ mol−1) and involve trans-hydride
shifts from either of two nonequivalent hydrogens (at C4 or
C5) or a frontside cis-hydride shift. Clearly these are not
kinetically competitive. Finally, deprotonation of the cyclized
adduct 19 ( PC-CYC) yields the product enol ether 6.
The preceding discussion concerns the cyclization and [1,2]-
hydride shift from 23 to 19 occurring by a concerted
mechanism (blue and red arrows in Scheme 5). The question
remains whether a stepwise mechanism involving the
intermediacy of 24 is also possible. Despite our best efforts,
no local minimum species corresponding to this secondary
carbocation on the MP2/6-31+G* potential energy surface has
been found. Another question concerns the possible involve-
ment of Baddeley’s postulated oxonium intermediate (18,
Scheme 4). The Gibbs energy of transition structure 4MR-TS
(Supporting Information) is lower than that of TS-CYC by 4 kJ
mol−1, but the four-membered ring 18 (PC-4MR) lies 78 kJ
mol−1 above the less-strained five-membered ring oxonium 19
(PC-CYC). The isomerization of 18 to 19 is formally a
dyotropic rearrangement involving concerted intramolecular
nucleophilic substitution at vicinal carbon atoms: the leaving
group of one component is the nucleophile for the other, and
vice versa.27 However, all attempts to locate a transition
structure for this direct isomerization have been unsuccessful,
Full computational details and further kinetic data, NMR
spectra, and experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
I.H.Williams@bath.ac.uk.
S.E.Lewis@bath.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Bath (studentship to C.L.L.), the
EPSRC (DTA studentship to M.U.-M.), the Pakistan Higher
Education Commission (IRSIP award to S.F.A.), and the Japan
Society for the Promotion of Science (Fellowship Grant-in-Aid
to M.S.). We thank the University of Bath and Rikkyo
University for access to their High Performance Computing
Facilities and Professor Hiroshi Yamataka (Rikkyo) for his
support and scientific inspiration.
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(26) This may be an artifact of the harmonic oscillator approximation
used for zero-point energies, thermal corrections, and vibrational
entropies, or it may indicate a vibrationally bound complex. TS-PT is a
true first-order saddle point on the PCM/MP2/6-31+G* potential
energy surface, lying 7.3 kJ mol−1 above RC-PT derived from the C2-
symmetrical decalinyl cation but 0.9 kJ mol−1 below it on the Gibbs
energy surface. An alternative structure for TS-PT (3.5 kJ mol−1 higher
in energy) is derived from the Cs-symmetrical decalinyl cation: this is
also a true first-order saddle point on the PCM/MP2/6-31+G*
potential energy surface, lying 6.4 kJ mol−1 above the corresponding
RC-PT structure but also 3.5 kJ mol−1 above it on the Gibbs energy
surface. Combining the single-point MP2/cc-pVTZ//MP2/6-31+G*
potential energies with the MP2/6-31+G* thermal corrections to the
H
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Gibbs energies causes both TS-PT structures to lie 12 kJ mol−1 below
the preceding RC-PT structures.
(27) Reetz, M. Angew. Chem., Int. Ed. Engl. 1972, 11, 129−130.
I
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