A photo-favorskii ring contraction reaction: The effect of ring size

Article abstract of DOI:10.1021/jo300850a

The effect of ring size on the photo-Favorskii induced ring-contraction reaction of the hydroxybenzocycloalkanonyl acetate and mesylate esters (7a-d, 8a-c) has provided new insight into the mechanism of the rearrangement. By monotonically decreasing the ring size in these cyclic derivatives, the increasing ring strain imposed on the formation of the elusive bicyclic spirocyclopropanone 20 results in a divergence away from rearrangement and toward solvolysis. Cycloalkanones of seven or eight carbons undergo a highly efficient photo-Favorskii rearrangement with ring contraction paralleling the photochemistry of p-hydroxyphenacyl esters. In contrast, the five-carbon ring does not rearrange but is diverted to the photosolvolysis channel avoiding the increased strain energy that would accompany the formation of the spirobicyclic ketone, the "Favorskii intermediate 20". The six-carbon analogue demonstrates the bifurcation in reaction channels, yielding a solvent-sensitive mixture of both. Employing a combination of time-resolved absorption measurements, quantum yield determinations, isotopic labeling, and solvent variation studies coupled with theoretical treatment, a more comprehensive mechanistic description of the rearrangement has emerged.

Full text of DOI:10.1021/jo300850a

Article
pubs.acs.org/joc
A Photo-Favorskii Ring Contraction Reaction: The Effect of Ring Size
†
†,‡
Viju Balachandran Kammath, Tomas Solomek, Bokolombe Pitchou Ngoy,†,‡ Dominik Heger,†,‡
̌
́
̌
Petr Klan,*,†,‡ Marina Rubina,§ and Richard S. Givens*,§
†Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5/A8, 625 00 Brno, Czech Republic
‡Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Kamenice 126/3, 625 00 Brno,
Czech Republic
§Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, 5010 Malott Hall, 66045 Lawrence, Kansas, United States
́
S
* Supporting Information
ABSTRACT: The effect of ring size on the photo-Favorskii induced ring-
contraction reaction of the hydroxybenzocycloalkanonyl acetate and
mesylate esters (7a−d, 8a−c) has provided new insight into the
mechanism of the rearrangement. By monotonically decreasing the ring
size in these cyclic derivatives, the increasing ring strain imposed on the
formation of the elusive bicyclic spirocyclopropanone 20 results in a
divergence away from rearrangement and toward solvolysis. Cyclo-
alkanones of seven or eight carbons undergo a highly efficient photo-
Favorskii rearrangement with ring contraction paralleling the photo-
chemistry of p-hydroxyphenacyl esters. In contrast, the five-carbon ring
does not rearrange but is diverted to the photosolvolysis channel avoiding
the increased strain energy that would accompany the formation of the spirobicyclic ketone, the “Favorskii intermediate 20”. The
six-carbon analogue demonstrates the bifurcation in reaction channels, yielding a solvent-sensitive mixture of both. Employing a
combination of time-resolved absorption measurements, quantum yield determinations, isotopic labeling, and solvent variation
studies coupled with theoretical treatment, a more comprehensive mechanistic description of the rearrangement has emerged.
hydroxyphenacyl esters (1, pHP X; X = carboxylate) releases
the leaving group X while the chromophore undergoes an
unusual rearrangement that has been described as a photo-
Favorskii rearrangement.14 The products, p-hydroxyphenyl-
acetic acid (2, 95%) and p-hydroxybenzyl alcohol (6, <5%), are
the signatures of this rearrangement (Scheme 1).15−18 The
INTRODUCTION
■
Photochemical rearrangements have been the testing ground
for many of the most important advances in development of a
mechanism-based understanding in organic photochemistry
beginning with the dienone rearrangements of α-santonin to
lumisantonin by Zimmerman in the early 1960s.1,2 Zimmerman
developed a four-step paradigm during his studies on the
mechanism of the reactions of 4,4-disubstituted cyclohexa-2,4-
dien-1-one as a model for α-santonin which has also provided a
simplified model for proposing mechanisms in photochemistry
using a classic “electron pushing” approach.3−5 The four-step
paradigm consisted of (1) excitation (defining the reactive
excited state), (2) bond alteration (in that excited state), (3)
demotion (relaxation to the ground state energy surface), and
(4) further bond alteration (through ground state, classical
processes) to the final photoproducts. This paradigm has
served the field of organic photochemistry very well for over
half a century and has been useful in predicting the
photochemical reactivity of complex organic molecules
including the more intricate subtleties of stereochemistry,
solvent, substituent, and steric effects that influence the product
distributions in a photochemical reaction like that of α-
santonin.2,6−13
Scheme 1. Photolysis of the pHP Chromophore
reaction is highly efficient and the photochemical yields are
quantitative. pHP has therefore developed into a useful
protecting group for the photorelease of bioactivators such as
amino acids, oligopeptides, nucleotides, and thiol derivatives in
In our investigations of the photochemistry of the p-
hydroxyphenacyl chromophore, one of the newer photo-
removable protecting groups, we have turned our attention to
the mechanism and versatility of the reaction. Irradiation of p-
Special Issue: Howard Zimmerman Memorial Issue
Received: April 29, 2012
© XXXX American Chemical Society
A
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fields such as neurobiology, enzyme catalysis, and biochemis-
try.19−22
parent cyclic ketones were chosen for this study to test the
limits of ring strain41,42 on both the known and hypothetical
intermediates (31, 3, 4, and 5) proposed for the photo-Favorskii
transformation. Precedence for ring-size effects on the ground-
state Favorskii rearrangement have been reported43−45 that may
serve as models to compare and contrast with results found of
the hydroxybenzocycloalkanones 7.
Here we report the synthesis, photophysical properties, and
photochemistry in water/acetonitrile solutions of a monotonic
series of ring-expanded acetates 7a−d (n = 1−4) and mesylates
8a−c (n = 1−3) (Chart 1). The mechanistic conclusions are
supported by the results from studies of the solvent effects,
isotope exchange reactions, quenching effects and laser flash
photolysis (LFP) experiments, and by quantum-chemical
calculations.
Whereas interest has centered on the photorelease reactions
of pHP and its applications, little work has been reported on
the full range of reactivity of this chromophore when embedded
in larger molecular frameworks.23 Unlike its namesake, the
classic ground-state Favorskii rearrangement that has received
extensive investigation,24−30 the range of possibilities and the
theoretical treatments of the photo-Favorskii rearrangement14
have not been adequately addressed. The current under-
standing of the photo-Favorskii mechanism also continues to be
the subject of considerable debate.31−37
The reaction mechanism begins with excitation to the pHP
triplet that releases the leaving group via an adiabatic, water-
3
assisted pathway to the triplet biradical 4 that collapses to a
ground-state spirodione 3, the Favorskii intermediate.38,39 The
spirodione 3, which has eluded detection, either is hydrolyzed
to p-hydroxyphenylacetic acid (2) or decarbonylates to p-
quinone methide (5) that adds water to form the minor
product p-hydroxybenzyl alcohol (6).
RESULTS
■
Synthesis of p-Hydroxybenzocycloalkanones Deriva-
tives. The acetates 7a−d (n = 1−4) were synthesized by direct
α-acetoxylation of the benzyloxybenzocycloalkanones 10 to
yield 1146 followed by removal of the benzyl protection.
Bromination of 9a−c (n = 1−3)47 and subsequent silver-
promoted sulfoxydebromination23 of 12 gave rise to the
mesylates 8a−c (n = 1−3; Scheme 2); see also the Supporting
Information for the synthesis of 9c,d (Scheme S1, Supporting
Information).
Just as in the history of its ground-state counterpart, the
mechanism of the photo-Favorskii rearrangement is the subject
of considerable conjecture on the details of the rearrangement
process, especially those surrounding the intermediacy of the
cyclopropanone 3. Investigations of cyclic ketones impose ring
strain on the reaction course and are intended to test the ease
of formation, the stability, and the relative reactivity of the
putative spirodione 3. Thus ring strain effects might help define
the partitioning of 3 among pathways available to the
intermediates using our spectroscopic and product study
techniques reported earlier40 and the theoretical advances on
the basic chromophore made available recently by the
examination of the photophysics of p-hydroxyacetophenone.31
In extending the reach of the photo-Favorskii reaction and
seeking more information on the mechanistic limits of the
rearrangement, a monotonic series of hydroxybenzocycloalka-
nones (7a−d, 8a−c) have been synthesized and their
photochemistry examined (Chart 1). The ring sizes of the
Photochemistry of Acetates and Mesylates. Each ester
(Scheme 3) was irradiated at 313 nm in acetonitrile/water
Scheme 3. Products from Photolysis of 7a−d and 8a−c
Chart 1. Hydroxybenzocycloalkanone Derivatives
mixtures (∼7 × 10−2 M) through a Pyrex filter (>300 nm). The
1
progress of the reaction was monitored by H NMR and GC
until 95% of the ketone was consumed (see Tables 1 and 2). In
most cases, four different photoproducts, reduction (9),
hydrolysis (13), and rearrangement to ring contracted acid
14 and benzyl alcohol 15, were observed. The rearrangement
products 14 and 15 were not observed among the photo-
Scheme 2. Synthesis of 7a−d and 8a−c
B
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rearrangement products 14 and 15 (shown in Scheme 4) was
determined by comparison of the fragmentation patterns for
the labeled and unlabeled derivatives (Supporting Information).
Quantum Yields Measurements. The quantum yields for
disappearance of 7a−d and 8a−c were obtained in degassed
D2O/CD3CN (30:70, v/v) by irradiation at λ = 313 nm (Table
Table 1. Photoproduct Distribution from Irradiation of 7a−
d in D2O/CD3CN (70:30, v/v)
a
b
b
c
c
compd
% yield of 9
% yield of 13
% yield of 14 % yield of 15
7a
7b
7c
7d
6
7
5
5
86
57
4
d
13
59
73
d
8
20
1
3). The reaction conversion was monitored by H NMR.
6
8
a
Nondegassed solutions (∼7 × 10−2 M) were irradiated in an NMR
a
Table 3. Quantum Yields for the Disappearance of 7 and 8.
tube at λ > 280 nm (Pyrex) to >95% conversion. Average yields are
shown. The confidence intervals at the 95% confidence level for all
b
ester
Φ
b
chemical yields determinations are below 3%. Determined by GC.
7a
7b
7c
7d
8a
8b
8c
0.38
0.24
0.26
0.34
0.70
0.64
0.63
c
d
1
Determined by H NMR. Not formed.
Table 2. Photoproduct Distribution as a Function of the
Ratio of D2O/CD3CN
D2O/
CD3CN (v/ % yield of % yield of % yield of % yield of
a
b
b
c
c
compd
v)
9b
13b
14b
15b
a
Degassed solutions (∼4 × 10−3 M) were irradiated in D2O/CD3CN
(30:70, v/v) at λ = 313 ( 5) nm. The conversion was less than 10%.
The confidence intervals at the 95% confidence level for all quantum
7b
5:95
10:90
20:80
30:70
70:30
70:30
17
14
11
11
7
28
29
41
47
57
56
16
17
18
17
13
16
13
14
12
12
8
b
yields determinations are below 0.05. Valerophenone was used as an
actinometer (Φ = 0.30 in benzene).48
8b
5
8
Quenching Experiment. To confirm the triplet multi-
plicity of the excited state responsible for the formation of
photoproducts, D2O/CD3CN (30:70, v/v) solutions of the
acetates of 7a or 7b (5.5 × 10−2 M) were irradiated at λ = 366
( 5) nm in the presence of naphthalene (1.6 × 10−1 M) as a
triplet quencher (ET = 60.5 kcal mol−1;49 naphthalene does not
absorb at this wavelength). The reaction progress was
monitored by NMR. Less than 5% conversion was observed
after 7 days of irradiation, while the reaction was completed
within several hours in the absence of a quencher. Dissolved
oxygen had no significant effect on the photoreaction efficiency.
Irradiation in the Presence of DCl. A solution of 7b in
D2O/CD3CN (30:70, v/v) mixture containing a small amount
of DCl was irradiated through a Pyrex filter until the conversion
reached ∼95%. The yield of 13b and the sum of yields of 14b
and 15b remained nearly unchanged compared to the
irradiation in the absence of DCl (see Table S2, Supporting
Information). However, the ratio 14b to 15b increased,
favoring 14b. The added acid had no effect on samples kept
in the dark.
Reaction of 12b under Favorskii Rearrangement
Conditions. Treatment of 2-bromo-6-hydroxynaphthalen-
1(2H)-one (12b) under Favorskii rearrangement conditions
using anhydrous ZnCl2 in refluxing MeOH44,45 gave 2-
methoxy-6-hydroxynaphthalen-1(2H)-one 16 and the reduced
ketone 9b in a ratio of 3:1. Neither of the Favorskii
rearrangement products 14b or 15b were detected (Scheme
5). However, similar treatment of pHP Br gave a good yield of
the rearranged methyl p-hydroxyphenyl acetate (19)50 and
solvolysis product 1851 in a 2:3 ratio, but none of the reduction
product.
a
Nondegassed solutions (∼7 × 10−2 M) were irradiated in an NMR
tube at λ > 300 nm (Pyrex) to >95% conversion. Average yields are
shown. The confidence intervals at the 95% confidence level for all
b
chemical yields determinations are below 3%. Determined by GC.
c
1
Determined by H NMR.
products when n = 1 but were most prominent for n = 3 and 4.
The structures of the photoproducts were established by
comparison of the H and 13C NMR and HPLC/HRMS data
1
with independently synthesized derivatives (Supporting In-
formation) or comparison with literature values. The chemical
yields from irradiations of all four acetates 7a−d in D2O/
CD3CN (70:30, v/v) mixture are shown in Table 1. The
photoproduct distribution for 7b and 8b as a function of the
concentration of H2O in CH3CN is summarized in Table 2;
complete photoproduct yields for all seven ketone irradiations
are shown in Tables S1−S4 (Supporting Information).
18O Exchange Experiments. Irradiation of 7a−c (∼7 ×
10−2 M) in D218O/CD3CN (20:80, v/v) was performed in an
NMR tube under the same conditions as those described above.
Incorporation of 18O into the three products 13, 14, and 15 was
determined by comparison of the observed exact mass with
theoretical values (Scheme 4). 18O was not incorporated into
the starting esters 7 or the reduction products 9. The location
of the 18O in the hydrolysis product 13 and the two Favorskii
Scheme 4. 18O Isotope Distribution in Photoproducts from
Photolysis in D218O/CD3CN Mixture
Quantum Chemical Calculations. The isodesmic reaction
shown in Scheme 6 is proposed such that the strain imposed on
the spirodione structures 20 by the presence of two small rings
could be compared to that in 20c, where the homologous p-
hydroxyphenyl ketones are assumed to be strain-free. This
approach has the advantage that errors which result from
neglecting a part of the electron correlation cancel. The same
approach connected with the levels of theory used (vide infra)
C
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to the spirodione 3 but no such minimum could be found.
However, we localized a transition state 21 resembling the
structure of the spirodione, which connects the energy
Scheme 5. Ground-State Favorskii Conditions for Reactions
of 12b and 17
3
minimum of the triplet biradical 4 and its rearranged product
22 (Scheme 7), which upon ISC and subsequent trapping by
water might yield the final acid 2. The barrier for this process
calculated at M06−2X/6-311+G(2df,2p) level of theory in
PCM at 0 K is 52.6 kcal mol−1.
Nanosecond Laser Flash Photolysis (LFP). Nanosecond
LFP (λexc = 266 nm) of a water/acetonitrile (30:70, v/v)
solution of 7b was performed using the conditions employed
for p-hydroxyacetophenone reported by Heger, Wirz, and co-
workers to confirm the decay pathways accompanying the p-
hydroxyphenacyl PPGs.31 Excitation of an aerated solution of
7b produced the transient absorption spectra of two species
with maxima at 410 and 358 nm within the first 30 ns (Figure
1, top, black) after the laser flash, which we attribute to the
Scheme 6. Isodesmic Reaction for Estimating the Relative
Ring Strains in 20a−d
has proven to give satisfactory results.52,53 The enthalpy change
calculated according to Scheme 6 is summarized in Table 4. In
Table 4. Ring Strain for 20a,b,d Relative to 20c Calculated
According to Scheme 6
a
a
compd ΔH (M06-2X, kcal mol−1, 0 K) ΔH (MP2, kcal mol−1, 0 K)
b
b
20a
20b
20c
20d
−25.2
−2.1
0.0
−25.7
−1.9
0.0
c
c
−1.3
−1.2
a
Calculated with the 6-311+G(2df,2p) basis set on B3LYP/6-31+G(d)
geometries. The ZPVE was scaled by 0.9857.55 An estimate based on
b
spirodione 20a with spiro bond length constrained to 1.69752 Å (see
c
text). Equals zero by definition (Scheme 6).
the case of 20a, optimizations at the RB3LYP or RMP2 levels
of theory with the 6-31G+(d) or 6-311+G(d,p) basis sets
resulted, however, in a spontaneous cleavage of the spiro bond
(highlighted in red, Scheme 6) and the formation of an open
planar structure resembling that of the corresponding triplet
biradical. The ring strain in 20a was, therefore, estimated from
geometry possessing the spiro bond constrained to 1.698 Å, the
bond length obtained from RB3LYP/6-31+G(d) optimization
of a related system, the bicyclo[2.1.0]pentan-5-one.54
Figure 1. Transient absorption spectra of 7b in an water/acetonitrile
(30:70, v/v) mixture without (top) and with (bottom) a drop of
perchloric acid recorded 30 ns (black), 100 ns (red), and 5 μs (blue)
after a 266 nm laser flash.
conjugate base of triplet 37b, the triplet anion 323b (Scheme 8),
and its tautomeric form, the triplet quinoid enol 324b,
An alternative pathway that has been proposed by Phillips56
suggested that the formation of the rearranged acid 2 occurs
adiabatically in the triplet manifold. We used the UB3LYP/6-
31+G(d) level of theory with polarizable continuum model
(PCM, acetonitrile) to account for the collective properties of
the surrounding solvent to model the triplet PES. We
attempted to find the local minimum, which would correspond
respectively.31 The anion 23 decays to 24 (Figure 1, top,
red), which then decays to the ground-state conjugate base of
7b with an absorption maximum at 332 nm as seen from the
end spectrum (>5 μs). Excitation of a solution of 7b with
addition of a drop of perchloric acid leads exclusively to the
3
3
3
formation of triplet quinone 24b (Figure 1, bottom), which
again subsequently decays to the ground state conjugate base of
3
Scheme 7. Reaction of the Triplet Biradical 4
D
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Scheme 8. Observed Transients in the LFP Experiments
Figure 2. Chemical yield dependence of the photoproducts (red
circles: 13b; blue triangles: the sum of 14b and 15b) formation from
7b on increasing concentrations of D2O in CD3CN.
7b. The same behavior as that of 7b was observed upon
excitation of 9b and 7a in water/acetonitrile solutions (Figures
S27−29 and Table S5, Supporting Information). Similar spectra
upon laser excitation in water/acetonitrile solutions were
recorded throughout the whole series of the hydroxybenzocy-
cloalkanones (7−9).
photolysis. To differentiate between the two pathways, 7b along
with 7c, the larger C7 ring, and 7a, the smaller C5 ring acetate
esters, were irradiated in 18O-enriched D2O. In each case, the
solvolysis product had incorporated an isotopically labeled 18O
(HRMS) at the α-hydroxy group (Scheme 4) establishing that
all three of these esters suffered heterolytic cleavage with the
departure of the intact leaving group paralleling the initial
photo-Favorskii rearrangement step. The 18O content for all
three α-hydroxy products (13a−c) was constant (75% 18O)
and reflected the solvent 18O content. Furthermore, the extent
of 18O incorporation in both of the rearrangement products 14
and 15 matched the results of the α-hydroxy products,
supporting the conclusion that the solvent, here H2O, serves
as the trapping agent for the penultimate reactive precursors
DISCUSSION
■
Our results establish that tethering the acetyl group of pHP to
the phenol ring does not prevent rearrangement for rings of
seven or eight carbons. In fact, photolysis of 7c,d and mesylate
8c in aqueous acetonitrile formed the Favorskii products 14c,d
and the accompanying benzyl alcohols 15c,d along with minor
amounts of an unrearranged reduction product 9c,d and
solvolysis α-hydroxy ketone 13c,d.
that form the three final products 14, 15, and 13 . Since no 18
O
The minor reduction products 9a−d (5−7%, Table 1) had
previously been reported for photolyses performed in reducing
solvents (THF, MeOH, or i-PrOH) and when reducing
additives are present.57−60 The yields for all four platforms
are not dependent on ring size, the leaving group, or solvent
variations within the range of our investigations and therefore
are not being considered further.
In a similar manner, the relative yields of α-hydroxy ketones
13c,d are nearly constant (4−9%) with changes in H2O
concentration (Tables S3 and S4, Supporting Information) as
are the total yields of the rearrangement products 14c,d +
15c,d. (The two “Favorskii” products will be treated as their
sum for remainder of this discussion.) Thus, the C7 and C8
ring platforms behave as anticipated using photo-Favorskii
rearrangement conditions.
A significant change from the C7 and C8 reactions occurs
with the photoproduct distribution from 7b, 8b (the 6-
hydroxydihydronaphthalen-1(2H)-one acetate and mesylate) as
evidenced by the increase in α-hydroxy ketone 13b
accompanied by decrease in the Favorskii products (14b +
15b) (Table 1). This shift in the product distribution is
reflected in the photolysis of the mesylate ester 8b in 70/30
D2O/CD3CN which resulted in essentially the same product
distribution. Thus, the two esters of widely different leaving
group nucleofugacity generated only minor variation in the
product concentrations. On the other hand, the α-hydroxy-
ketone solvolysis product did increase significantly for both
esters with an increase in the solvent water content (Table 2
and Figure 2).
incorporation was found for the starting ester nor in the
reduction product, any ground state prephotolysis or photo-
induced ketone or leaving group exchange processes had not
occurred.
The C5 esters 7a and 8a gave only the α-hydroxy ketone 13a
and the reduction product upon photolysis. No rearrangement
products are detected from either the acetate or the mesylate
(Table 1 and Table S1, Supporting Information). Neither the
solvent water content nor the change in leaving group
significantly changed the ratio of these two products, the
ratio being less sensitive to solvent variation than found for 7b
and 8b. For 7a and 8a, photosolvolysis is, by far, the major
pathway.
The quantum efficiencies for disappearance for all seven
reactions were dependent on the nature of the leaving group
but were apparently independent of ring size (Table 3). The
acetate quantum efficiencies were ∼0.30
0.08, typical of
= 0.4)
many pHP acetate esters (e.g., pHP OAc Φ
−OAc
whereas the mesylate esters were narrowly clustered around
0.66 0.04, nearly twice that of the acetates but somewhat less
than the mesylates in the pHP series (pHP MsO, Φ
=
−MsO
0.93).19,61 The trend for the product ratios and the constancy
of the quantum efficiencies for the acetates are clearly
demonstrated for this series of hydroxybenzocycloalkanones
in Figure 3 and Table 5, respectively.
The same dramatic departure from a Favorskii reaction
favoring rearrangement to other pathways was found with 6-
membered ring ground-state reactions for the two examples
shown in Scheme 9. No rearrangement products were formed
from either the α-bromo or α-diiodo cyclohexanones, whereas
larger ring sizes successfully rearranged to the carboxylic esters
under Favorskii conditions.43−45 There is a resistance to
rearrangement in the ground state which may be imposed on
Because the source of the α-hydroxy ketone had not been
pursued in past studies,32,61 we felt that it was imperative that
we explore its origin. In question is whether the α-C−OAc
bond or the O−COCH3 acetate ester bond was broken by
E
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the transition state to the spiroketone by ring strain. As a result,
the other divergent pathways such as solvolysis become more
competitive when the rearrangement pathway involves the
strained bicyclo[3.1.0]hexane intermediate (vide infra).
The current study brings clarity to the photochemistry of the
p-hydroxyphenacyl protecting group. The results provided here
reveal the factors that influence the partitioning of the pHP
triplet excited state between product formation and return to
ground-state reactant but also provide a triplet-state inventory
for these processes.
The triplet states of 37a−d, which are quantitatively
generated upon excitation, initially partition among three
pathways, a minor reduction pathway and two major channels;
a proton transfer channel that generates the triplet conjugate
base 323 and its quinoid tautomer 324 and a heterolytic
departure of the leaving group. The former process is the
excited-state proton transfer (ESPT) channel31,32 that has been
well documented including the recent report on the parent
chromophore, p-hydroxyacetophenone31 and confirmed here
for the cycloalkanones 9a−d. The governing factor for the
partition between these two channels is the nature of the
leaving group X; the better the leaving group, the more
dominant the heterolysis pathway. This has been quantitatively
formalized for other pHP derivatives through a linear free
energy Bronsted relationship between the rate constants for
release and the pKa of the leaving group.19,22 In the current
study, the two leaving groups fall in the intermediate and high
reactivity positions on the pKa coordinate.
These two channels operate independently as demonstrated
by the effects of pH on the photochemistry. Throughout the
pH range of 4−7, heterolytic reaction is insensitive to the
conditions as has been shown by the constancy of the quantum
yields in this pH range by detailed examination of many pHP
derivatives.32,40 In contrast, the ratio of ESPT triplet products
varies greatly between conjugate base formation (at higher pH)
and the quinoid tautomer (at low pH, Figure 1). Traditionally,
the ESPT pathways are understood to be nonproductive
channels because the intermediates eventually return to the
reactants.31 When in competition with other product forming
reactions, these are considered “energy wasting” processes.40
This was shown to be the case for the two series examined here,
where the nonproductive ESPT process accounted for the
difference between quantum yields for product formation and
unity. Thus, the ESPT processes account for the remainder of
the total energy inventory of the triplet state.
Figure 3. Dependence of photoproducts chemical yields (red circles:
13; blue triangles: the sum (14 + 15) on the ring size of 7a−d
irradiated in water/acetonitrile (70:30, v/v).
Table 5. Effect of Ring Size on Change in the Distribution of
the Major Products from 7a−d
a
,
b
c
ring size
n
Φ
ΔH (MP2) % of 13 % of (14 + 15)
d
no ring (pHP)
8 (7d)
0
4
3
2
1
0.4032
0.34
0.26
0.24
0.38
N/A
−1.2
0.0
<532,62
>95
81
79
21
0
7
4
e
f
7 (7c)
6 (7b)
−1.9
−25.7
57
86
5 (7a)
a
b
c
The confidence intervals at the 95% confidence level are shown.
Valerophenone was used as an actinometer (Φ = 0.30 in benzene).48
Strain Energy (kcal mol−1, 0 K) calculated with the 6-311+G(2df,2p)
basis set on B3LYP/6-31+G(d) geometries. The ZPVE was scaled by
0.9857.55 Not available by the computational protocol used here (see
Scheme 6). Equals zero by definition (see Scheme 6). An estimate
based on spirodione 20a with spiro bond length constrained to
1.69752 Å (see text).
d
e
f
Scheme 9. Favorskii Ring-Contraction Reactions for a Series
of Medium-Sized Rings43−45
Scheme 10. Effect of Ring Size on Two Diverging Heterolysis Channels in the Photo-Favorskii Rearrangement
F
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UV spectra were obtained with matched 1.0-cm quartz cells. All
column chromatography purification procedures were performed with
silica gel. The reagents and solvents of the highest purity available were
used as purchased, or they were purified/dried when necessary. All
glassware was flame-dried prior to use when water- and/or air-sensitive
compounds were used. Compounds 9a,b and 26a,b (see Scheme S1 in
the Supporting Information) are commercially available; synthesis and
characterization of compounds 10a,23 10b,63 27a,64 27b,65 28a,66
28b,67 29a,67 29b,68 30c,69 9c,70 14b,71 14c70 have been previously
described. Synthetic protocols and analytical data for all new
compounds are provided below. Compounds 13d and 14d could
neither be synthesized nor isolated. Their formation has been
confirmed by HPLC/HRMS analysis.
General Procedure for the Synthesis of 10a−d. This
procedure has been adapted from our previous work.23 Potassium
carbonate (1.9 g, 13.7 mmol) was added to a solution of 9 (6.1 mmol)
and benzyl bromide (0.83 mL, 6.7 mmol) in acetonitrile (35 mL), and
the mixture was stirred overnight at 20 °C. The reaction mixture was
concentrated under reduced pressure and diluted with water, and the
organic material was extracted with ethyl acetate (2 × 20 mL). The
organic layers were washed with water (2 × 20 mL) and brine (20
mL), dried over anhydrous MgSO4, and filtered, and the solvent was
removed under reduced pressure. The title product was purified by
column chromatography (ethyl acetate/hexane, 3:7).
The heterolytic channel is responsible for the formation of
3
the triplet biradical 25 (34 in the case of pHP; Scheme 10).
3
The triplet biradical 25 cannot lead to the Favorskii product
formation adiabatically as suggested by Phillips and co-
workers56 (Scheme 7) because of considerable energy demands
of the rearrangement.59 The Favorskii product most likely
3
forms after isc relaxation of triplet biradical 25 (34) to the
ground-state surface forming the spiroketone 20 (3). The
observation that the methyl ester of 2 is readily formed by the
ground-state, Lewis-acid catalyzed rearrangement of pHP Br
(17, Scheme 5) argues against the Phillips mechanism. The
controlling factor in the partitioning between the Favorskii
rearrangement and solvolysis channels is the ease of formation
of the singlet-ground-state spirodienedione 20 and 3. With the
seven- and eight-membered rings and the noncyclic pHP
analogues, the rearrangement channel is available and
dominates the photo initiated reaction, while the five- and
six-membered rings falter. The alternative pathway open to the
latter two ring systems is solvolysis which accounts for the
decrease in the efficiencies of the photorearrangement channel.
Consequently, the total quantum yields remain essentially
constant within the series in keeping with the triplet state
inventory.
2-(Benzyloxy)-6,7,8,9-tetrahydrobenzo[7]annulen-5-one (10c).
Prepared from 9c. Yield: 1.25 g (83%). Tan solid. Mp: 140.1−141.5
°C. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.78−1.83 (m, 2H), 1.85−
1.90 (m, 2H), 2.72 (t, 2H, J = 5.9 Hz), 2.9 (t, 2H, J = 6.1 Hz), 5.10 (s,
2H), 6.79 (d, 1H, J = 2.1 Hz), 6.88 (dd, 1H, J = 8.6, 2.3 Hz), 7.32−
7.43 (m, 5H), 7.78 (d, 1H, J = 8.62 Hz). 13C NMR (75.5 MHz,
CDCl3): δ (ppm) 20.7, 25.0, 32.8, 40.7, 70.0, 112.5, 115.8, 127.4,
128.1, 128.6, 131.2, 131.8, 136.4, 144.1, 161.8, 204.1. MS (EI, 70 eV):
m/z 266, 175, 147, 105, 91, 65, 39. HRMS (APCI+): calcd for
The source or origin of the governing factor, ring size, is the
rising cost in energy of the bridge closure to form the
cyclopropanones 20a−d which translates into increased ring
strain (ΔH, Table 5). As the length of the ring tether decreases
below a critical level, the formation of 20 becomes strongly
disfavored (7a,b and 8a,b) and an alternative hydrolysis
channel dominates for them (Scheme 10). The bifurcation
+
C18H19O2 (M + H+) 267.1379, found 267.1388. This compound has
3
into two parallel pathways occurs as the triplet biradical 25
also been characterized previously.72
intersystem crosses to the ground state before spiroketone 20 is
2-(Benzyloxy)-7,8,9,10-tetrahydrobenzo[8]annulen-5(6H)-one
(10d). Prepared from 9d. Yield: 1.22 g (83%). Tan solid. Mp: 151.7−
152.8 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.42−1.50 (m, 2H),
1.76−1.90 (m, 4H), 3.0 (t, 2H, J = 7.1 Hz), 3.13 (t, 2H, J = 6.7 Hz),
5.10 (s, 2H), 6.78 (d, 1H, J = 2.6 Hz), 6.89 (dd, 1H, J = 8.8, 2.6 Hz),
7.33−7.44 (m, 5H), 7.95 (d, 1H, J = 8.8 Hz).13C NMR (75.5 MHz,
CDCl3): δ (ppm) 23.4, 24.5, 27.7, 35.4, 42.9, 70.0, 112.3, 117.5, 127.5,
128.1, 128.6, 131.5, 132.7, 136.4, 143.1, 161.9, 203.19. MS (EI, 70 eV):
m/z 280, 237, 195, 165, 105, 91, 65, 39. HRMS (APCI+): calcd for
formed. This suggests that another short-lived intermediate
connecting 25 and 20 might intervene in the photorearrange-
ment. Additional work is in progress that will explore the
factors influencing the partitioning of the two pathways and
that tests the tenets of the mechanism proposed here (Scheme
10) including its relationship with the Lewis acid catalyzed
rearrangement (Scheme 5).
3
+
C19H21O2 (M + H+) 281.1536, found 281.1546.
CONCLUSION
■
General Procedure for the Synthesis of 11a−d. This
procedure has been adapted from Demir and Findik.46 KMnO4 (300
mg, 3 mmol) in a benzene−acetic acid (10:1, 50 mL) mixture was
stirred under reflux (a Dean−Stark apparatus) until the purple color of
KMnO4 turned brown (∼30 min). Compound 10 (1 mmol) was then
added to the solution, and reflux was continued. After the starting
material was consumed (TLC), the reaction mixture was cooled,
diluted with diethyl ether, and neutralized with saturated aq NaHCO3
(20 mL). The resulting organic phase was washed with water (3 × 20
mL) and brine (25 mL) and dried with MgSO4. The solvents were
removed under reduced pressure, and the crude mixture of products
was purified by column chromatography (ethyl acetate/hexane, 3:7) to
give the title compound.
We have shown that, through design testing, a monotonic
decrease in tether ring size discourages the formation of the
Favorskii spirocyclopropanone intermendiate 20, diverting the
Favorskii rearrangement channel toward solvolysis to un-
rearranged α-hydroxy ketone products. Conversely, the large
ring hydroxybenzocycloalkanones (7c,d and 8c) and p-
hydroxyphenacyl analogues (1) overwhelmingly follow the
now well-known photo-Favorskii rearrangement pathway in
aqueous media. When the strain energy of the intermediate
spiroketone reaches levels that are resistant to closure, the
pathway diverts toward solvolysis.
5-(Benzyloxy)-2,3-dihydro-1-oxo-1H-inden-2-yl Acetate (11a).
Prepared from 10a. Yield: 210 mg (72%). Yellow solid. Mp: 123.3−
EXPERIMENTAL SECTION
1
■
124.5 °C. H NMR (300 MHz, CDCl3): δ (ppm) 2.17 (s, 3H), 2.97
Materials and Methods. NMR spectra were recorded on a 300
MHz spectrometer calibrated to the residual peak of the (major) d-
solvent. Gas chromatography was performed on a chromatograph
equipped with a 15 m (5% diphenyldimethylsiloxane) column with
FID detector. Mass spectra were recorded on a GC-coupled (30-m
DB-XLB column) mass spectrometer in a positive mode with EI.
HRMS data were obtained on a UPLC/MS-TOF apparatus equipped
with an ESI interface and a C-18 (1.7 μm, 2.1 × 50 mm) column,
using ammonium carbonate in methanol (0.005 M) as a mobile phase.
(dd, 1H, J = 17.0, 4.4 Hz), 3.60 (dd, 1H, J = 17.1, 7.8 Hz), 5.1 (s, 2H),
5.40 (dd, 1H, J = 7.8, 4.6 Hz), 6.93 (d, 1H, J = 1.7 Hz), 7.02 (dd, 1H, J
= 8.5, 2.1 Hz), 7.35−7.42 (m, 5H), 7.74 (d, 1H, J = 8.5 Hz). 13C NMR
(75.5 MHz, CDCl3): δ (ppm) 21.2, 34.1, 70.8, 74.4, 111.2, 117.1,
126.8, 127.85, 128.3, 128.8, 129.1, 136.2, 153.8, 165.7, 170.9, 198.9.
MS (EI, 70 eV): m/z 296, 236, 135, 107, 91, 65, 43. HRMS (APCI+):
+
calcd for C18H17O4 (M + H+) 297.1121, found 297.1118.
6-(Benzyloxy)-1,2,3,4-tetrahydro-1-oxonaphthalen-2-yl Acetate
(11b). Prepared from 10b. Yield: 230 mg (74%). Yellow solid. Mp:
G
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112.2−113.1 °C. 1H NMR (300 MHz, DMSO): δ (ppm) 2.17 (s, 3H),
2.24−2.38 (m, 2H), 3.02 (td, 1H, J = 4.3 Hz, 7.9 Hz), 3.10−3.22 (m,
1H), 5.12 (s, 2H), 5.51 (dd, 1H, J = 12.9, 5.2 Hz), 6.78 (d, 1H, J = 1.9
Hz), 6.93 (dd, 1H, J = 8.7, 2.3 Hz), 7.34−7.46 (m, 5H), 8.01 (d, 1H, J
= 8.74 Hz). 13C NMR (75.5 MHz, DMSO): δ (ppm) 20.4, 27.2, 28.5,
69.4, 73.9, 113.4, 114.2, 124.4, 127.6, 127.9, 128.3, 129.0, 136.2, 146.3,
162.5, 169.2, 191.1. MS (EI, 70 eV): m/z 310, 268, 250, 177, 149, 91,
77.3, 113.9, 116.6, 128.4, 132.2, 145.5, 159.7, 170.9, 197.1. MS (EI, 70
eV): m/z 234, 216, 192, 174, 163, 145, 135, 91, 77, 43. UV−vis: ε313
(CH3CN/H2O, 30:70, v/v) = 2275 dm3 mol−1 cm−1; ε313 (CH3CN) =
465 dm3 mol−1 cm−1. HRMS (APCI+): calcd for C13H15O4+ (M + H+)
235.0965, found 235.0968.
5,6,7,8,9,10-Hexahydro-2-hydroxy-5-oxobenzo[8]annulen-6-yl
Acetate (7d). Prepared from 11d. Yield: 280 mg (75%). White solid.
Mp: 129.0−130.1 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.37 (m,
1H), 1.68 (m, 2H), 1.81 (m, 2H), 2.01 (m, 1H), 2.18 (s, 3H), 2.80 (m,
1H), 3.20 (dt, 1H, J = 14.7, 5.7 Hz), 5.98 (t, 1H), 6.43 (s, 1H), 6.54
(d, 1H, J = 1.4 Hz), 6.68 (dd, 1H, J = 8.6, 1.9 Hz), 7.93 (d, 1H, J = 8.7
Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.86, 20.89, 27.3, 30.2,
35.5, 77.5, 113.8, 118.0, 130.5, 132.1, 142.5, 160.1, 171.0, 196.8. MS
(EI, 70 eV): m/z 248, 206, 177, 159, 147, 107, 77, 43. UV−vis: ε313
(CH3CN/H2O, 30:70, v/v) = 2795 dm3 mol−1 cm−1; ε313 (CH3CN) =
424 dm3 mol−1 cm−1. HRMS (APCI+): calcd for C14H17O4+ (M + H+)
249.1121, found 249.1125.
General Procedure for the Synthesis of 12a−c. This
procedure has been adapted from our previous work.23 A solution
of 9 (6.2 mmol) and copper(II) bromide (3 g, 13.6 mmol) in ethyl
acetate/CHCl3 (50 mL, 1:1, v/v) was refluxed overnight. The mixture
was cooled to 20 °C, filtered through a pad of silica, concentrated
under reduced pressure, and purified by column chromatography
(ethyl acetate/hexane, 3:7) to give the title compound.
2-Bromo-2,3-dihydro-5-hydroxyinden-1-one (12a). Prepared
from 9a. Yield: 1.10 g (76%). Yellow solid. Mp: 173.8−174.8 °C.
1H NMR (300 MHz, DMSO): δ (ppm) 3.22 (dd, 1H, J = 18.3, 2.8
+
64, 43. HRMS (APCI+): calcd for C19H19O4 (M + H+) 311.1277,
found 311.1287.
2-(Benzyloxy)-6,7,8,9-tetrahydro-5-oxo-5H-benzo[7]annulen-6-yl
Acetate (11c). Prepared from 10c. Yield: 190 mg (59%). Yellow solid.
1
Mp: 106.1−107.4 °C. H NMR (300 MHz, CDCl3): δ (ppm) 1.73−
1.81 (m, 1H), 1.93−2.03 (m, 1H), 2.12−2.22 (m, 5H), 2.89−3.09 (m,
2H), 5.10 (s, 2H), 5.47 (dd, 1H, J = 10.9, 5.4 Hz), 6.81 (d, 1H, J = 2.3
Hz), 6.90 (dd, 1H, J = 8.7, 2.4 Hz), 7.33−7.41 (m, 5H), 7.84 (d, 1H, J
= 8.6 Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.7, 23.1, 28.2,
34.1, 70.0, 77.1, 112.7, 116.2, 127.4, 128.2, 128.6, 129.2, 132.0, 136.2,
144.8, 161.8, 170.2, 197.0. MS (EI, 70 eV): m/z 324, 282, 264, 236,
+
173, 91, 65, 43. HRMS (APCI+): calcd for C20H21O4 (M + H+)
325.1434, found 325.1436.
2-(Benzyloxy)-5,6,7,8,9,10-hexahydro-5-oxobenzo[8]annulen-6-
yl Acetate (11d). Prepared from 10d. Yield: 130 mg (41%). Yellow
1
solid. Mp: 117.2−118.5 °C. H NMR (300 MHz, CDCl3): δ (ppm)
1.34−1.48 (m, 1H), 1.58−1.67 (m, 1H), 1.71%1.86 (m, 2H), 1.96−
2.05 (m, 2H), 2.17 (s, 3H), 2.84−2.93 (m, 1H), 3.21−3.31 (m, 1H),
5.1 (s, 2H), 5.96 (dd, 1H, J = 9.9, 7.8 Hz), 6.78 (d, 1H, J = 2.5 Hz,
1H), 6.91 (dd, 1H, J = 8.8, 2.5 Hz, 1H), 7.33−7.43 (m, 5H), 8.02 (d,
1H, J = 8.8 Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.7, 20.9,
27.5, 30.2, 35.5, 70.0, 77.2, 112.5, 117.7, 127.4, 128.2, 128.6, 131.0,
131.8, 136.2, 142.0, 162.4, 170.3, 197.0. MS (EI, 70 eV): m/z 338, 296,
251, 160, 91, 65, 43. HRMS (APCI+): calcd for C21H23O4+ (M + H+)
339.1590, found 339.1600.
Hz), 3.78 (dd, 1H, J = 18.3, 7.3 Hz), 4.92 (dd, 1H, J = 7.4, 2.9 Hz),
6.84−6.86 (m, 1H), 6.88 (d, 1H, J = 2.1 Hz), 7.59 (d, 1H, J = 8.2 Hz),
10.79 (s, 1H). 13C NMR (75.5 MHz, DMSO): δ (ppm) 37.1, 46.0,
111.7, 116.6, 124.5, 126.2, 154.5, 164.8, 196.8. MS (EI, 70 eV): m/z
226, 147, 119, 91, 77, 63. HRMS (APCI+): calcd for C9H8BrO2+ (M +
H+) 226.9702, found 226.9708.
General Procedure for the Synthesis of 7a−d. This procedure
has been adapted from Givens and co-workers.40 Pd/C (10%, 50 mg)
was added to a solution of 11 (1.5 mmol) in ethyl acetate (25 mL),
and the mixture was stirred under hydrogen atmosphere at 20 °C until
the starting material was consumed (TLC). The mixture was filtered
through a pad of Celite, and the solvent was evaporated under reduced
pressure. The title compound was purified using column chromatog-
raphy (ethyl acetate/hexane, 2:3).
2-Bromo-3,4-dihydro-6-hydroxynaphthalen-1(2H)-one (12b).
Prepared from 9b. Yield: 1.10 g (83%). Yellow solid. Mp: 152.1−
153.5 °C. 1H NMR (300 MHz, DMSO): δ (ppm) 2.25−2.35 (m, 1H),
2.46−2.56 (m, 1H), 2.87 (td, 1H, J = 16.9, 4.79 Hz), 2.98−3.07 (m,
1H), 4.92 (dd, 1H, J = 5.6, 3.6 Hz), 6.69 (d, 1H, J = 2.3 Hz), 6.78 (dd,
1H, J = 8.6, 2.4 Hz), 7.81 (d, 1H, J = 8.6 Hz), 10.52 (s, 1H). 13C NMR
(75.5 MHz, DMSO): δ (ppm) 25.9, 31.7, 52.2, 114.1, 114.9, 121.5,
130.3, 145.9, 162.6, 188.4. MS (EI, 70 eV): m/z 240, 185, 161, 134,
2,3-Dihydro-5-hydroxy-1-oxo-1H-inden-2-yl Acetate (7a). Pre-
+
106, 77, 51. HRMS (APCI+): calcd for C10H10BrO2 (M + H+)
pared from 11a. Yield: 260 mg (85%). White solid. Mp: 124.1−
1
125.7 °C. H NMR (300 MHz, CDCl3): δ (ppm) 2.17 (s, 3H), 2.97
240.9858, found 240.9858.
(dd, 1H, J = 17.1, 4.5 Hz), 3.59 (dd, 1H, J = 17.1, 7.8 Hz), 5.42 (dd,
1H, = 7.8, 4.6 Hz), 6.63 (s, 1H), 6.86−6.90 (m, 2H), 7.72 (d, 1H, J =
8.3 Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.7, 35.5, 74.1,
112.3, 116.8, 126.9, 127.5, 153.8, 163.1, 170.7, 199.0. MS (EI, 70 eV):
m/z 206, 163, 146, 135, 107, 77, 43. UV−vis: ε313 (CH3CN/H2O,
30:70, v/v) = 5711 dm3 mol−1 cm−1; ε313 (CH3CN) = 1172 dm3
6-Bromo-6,7,8,9-tetrahydro-2-hydroxybenzo[7]annulen-5-one
(12c). This compound was not purified. A crude reaction mixture was
used in the subsequent synthetic step.
General Procedure for the Synthesis of 8a−c. This procedure
has been adapted from our previous work.23 A solution of 12 (2.7
mmol), silver(I) oxide (900 mg, 4.0 mmol), and methanesulfonic acid
(0.35 mL, 5.4 mmol) in acetonitrile (30 mL) was stirred overnight at
60 °C. The reaction mixture was cooled to 20 °C and filtered through
a pad of Celite, and the solvent was removed under reduced pressure.
The crude product mixture was purified by flash chromatography
(ethyl acetate/hexane, 1:1).
+
mol−1 cm−1. HRMS (APCI+): calcd for C11H11O4 (M + H+)
207.0651, found 207.0657.
1,2,3,4-Tetrahydro-6-hydroxy-1-oxonaphthalen-2-yl Acetate
(7b). Prepared from 11b. Yield: 280 mg (85%). White solid. Mp:
119.1−120.4 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.21 (s, 3H),
2.26−2.36 (m, 2H), 3.0 (dt, 1H, J = 7.2, 3.6 Hz), 3.08−3.19 (m, 1H),
5.51 (dd, 1H, J = 12.9, 5.3 Hz), 5.66 (s, 1H), 6.71 (d, 1H, J = 1.9 Hz),
6.78 (dd, 1H, J = 8.5, 2.4 Hz), 7.97 (d, 1H, J = 8.6 Hz). 13C NMR
(75.5 MHz, CDCl3/CD3CN): δ (ppm) 20.7, 27.8, 29.0, 74.2, 114.1,
116.2, 124.3, 130.2, 145.8, 161.6, 170.1, 191.6. MS (EI, 70 eV): m/z
220, 202, 177, 160, 149, 121, 91, 77, 43. UV−vis: ε313 (CH3CN/H2O,
30:70, v/v) = 2665 dm3 mol−1 cm−1; ε313 (CH3CN) = 380 dm3 mol−1
2,3-Dihydro-5-hydroxy-1-oxo-1H-inden-2-yl Methanesulfonate
(8a). Prepared from 12a. Yield: 300 mg (45%). White solid. Mp:
1
204.1−205.3 °C. H NMR (300 MHz, CD3CN): δ (ppm) 3.14 (dd,
1H, J = 17.3, 4.5 Hz), 3.22 (s, 3H), 3.63 (dd, 1H, J = 17.2, 8.0 Hz),
5.30 (dd, 1H, J = 8.0, 4.5 Hz), 6.89 (d, 1H, J = 2.1 Hz), 6.91 (m, 1H),
7.62 (d, 1H, J = 9.1 Hz), 7.97 (s, 1H). 13C NMR (75.5 MHz, CDCl3):
δ (ppm) 34.1, 39.3, 80.2, 113.0, 117.7, 127.0, 127.3, 154.7, 165.4,
197.2. MS (EI, 70 eV): m/z 242, 226, 163, 146, 135, 107, 91, 77, 65.
UV−vis: ε313 (CH3CN/H2O, 30:70, v/v) = 11,777 dm3 mol−1 cm−1;
ε313 (CH3CN) = 3460 dm3 mol−1 cm−1. HRMS (APCI+): calcd for
C10H11O5S+ (M + H+) 243.0321, found 243.0318.
+
cm−1. HRMS (APCI+): calcd for C12H13O4 (M + H+) 221.0808,
found 221.0809.
6,7,8,9-Tetrahydro-2-hydroxy-5-oxo-5H-benzo[7]annulen-6-yl
Acetate (7c). Prepared from 11c. Yield: 280 mg (81%). White solid.
1
Mp: 123.9−125.2 °C. H NMR (300 MHz, CDCl3): δ (ppm) 1.66−
1,2,3,4-Tetrahydro-6-hydroxy-1-oxonaphthalen-2-yl Methane-
1.79 (m, 1H), 1.92−2.02 (m, 1H), 2.17−2.26 (m, 5H, −CH3, −CH2),
2.84−3.03 (m, 2H), 5.48 (dd, 1H, J = 11.0, 5.5 Hz), 6.54 (s, 1H), 6.6
(d, 1H, J = 2.3 Hz), 6.69 (dd, 1H, J = 8.3, 1.9 Hz), 7.74 (d, 1H, J = 8.5
Hz). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 20.8, 23.0, 28.1, 33.8,
sulfonate (8b). Prepared from 12b. Yield: 290 mg (42%). White
1
solid. Mp: 172.5−173.5 °C. H NMR (300 MHz, CDCl3) δ (ppm)
2.31 (m, 1H), 2.48 (m, 1H), 3.06 (m, 2H), 3.19 (s, 3H), 5.28 (dd, 1H,
J = 12.6, 5.1 Hz), 6.72 (d, 1H, J = 1.6 Hz), 6.80 (dd, 1H, J = 8.6, 2.0
H
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The Journal of Organic Chemistry
Article
Hz), 7.27 (s, 1H), 7.89 (d, 1H, J = 8.6 Hz). 13C NMR (75.5 MHz,
CD3CN/DMSO): δ (ppm): 27.9, 31.2, 39.0, 81.6, 115.1, 115.9, 124.1,
130.9, 147.3, 164.1, 190.9. MS (EI, 70 eV): m/z 256, 240, 160, 149,
134, 121, 107, 91, 77, 65. UV−vis: ε313 (CH3CN/H2O, 30:70, v/v) =
3840 dm3 mol−1 cm−1; ε313 (CH3CN) = 1257 dm3 mol−1 cm−1.
HRMS (APCI+): calcd for C11H13O5S+ (M + H+) 257.0478, found
257.0478.
mL) was stirred at 0 °C for 3 h. Water (50 mL) was then added to the
reaction mixture, and the organic material was extracted with ethyl
acetate (2 × 20 mL). The organic layers were washed with brine (2 ×
20 mL), dried with MgSO4, and filtered. The solvent was removed
under reduced pressure to give crude reaction mixture which was
redissolved in ethyl acetate (25 mL). To the resulting solution Pd/C
(10%, 10 mg) was added, and the mixture was stirred under a
hydrogen atmosphere (H2 balloon) at 20 °C until the starting material
was consumed (TLC). The mixture was then filtered through a pad of
Celite, and the solvent was evaporated under reduced pressure. The
title compound 7 (X = OH) was purified by column chromatography
(ethyl acetate/hexane, 3:7).
6,7,8,9-Tetrahydro-2-hydroxy-5-oxo-5H-benzo[7]annulen-6-yl
Methanesulfonate (8c). Prepared from 12c (reaction mixture). Yield:
1
220 mg (32%). White solid. Mp: 148.6−149.5 °C. H NMR (300
MHz, DMSO) δ (ppm) 1.53−1.60 (m, 1H), 1.82−1.89 (m, 1H), 2.10
(m, 1H), 2.20−2.27 (m, 1H), 2.84 (dd, 1H, J = 15.6, 4.7 Hz), 3.09 (t,
1H, J = 13.13 Hz), 3.23 (s, 3H), 5.46 (dd, 1H, J = 10.4, 5.6 Hz), 6.6 (d,
1H, J = 1.6 Hz), 6.74 (dd, 1H, J = 8.5, 2.0 Hz), 7.65 (d, 1H, J = 8.4
Hz), 10.28 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 22.1,
28.7, 32.4, 37.9, 82.4, 113.6, 116.3, 126.4, 131.5, 145.6, 161.3, 194.8.
(EI, 70 eV): m/z 270, 191, 163, 145, 127, 107, 91, 77, 65. UV−vis: ε313
(CH3CN/H2O, 30:70, v/v) = 2703 dm3 mol−1 cm−1; ε313 (CH3CN) =
989 dm3 mol−1 cm−1. HRMS (APCI+): calcd for C12H15O5S+ (M +
H+) 271.0634, found 271.0638.
3,4-Dihydro-2,6-dihydroxynaphthalen-1(2H)-one (13b). Prepared
from 11b. Yield: 70 mg (60%). White solid. Mp: 140.1−141.7 °C. 1H
NMR (300 MHz, DMSO): δ (ppm) 1.85 (dq, 1H, J = 12.2, 4.4 Hz),
2.20 (m, 1H), 2.87 (td, 1H, J = 16.7, 3.6 Hz), 2.97 (m, 1H), 4.18 (dd,
1H, J = 12.2, 4.8 Hz), 5.19 (s, 1H), 6.63 (d, 1H, J = 2.1 Hz), 6.73 (dd,
1H, J = 8.5, 1.9 Hz), 7.76 (d, 1H, J = 8.6 Hz), 10.38 (s, 1H). 13C NMR
(75.5 MHz, CDCl3): δ (ppm) 27.2, 31.8, 72.4, 114.0, 114.4, 123.1,
129.2, 146.6, 162.2, 196.9. MS (EI, 70 eV): m/z 178, 160, 134, 106, 91,
−
77, 65. HRMS (APCI+): calcd for C10H9O3 (M − H+) 177.0557,
Synthesis of 7,8,9,10-Tetrahydro-2-methoxybenzo[8]-
annulen-5(6H)-one (30d). This procedure has been adapted from
Ho and Yang.73 MeSO3H (53 mL, 0.82 mol) was stirred with 29b
(11.3 mmol) at 20 °C. P2O5 (7.7 g, 54.0 mmol) was then added
portionwise to the reaction mixture which was stirred for 24 h at 20
°C. The mixture was poured into water (50 mL) and extracted by
ethyl acetate (3 × 20 mL). The organic layer was washed with water (3
× 25 mL), aq K2CO3 (2 × 20 mL), and brine (25 mL) and dried with
MgSO4. The solvent was removed under reduced pressure and the title
compound was obtained after purification by column chromatography
(ethyl acetate/hexane, 1:4). Yield: 760 mg (33%). White solid. Mp:
found 177.0556.
6,7,8,9-Tetrahydro-2,6-dihydroxybenzo[7]annulen-5-one (13c).
Prepared from 11c. Yield: 68 mg (56%). White solid. Mp: 127.2−
1
128.5 °C. H NMR (300 MHz, CD3CN): δ (ppm) 1.49−1.57 (m,
1H), 1.60−1.68 (m, 1H), 2.06−2.10 (m, 1H), 2.17−2.22 (m, 1H),
2.81−2.85 (m, 1H), 2.97−3.02 (m, 1H), 3.93 (d, 1H, J = 3.3 Hz),
4.46−4.50 (m, 1H), 6.71 (d, 1H, J = 2.2 Hz), 6.78 (dd, 1H, J = 8.5, 1.6
Hz), 7.54 (s, 1H), 7.87 (d, 1H, J = 8.5 Hz). 13C NMR (75.5 MHz,
CDCl3): δ (ppm) 23.6, 31.8, 34.6, 75.8, 114.6, 117.5, 128.1, 133.0,
147.8, 162.0, 203.2. MS (EI, 70 eV): m/z 192, 163, 145, 135, 91, 77,
1
+
63, 39. HRMS (APCI+): calcd for C11H13O3 (M + H+) 193.0859,
137.7−139.1 °C. H NMR (300 MHz, CDCl3): δ (ppm) 1.40−1.48
(m, 2H), 1.75−1.89 (m, 4H), 2.99 (t, 2H, J = 7.1 Hz), 3.12 (t, 2H, J =
6.8 Hz), 3.83 (s, 3H), 6.67 (d, 1H, J = 2.5 Hz), 6.80 (dd, 1H, J = 8.7,
2.6 Hz), 7.95 (d, 1H, J = 8.7 Hz). 13C NMR (75.5 MHz, CDCl3): δ
(ppm) 23.2, 24.5, 27.7, 35.4, 42.8, 55.2, 111.5, 116.6, 131.5, 132.5,
143.1, 162.7, 203.0. MS (EI, 70 eV): m/z 204, 189, 177, 161, 148, 120,
91, 77, 63. HRMS (APCI+): calcd for C13H17O2+ (M + H+) 205.1223,
found 205.1229.
193.0857.
Synthesis of 15b−d. NaBH4 (5 mg, 0.12 mM) was added to a
methanol-d4 solution of 9 (0.06 mM) in an NMR tube under argon
atmosphere at 0 °C (Scheme 12). The reaction was analyzed by NMR
and used for spiking and HRMS analyses.
Scheme 12. Synthesis of 15b−d
Synthesis of 7,8,9,10-Tetrahydro-2-hydroxybenzo[8]-
annulen-5(6H)-one (9d). This procedure has been adapted from
Itoh and co-workers.74 A mixture of 30d (600 mg, 2.0 mmol) and
AlCl3 (1.3 g, 9.8 mmol) in benzene (50 mL) was refluxed for 3 h. After
cooling, the reaction mixture was poured into aq HCl (10%, 30 mL),
and the organic species were extracted with ethyl acetate (2 × 30 mL),
washed with water (2 × 20 mL), and brine (20 mL), and dried with
MgSO4. The solvent was removed under reduced pressure and the title
compound was obtained after purification by column chromatography
(ethyl acetate/hexane, 3:7). Yield 300 mg (78%).White solid. Mp:
143.1−144.5 °C. 1H NMR (300 MHz, DMSO): δ (ppm) 1.3 (m, 2H),
1.7 (m, 4H), 2.91 (t, 2H, J = 7.1 Hz), 3.07 (t, 2H, J = 6.7 Hz), 6.62 (d,
1H, J = 2.2 Hz), 6.70 (dd, 1H, J = 8.5, 2.2 Hz), 7.75 (d, 1H, J = 8.5
Hz), 10.07 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 22.5,
23.9, 27.1, 34.3, 41.9, 113.3, 117.6, 130.5, 130.9, 143.1, 161.2, 201.0.
MS (EI, 70 eV): m/z 190, 161, 147, 134, 106, 91, 77, 65. HRMS
2,3-Dihydro-1H-indene-1,5-diol (15b). 1H NMR (300 MHz,
CD3CN): δ (ppm) 1.87−1.93 (m, 1H), 2.35−2.39 (m, 1H), 2.66−
2.72 (m, 1H), 2.93−2.99 (m, 1H), 5.08 (t, 1H), 6.67 (s, 2H), 7.17 (d,
1H, J = 7.8 Hz). HRMS (APCI−): calcd for C9H9O2 (M − H+)
−
149.0608, found 149.0607.
1,2,3,4-Tetrahydronaphthalene-1,6-diol (15c). 1H NMR (300
MHz, CD3CN): δ (ppm) 1.67−1.71 (m, 1H), 1.84−1.95 (m, 3H),
2.58−2.64 (m, 1H), 2.68−2.74 (m, 1H), 4.64 (t, 1H, J = 4.7 Hz), 6.52
(s, 1H), 6.63 (d, 1H, J = 7.2 Hz), 7.19 (d, 1H, J = 8.4 Hz). 13C NMR
(75.5 MHz, MeOD): δ (ppm) 19.9, 30.5, 33.7, 68.4, 114.7, 116.0,
+
(APCI+): calcd for C12H15O2 (M + H+) 191.1066, found 191.1068.
General Procedure for the Synthesis of the Photoproducts
as the Analytical Standards. Synthesis of 13b,c. The title
compounds were prepared in two steps from the acetates 11 (Scheme
11) according to the known procedures.40,75 A mixture of 11 (0.65
mmol) and K2CO3 (106 mg, 0.77 mmol) in aq methanol (50%, 30
−
131.2, 139.4, 158.1, 170.6. HRMS (APCI−): calcd for C10H11O2 (M
− H+) 163.0764, found 163.0766.
6,7,8,9-Tetrahydro-5H-benzo[7]annulene-2,5-diol (15d). 1H
NMR (300 MHz, CD3CN): δ (ppm) 1.44−1.50 (m, 1H), 1.68−
1.77 (m,3H), 2.00−2.06 (m, 1H), 2.58−2.63 (m, 1H), 2.832.87 (m,
1H), 4.76−4.77 (m, 1H), 6.53−6.57 (m, 2H), 7.18 (d, 1H, J = 8.2
Hz). 13C NMR (75.5 MHz, MeOD): δ (ppm) 28.7, 29.2, 36.8, 38.0,
74.6, 113.0, 117.6, 127.7, 136.7, 143.5, 157.3. HRMS (APCI+): calcd
Scheme 11. Synthesis of 13b,c
−
for C11H13O2 (M − H+) 177.0921, found 177.0918.
Irradiation in NMR Tubes (General Procedure). A solution of a
phenacyl derivative 7a−d, 8a−c (5−8 mg) in D2O/CD3CN, (0.45−
0.5 mL) was irradiated using 40 W medium-pressure mercury lamp
with DMF (in a capillary tube) as an internal standard. Progress of the
I
dx.doi.org/10.1021/jo300850a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
reaction was monitored at regular time intervals by 1H NMR.
Identification of the photoproducts was based on spiking with
authentic samples and/or using HPLC/MS. After >95% of the
starting material was consumed, the reaction mixture was diluted and
analyzed by GC (with hexadecane, c = 10−3 M, as an internal
standard).
Preparative Irradiation. A solution of a phenacyl derivative (7a,c;
20−25 mg) in D2O/CD3CN, (0.7−0.9 mL) was irradiated using 40 W
medium-pressure mercury lamp until the starting material disappeared
(1H NMR). The solvents were removed under reduced pressure, and
major photoproducts were isolated using column chromatography
(ethyl acetate/hexane, 1:1).
(UPLC/MS-TOF). The products were identified by comparison
with the authentic samples and their exact masses.
Quantum Yield Measurements. Quantum yields were obtained
on an optical bench consisting of high-pressure 350 or 450 W UV
lamps, a 1/8 m monochromator with 200 to 1600 nm grating, set to
313 5 nm. The light intensity was monitored by a Si photodiode
detector (UV enhanced) with a multifunction optical power meter.
Degassed solutions of 7a−d, 8a−c (c ≈ 4 × 10−3 M) in D2O/CD3CN
were irradiated. The reaction conversion was kept below 10% (NMR)
to avoid interference of the photoproducts. DMF (in a capillary tube)
was used as internal standard. Valerophenone48 was used as an
actinometer.
Quenching Experiments. Two independently prepared solutions
of 7a,b (∼55 mM) in D2O/CD3CN with naphthalene (∼160 mM) as
a triplet quencher49 in one of the solutions were degassed and
irradiated at 366 nm. The reaction progress was monitored by NMR.
Laser Flash Photolysis Studies. The nanosecond laser flash
photolysis (LFP) setup was operated in a right angle arrangement of
the pump and probe beams. Laser pulses of ≤700 ps duration at 266
nm (30−80 mJ) were obtained from a Nd:YAG laser and were
dispersed over a 4-cm optical path of the quartz cell by a cylindrical
concave lens. The absorbance of the sample solution was adjusted to
0.3−0.5 in a 1-cm cuvette at the wavelength of excitation. A pulsed 75-
W xenon lamp was used as the source of probe white light. Kinetic (a
photomultiplier) and spectrographic (an ICCD camera) detection of
the transient absorption was available. Measurements were done at
2,3-Dihydro-2,5-dihydroxyinden-1-one (13a). Prepared from 7a in
82% yield. Yellow solid. Mp: 156.1−157.8 °C. H NMR (300 MHz,
1
CDCl3): δ (ppm) 2.72 (dd, 1H, J = 16.8, 4.5 Hz), 3.37 (dd, 1H, J =
16.8, 7.7 Hz), 4.29 (dd, 1H, J = 7.6, 4.7 Hz), 5.16 (d, 1H), 6.81 (m,
2H), 7.49 (d, 1H, J = 8.9 Hz), 10.22 (s, 1H). 13C NMR (75.5 MHz,
CDCl3): δ (ppm) 35.4, 72.6, 111.9, 116.0, 125.4, 126.0, 153.8, 164.1,
203.5. MS (EI, 70 eV): m/z 164, 147, 135, 121, 107, 91, 77, 57. HRMS
+
(MS ES+): calcd for C9H9O3 (M + H+) 165.0546, found 165.0552.
1,2,3,4-Tetrahydro-6-methoxynaphthalene-1-carboxylic Acid
1
(14c). Prepared from 7c in 54% yield. White solid. H NMR (300
MHz, D2O): δ (ppm) 1.67−1.71 (m, 1H), 1.85−1.92 (m, 1H), 2.02−
2.08 (m, 2H), 2.67−2.78 (m, 2H), 3.62 (t, 1H, J = 5.9 Hz), 6.67−6.72
(m, 2H), 7.03 (d, 1H, J = 8.0 Hz). 13C NMR (75.5 MHz, CD3CN/
D2O): δ (ppm) 21.6, 28.6, 29.8, 48.7, 113.9, 115.8, 129.3, 131.4, 139.9,
−
154.3, 185.6. HRMS (MS ES+): calcd for C11H11O3 (M − H+):
ambient temperature (22
2 °C). The samples were degassed by
repeating freeze−thaw cycles under reduced pressure (5 Pa).
Quantum Chemical Calculations. Quantum chemical calcula-
tions using density functional theory or MP2 method were performed
with the Gaussian 09 package (revision A.02)76 of programs.
Geometries were fully optimized at the RB3LYP/6-31+G(d) level of
theory in the case of closed shell species. Unrestricted versions of
functionals were employed in calculations of the triplet states. For all
stationary points, the harmonic vibrational frequencies were computed
to obtain the ZPVE correction which was scaled by 0.9857.55 Single
point energies at the B3LYP geometries were computed with the M06-
2X functional or with the MP2 method using the 6-311+G(2df,2p)
basis set. This approach has proven to perform satisfactorily well in
computations of thermodynamic properties of both closed- and open-
shell species.77 The resulting enthalpies are given at 0 K (E + scaled
ZPVE).
191.0714, found 191.0716.
Irradiation of 7b in the Presence of an Acid. Two solutions of
7b (5−8 mg) in D2O/CD3CN (30:70, v/v) with a drop of DCl were
placed in two NMR tubes. One was kept at ambient temperature for
24 h as a blank sample to monitor the stability of 7b in the dark. The
other was irradiated using a 40 W medium-pressure mercury lamp
through a Pyrex filter until the conversion reached ∼95% (1H NMR)
with DMF (in a capillary tube) as an internal standard.
ZnCl2 Reaction with 12b. This procedure has been adapted from
Maiti and co-workers.45 Anhydrous ZnCl2 (176 mg, 1.3 mM) is added
at room temperature under an atmosphere of nitrogen to methanol (4
mL). The resulting stirred solution was heated at 115 °C and a
solution of 12b (30 mg, 0.13 mM) in methanol (1 mL). The mixture
was kept under nitrogen and stirred at 115 °C until the complete
conversion of the starting material (TLC). The mixture was then
cooled to room temperature, poured into water (5 mL), and extracted
with a mixture of diethyl ether/dichloromethane (3 × 5 mL). The
combined organic extract was washed with water (2 × 5 mL) and
dried with Na2SO4. Solvent was evaporated under reduced pressure,
and the reaction mixture was submitted for HPLC (UPLC/MS-TOF)
analysis (chromatograms are in the Supporting Information, Figures
S14 and S15).
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthetic and photochemical procedures; laser flash photolysis
and computational data; 1H, 13C NMR, absorption, and HRMS
spectra of the compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Likewise, p-hydroxyphenacyl bromide was reacted with ZnCl2 in the
same manner. Anhydrous ZnCl2 (634 mg, 4.6 mM) in methanol (4
mL) was heated at 115 °C, and a solution of 17 (100 mg, 0.46 mM) in
methanol (1 mL) was added. At complete conversion, the mixture was
worked up as above and extracted with dichloromethane (3 × 15 mL),
the combined organic extract was washed with water (2 × 15 mL) and
dried (MgSO4), and the solvent was evaporated. The products were
isolated by column chromatography, and the individual products, 18
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: (P.K.) klan@sci.muni.cz, (R.S.G.) givensr@ku.edu.
Notes
The authors declare no competing financial interest.
1
and 19, were determined by comparison of the H NMR, MS, GC,
and GC/MS properties with authentic samples or the literature values
for 18.51 A significant amount of Cl/Br exchange occurred as shown
by GC/MS. Neither 2-hydroxy-1-(4-hydroxyphenyl)ethanone nor 4-
hydroxyacetophenone was shown to be present by GC/MS
coinjection of authentic samples.
ACKNOWLEDGMENTS
■
Support for this work was provided by the Ministry of
Education, Youth and Sports of the Czech Republic (ME09021,
KONTAKT/AMVIS), the Grant Agency of the Czech
Republic: 203/09/0748 (T.S., P.K.), the project CETOCOEN
(CZ.1.05/2.1.00/01.0001) granted by the European Regional
Development Fund, and R01 GM72910 (R.S.G.). T.S. profited
from the Brno Ph.D. Talent program funded by Brno City
Municipality. We thank Dr. Sanjeewa Senadheera for the Lewis
acid catalyzed rearrangement reaction study on pHP Br. We
Isotope Labeling Experiments with D218O. A phenacyl
derivative (7a−c, 5−8 mg) was dissolved in two NMR tubes in
CD3CN (0.45−0.5 mL). D2O (0.1 mL) was added to the first one; the
same amount of D218O was placed to the other. Both solutions were
irradiated with a 40 W medium-pressure mercury lamp through a
1
Pyrex filter until the starting material was observable by H NMR.
Both reaction mixtures were subsequently analyzed by HRMS
J
dx.doi.org/10.1021/jo300850a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
́
thank Lukas Maier and Blanka Vrbkova for their help with the
Article
(34) Chen, X. B.; Ma, C. S.; Kwok, W. M.; Guan, X. G.; Du, Y.;
Phillips, D. L. J. Phys. Chem. A 2006, 110, 12406.
(35) Chen, X. B.; Ma, C. S.; Kwok, W. M.; Guan, X. G.; Du, Y.;
́
̌
NMR and mass spectrometry analyses.
Phillips, D. L. J. Chem. Phys. B 2007, 111, 11832.
DEDICATION
■
(36) Ma, C. S.; Kwok, W. M.; Chan, W. S.; Du, Y.; Kan, J. T. W.;
Toy, P. H.; Phillips, D. L. J. Am. Chem. Soc. 2006, 128, 2558.
(37) Ma, C. S.; Kwok, W. M.; Chan, W. S.; Zuo, P.; Kan, J. T. W.;
Toy, P. H.; Phillips, D. L. J. Am. Chem. Soc. 2005, 127, 1463.
(38) Burr, J. G.; Dewar, M. J. S. J. Chem. Soc. 1954, 1201.
(39) Aston, J. G.; Newkirk, J. D. J. Am. Chem. Soc. 1951, 73, 3900.
(40) Givens, R. G., R. S.; Stensrud, K.; Conrad, P. G.; Yousef, A. L.;
Perera, C.; Senadheera, S. N.; Heger, D.; Wirz, J. Can. J. Chem. 2011,
89, 364.
This article is dedicated to the memory of Professor Howard E.
Zimmerman, University of Wisconsin, Madison (July 5,
1926−February 11, 2012).
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