Mechanistic studies of adamantylacetophenones with competing reaction pathways in solution and in the crystalline solid state

Article abstract of DOI:10.1021/acs.joc.9b01720

Photochemical reactions in crystals occur under conditions of highly restricted molecular mobility such that only one product is generally obtained, even when there are many others that can be observed in the gas phase or in solution. A series of 2-(1-ada

Full text of DOI:10.1021/acs.joc.9b01720

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Article
Mechanistic Studies of Adamantylacetophenones with Competing
Reaction Pathways in Solution and in the Crystalline Solid State
Vince M. Hipwell, and Miguel A. Garcia-Garibay
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01720 • Publication Date (Web): 14 Aug 2019
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The Journal of Organic Chemistry
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Mechanistic Studies of Adamantylacetophenones with Competing
Reaction Pathways in Solution and in the Crystalline Solid State
Vince M. Hipwell and Miguel A. Garcia-Garibay*
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Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
*email: mgg@chem.ucla.edu
ABSTRACT: Photochemical reactions in crystals occur under conditions of highly restricted molecular mobility such that only
one product is generally obtained, even when there are many others that can be observed in the gas phase or in solution. A se-
ries of 2-(1-adamantyl)-ortho-alkyl-acetophenones with gamma hydrogen atoms on both the adamantyl and ortho-aromatic
groups was selected to determine whether or not one can engineer and observe competing Norrish Type II reaction pathways in
the crystalline state. It was shown that excited state competition for hydrogen abstraction between secondary adamantyl and
benzylic hydrogens is affected not only by the relative bond dissociation energies but also by the molecular conformation in the
crystal. The subsequent fate of the resulting biradical species is determined by competition between radical recombination to
form photoproduct and reverse hydrogen atom transfer to regenerate the starting ketone. Crystallographic information, photo-
product distributions in solution and in the solid state, and the results of multiple mechanistic experiments including transient
absorption spectroscopy in acetonitrile and with nanocrystals suspended in water are reported. The results demonstrate that it is
possible to engineer competing reactions in crystals and that consideration of all of the aforementioned factors is necessary in
order to account for the observed photoproduct selectivity.
Me
H
OMe
Me
INTRODUCTION
H
H
O
O
H
H
H
H
The Norrish Type II reaction is one of the most widely
studied photochemical processes, and many mechanistic
studies have been reported on a broad range of compounds
both in solution and in the solid state.1–6 In a recent study,
crystals of adamantyl-para-methoxy-acetophenone (1, Fig-
ure 1) were utilized for one of the first mechanistic investiga-
tions of the Norrish Type II reaction based on absolute pho-
tochemical kinetics in the solid state using laser flash pho-
tolysis (LFP) of aqueous nanocrystalline suspensions.7
Along with the identification of transient intermediates and
their lifetimes, it was shown that the photoproduct diastere-
oselectivity for 1 is affected by the rotation of the globular
adamantane group, which occurs in both solution and the
solid state. Given this interesting result, we decided to use
the adamantylacetophenone structure as a platform for fur-
ther investigation of the Norrish Type II reaction. In particu-
lar, we sought to probe the reaction mechanism and product
selectivity for compounds designed to facilitate multiple
hydrogen transfer pathways such that reactivity trends and
product selectivity factors may be elucidated.
Modifications of the structure 1 to include ortho-alkyl
substituents to the acetophenone chromophore provides an
opportunity for competition between two analogous photo-
chemical reaction pathways in the ortho-aryl substituted
adamantylacetophenones 2-5 (Figure 1). There is one set of
abstractable gamma hydrogens on the adamantyl group,
shown in blue for compounds 1 and 2, and another one on
the ortho-alkyl groups in the case of 2-4, which are shown in
red for compound 2. The latter structures contain chemodiv-
1 (m.p. 77-80 oC)
2 (m.p. 69-72 oC)
O
O
O
tBu
tBu
OMe
3 (m.p. 118-120 oC) 4 (m.p. 58-60 oC)
5 (m.p. 184-186 oC)
----------------------------------------------------------------------
10) kcy(trans-ACB)
HO
OMe
H
OH
1
1)
k
cy(
cis
trans-ACB-3
ISC
k
-ACB)
8)
7) kHAT
T
HA
k
9)
H
H
O
H
H
H
3
*
O
1) hν
OMe
OMe
H
OH
H
OMe
H
OMe
2) kISC
H
H
H
H
H
cis-ACB-3
5) k[1,5]
3) kHAT
HO
6) kcy(BCB)
OMe
4) kISC
HO
HO
OMe
QDM-3
BCB-3
Figure 1. (Top) Structures and melting points of adaman-
tylacetophenone derivatives, including adamantyl-para-
methoxy-acetophenone 1 with abstractable secondary hydrogen
atoms
highlighted
in
blue
and
adamantyl-2,4,6-
trimethylacetophenone 2 with abstractable primary benzylic
hydrogens in red. (Bottom) Photochemical reaction mechanism
for adamantyl-4-methoxy-2,6-dimethyl-acetophenone 3. Col-
ored boxes highlight reaction pathways available upon abstrac-
tion of one of the two types of γ-hydrogen atoms from the T1
state of the ketone.
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ergent hydrogen atom transfer (HAT) pathways potentially
Page 2 of 13
section along with full characterization data. Their 1H NMR,
13C{1H} NMR, UV-Vis, and IR spectra can be found in the
supporting information (SI) section.
1
2
3
4
5
6
7
8
leading to Yang cyclizations and photoenolization reactions.
Ketone 5 was selected to explore the competition for hydro-
gen abstraction between secondary adamantyl γ-hydrogens
and the primary δ-hydrogens of the ortho-tert-butyl groups.
A general mechanistic scheme for these compounds is
shown in the bottom part of Figure 1 with adamantyl-4-
methoxy-2,6-dimethylacetophenone 3 as a representative
example. The reaction starts by electronic excitation and
intersystem crossing (ISC) to the T1 state (steps 1, 2 in Fig-
ure 1) and is followed by HAT from either a benzylic posi-
tion (step 3), to yield a biradical species corresponding to the
triplet excited state of ortho-quinonedimethide QDM-3, or
from the adamantyl methylene hydrogens (step 7) to yield a
triplet 1,4-ketyl-adamantyl biradical. If HAT occurs from the
adamantyl group, ISC and reverse HAT (steps 8, 9) lead
back to ketone 3. Alternatively, recombination of the biradi-
cal (steps 10, 11) can form photoproducts trans-ACB-3
(trans referring to the relative positions of the adamantane
and aromatic group with respect to the cyclobutanol ring,
and ACB meaning adamantane cyclobutanol), or cis-ACB-3
depending on the orientation of the radicals upon recombina-
tion. If HAT occurs from the benzylic position (step 3),
intersystem crossing and radical recombination yields the
benzocyclobutanol photoproduct BCB-3 (step 6). However,
ISC can also form the ortho-quinonedimethide QDM-3 (step
4), which is subject to facile [1,5]-sigmatropic shift to reform
ketone 3 (step 5). In the case of ketone 5, HAT competition
would occur between the secondary adamantyl γ-hydrogens
Single Crystal X-Ray Diffraction Analysis. While the
lower bond dissociation energy (BDE) of the benzylic C-H
bonds relative to the secondary C-H bonds of the adamantyl
group may suggest that step 3 should predominate over step
7, one should expect the selectivity of the initial HAT step to
also be dependent on crystal conformation. Crystals of each
ketone were obtained by slow evaporation of ethanol solu-
tions. Single crystal X-ray diffraction analysis with ketones
2-4 was successful and selected crystallographic parameters
for each of these structures are shown in Table S2 along with
data from 1, which had been previously reported.7 Crystals
of 5 prepared in this way displayed significant twinning.
Despite attempts with many different crystallization methods
and solvent mixtures, samples of 5 only yielded polycrystal-
line material that was not amenable to X-ray diffraction.
The similarity between the molecular structures 2 and 3
extends to their crystal packing. As shown in Table S2, both
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crystallize in the P1 space group and have similar unit cell
lengths and angles. The crystal structures of ketones 1 and 4
feature greater numbers of molecules per unit cell with a
corresponding increase in the length of at least one unit cell
dimension.
The molecular conformation of each ketone in the crystal-
line solid state are shown in Figure 2. Again, the similarity
of 2 and 3 manifests in nearly identical conformations with
the carbonyl group almost completely perpendicular to the
plane of the aromatic ring as indicated by dihedral angles of
81.6° and 85.2°, respectively. Interestingly, the carbonyl
group in 4 is rotated toward the ortho-isopropyl group de-
spite the potential to achieve coplanarity with the aromatic
ring (as in 1) if it were to be rotated in the opposite direction
where there is a hydrogen atom. The dihedral angles between
the plane of the carbonyl and the plane of the aromatic
groups are 0.5° and 43.0° in ketones 1 and 4, respectively.
and the primary δ-hydrogens of the tert-butyl groups.
A
detailed product analysis in solution and in the solid state,
combined with LFP experiments of nanocrystalline suspen-
sions of ketones 2-5, revealed the feasibility of engineering
competing reactions in crystals.
RESULTS AND DISCUSSION
Synthesis and Characterization. Ketones 1, 2, and 4
were synthesized via Friedel-Crafts acylation of the appro-
priate aromatic compounds with 1-adamantylacetyl chloride.
Interestingly, 4 was the product isolated from the reaction
with 1,4-diisopropylbenzene. A control experiment in which
the acid chloride was excluded showed that the isomerization
of 1,4-diisopropylbenzene occurs in the presence of alumi-
num chloride, as previously documented under similar con-
ditions.8 Therefore, the formation of 4 likely proceeds fol-
lowing the in situ isomerization of 1,4-diisopropylbenzene to
1,3-diisopropylbenzene, rather than as a result of a 1,2-
isopropyl shift during reaction with the acid chloride.
1
2
Analogous conditions for the preparation of 3 failed due to
regiospecific acylation occurring ortho to the methoxy group
of the 1-methoxy-3,5-dimethylbenzene reactant. Also, since
ipso substitution was observed for the reaction involving 1,4-
di-tert-butylbenzene, it was assumed that 5 could also not be
prepared by this method. Thus, ketones 3 and 5 were pre-
pared by treatment of 1-adamantylacetyl chloride with the
aryllithium species generated from the corresponding aryl
bromide. Acetophenone derivatives 1-5 were isolated as
colorless crystals with melting points well above room tem-
perature as noted in Figure 1. Detailed synthetic procedures
for the preparation of 1-5 are reported in the experimental
3
4
Figure 2. Molecular conformations of ketones 1-4 in the crys-
talline solid state as determined by SCXRD.
Our group has previously shown that the product selectivi-
ty of 1 is complicated by the ability of the adamantane
groups to rotate in the solid state, such that the position of
the adamantyl radical center can vary to give rise to the for-
mation of products cis- and trans-ACB-1. Similar to the
2
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the γH with the geometric parameters closer to the ideal val-
crystal packing of 1, the SCXRD structure of ketones 2 and 3
1
2
3
4
5
6
7
8
have the adamantane and aromatic groups form alternating
layers in the crystal lattice, as shown for ketone 2 in the top
part of Figure 3. Crystals of ketone 4, however, contain only
1-dimensional chains of adamantane groups (Figure 3, bot-
tom). While this arrangement may not eliminate the ability
of the adamantane groups to rotate in the solid state, it is
likely that the rotational rate would be reduced, with possible
implications for reaction selectivity.
ues. For derivatives 2-4 in Table 1, all of the parameters
show a consistent preference for either benzylic (Benz) or
adamantyl (Adam) hydrogen abstraction, with the adamantyl
hydrogens being favored in 2 and 3, and the benzylic hydro-
gen being favored in 4. However, this analysis based solely
on the geometric parameters incorrectly predicts the photo-
products in each case as will be shown. Also, 5 exhibits no
photochemical reactivity in solution or the solid state, de-
spite the calculated structure giving geometric parameters
that indicate that hydrogen abstraction should be possible.
All of these results suggest that there are additional factors to
consider when predicting the outcome of this set of solid
state Norrish Type II reactions.
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Table 1. Geometric parameters relating carbonyl group
and nearest gamma hydrogens in ketones 1-5.
d
H
O
H
Θ
Δ
O
D
ω
R
R
d
Δ
Θ
ω
D
[Å]
Ketone H-Type
[Å]
[°]
[°]
[°]
90-
120
Ideal
1
γ
N/A
<2.7
180
0
Adam
Benz
Adam
Benz
Adam
Benz
Adam
δb
3.015 2.651 79.12 107.94 64.39
2.895 2.811 76.67 110.95 61.92
3.201 2.504 97.16 120.95 22.21
2.926 2.786 70.67 120.93 68.54
3.157 2.455 96.75 121.89 26.03
3.067 2.354 86.88 122.32 52.17
3.031 3.005 64.78 106.00 73.82
2.894 2.409 91.93 110.85 69.81
3.241 2.536 97.03 118.35 31.12
2
3
Figure 3. (Top) Crystal packing of 2 viewed down the a-axis
with alternating layers of aromatic and adamantane groups.
(Bottom) Crystal packing of 4 with alternating one dimensional
chains of adamantane and aromatic groups generated by transla-
tion down the a-axis.
4
5a
Adam
Solid State Reaction Geometry. A set of descriptors
relating the ideal geometric parameters describing the posi-
tion of γ-hydrogen (γH) atoms with respect to the carbonyl
n-orbital involved in Norrish Type II reactivity have been
developed by Scheffer.6,9–12 These include the distance be-
tween the carbonyl carbon and the γ carbon (D), the distance
between the carbonyl oxygen and the γH (d), the C=O···γH
angle (Δ), the γCH···O angle (Θ), and the angular displace-
ment of the γH from the plane of the carbonyl group (ω).
The ideal values for these geometric parameters as well as
those determined for ketones 1-4 based on SCXRD can be
found in Table 1. Geometric parameters for ketone 5 were
obtained from a calculated lowest energy structure obtained
from a molecular mechanics (MMFF) conformer distribution
followed by DFT calculation of its equilibrium geometry using
the B3LYP functional and 6-31G* basis set. Since 1 is known
to undergo Norrish-Yang cyclization in the solid state, it is
apparent that these bond angles and distances may deviate
significantly from their ideal values in a substrate that exhib-
its photochemical reactivity. For ketones 2-4, one would
expect that hydrogen atom abstraction would take place from
aGeometric parameters for 5 were determined from the lowest
energy conformer minimized with the B3LYP/6-31G* method
b
(SI). The hydrogen atoms of the tert-butyl groups of 5 are δ
hydrogens. Geometric parameters are measured in an analogous
manner.
Nanocrystalline Suspensions. Solid state samples for
transient absorption spectroscopy were prepared via the re-
precipitation method.13 Generally, this method involves dis-
solving the compound of interest in a water miscible organic
solvent followed by rapid injection or dropwise addition of
the resulting solution into vortexing water. The insolubility
of the compound in the water causes instantaneous precipita-
tion, while the motion of the water distributes the material
such that the particle size is limited. The use of a dilute
aqueous surfactant solution in the place of pure water is of-
ten necessary; the surfactant molecules passivate the surface
of the particles once formed in order to limit aggregation.
With appropriate conditions (stock solution concentration,
surfactant type and concentration, addition method and vol-
3
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Page 4 of 13
ume, etc.), stable suspensions of crystalline particles with PXRD pattern matched that of the bulk powder and the
1
2
3
4
5
6
7
8
average size in the sub-micron regime can be prepared. We
term such mixtures nanocrystalline suspensions, which have
been shown to be amenable to spectroscopic analysis using
standard solution-phase methods.7,14–19 For each derivative,
nanocrystalline suspensions were prepared using 0.04 mM
CTAB surfactant solution and stock solutions in acetonitrile.
For ketone 4, 0.2 mL of a 2.5 mg/mL acetonitrile solution
was added dropwise to ~20 mL of vortexing surfactant solu-
tion. SEM imaging (Figure 4) of a dried droplet of this sus-
pension indicated that the particles were crystalline and ex-
hibited a size distribution in agreement with dynamic light
scattering (DLS) results. Figure 4 also contains a set of UV-
Vis spectra for this suspension at several time points, along
with an equimolar (0.025 mg/mL) solution of 4 in acetoni-
trile. As expected, the spectral features of the solution and
solid state samples are identical. Despite the equivalent con-
centrations, the suspension spectra have a higher apparent
absorbance due to Rayleigh scattering, which is proportional
to 1/λ4. The similarity of the suspension spectrum over a 30-
minute time period indicates that the suspension is stable
(i.e. not prone to significant aggregation or decomposition)
on the timescale of the transient absorption experiments.
simulated pattern from the SCXRD structure of 4 (Figure 5).
The higher loading of suspensions for PXRD analysis is
necessitated by the difficulty of collecting enough material
from the dilute suspensions used for transient absorption
spectroscopy. It is assumed that the crystals in each suspen-
sion share the same polymorph due to the similarity of the
environments during the crystallization process. Additional
SEM images of the suspension of 4 along with UV-VIS (so-
lution and suspension), SEM, and PXRD data for suspen-
sions of the other derivatives can be found in the SI.
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1.0
Solution
0 min.
0.8
Figure 5. Powder X-ray diffraction (PXRD) of 4 (A) simulated
from single crystal XRD structure, (B) bulk powder, (C) powder
from dried aqueous suspension.
10 min.
0.6
20 min.
30 min.
0.4
0.2
0.0
Solution and Solid State Photochemistry. Ketones 1-5
were subjected to irradiation with a medium pressure mercu-
ry lamp in both deuterated acetonitrile and in aqueous sus-
pensions. The solution for 1 was prepared with 5.0 mg/mL
concentration, and the remaining solutions were made such
that all solutions were equimolar. Aqueous suspensions were
prepared by injecting 0.1 mL of acetonitrile stock solution
into 0.9 mL vortexing Millipore water. Stock solution con-
centrations were controlled such that the total amount of
each ketone in the suspensions matched that of the solution
samples. All samples were sparged with argon, then sealed
in NMR tubes and irradiated simultaneously for 10 minutes
225
325
425
525
Wavelength (nm)
1
and 2 hours, with H NMR spectra being taken after each
irradiation time period. Product distribution percentages for
the 2-hour time point in Table 2 represent relative NMR
yields of recognizable photoproducts (ignoring minor or
unassignable side products) as determined by comparison to
spectra of the isolated photoproducts or by inference follow-
ing the isolation of the dehydrated alcohol photoproducts.
Further discussion of photoproduct identification can be
found in the experimental section.
Results for the 10-minute time point (SI, Table S1) exhibit
a larger conversion of 1 relative to those of all other deriva-
tives. For 2, 3, and 4, the limited conversion is likely due to
the favorable but unproductive reaction pathway to reform
the starting material after formation of the photoenol QDM
(Figure 2, steps 1-5). For 2 and 3, this pathway was shown to
be operating in solution by irradiation of solutions in 9:1
MeCN-d3 : D2O with concentrations that match those of the
previously discussed product analysis experiments. The enol
Figure 4. (Top) UV-Vis spectrum of equimolar MeCN solution
and nanocrystalline suspension (several time points) of 4. The
consistency of the absorption spectrum for the suspension sam-
ple is indicative of its stability over the timeframe of the transi-
ent absorption experiments. (Bottom) SEM image of a nano-
crystalline suspension of 4. The crystal sizes were consistent
with size distribution determined by DLS (232 ± 112 nm).
Lastly, an aqueous suspension of 4 with higher loading
(1.0 mL of a 10.0 mg/mL solution injected into 3.0 mL of
water) was dried under an air stream. The resulting powder
was analyzed by powder x-ray diffraction (PXRD). The
4
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The Journal of Organic Chemistry
Table 2. Photoproduct distributions of 1-4 in MeCN solutions and aqueous nanocrystalline suspensions.a
1
2
3
4
R1
R1
OH
R1
OH
R1
R2
O
R2
R2
H
H
hν
HO
+
+
R2
R3
R4
R4
R3
R3
R3
R5
R5
R4
R5
R4
1 - 4
cis-ACB
trans-ACB
BCB
5
6
7
8
9
%
BCB
Ketone
R1 (o)
H
R2 (p)
OMe
Me
R3
N/A
H
R4
R5
Medium
% Conversion
% cis-ACB
% trans-ACB
% Deuteration
MeCN
Suspension
MeCN
96
72
26
43
21
22
6
38
69
0
62
31
0
N/A
N/A
100
100
63
N/A
N/A
13
1
2
N/A
H
N/A
H
10
11
12
13
14
15
16
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Me
Suspension
MeCN
0
0
N/A
26
16
13
70
78
21
49
30
22
3
4
Me
H
OMe
iPr
H
H
H
Suspension
MeCN
37
N/A
58b
0
Me
Me
H
Suspension
6
0
N/A
aAll samples were prepared as degassed MeCN-d3 solutions or aqueous suspensions (all equimolar) and irradiated for 120 minutes with a
450 W medium pressure mercury lamp. Values in the final column (% Deuteration) are derived from an analogous set of experiments with
a 9:1 MeCN-d3 : D2O solvent mixture. bBenzylic deuteration percentage for ketone 4 after 120 minutes irradiation in 8:1:1 MeCN-d3 : D2O
: TFA-d. No benzylic deuteration of ketone 4 was observed when irradiated in 9:1 MeCN-d3 : D2O.
hydrogen of the QDM is able to exchange with deuterons
from the D2O, and after step 5 the exchanged deuterium at-
om replaces a hydrogen on the methyl groups ortho to the
ketone. Multiple cycles of this reaction pathway for an indi-
vidual ketone molecule results in partial or complete deuter-
ation of these benzylic positions. Percent deuteration values
for an equivalent amount of time exhibited no deuteration,
ruling out a ground-state acid-catalyzed exchange mecha-
nism (SI). Thus, it may be concluded that the formation of
the QDM species as a photochemical intermediate occurs in
ketones 2, 3, and 4. We propose that this reaction pathway
may also be active in the solid state samples and be the pri-
mary factor responsible for the reduced conversion percent-
ages observed for both the solution and solid state samples of
2, 3, and 4 relative to those of 1.
1
(determined by H NMR) of recovered starting material fol-
lowing 2 hours of irradiation of these samples are shown in
Table 2. Figure 6 represents an example of the comparison
1
of H NMR spectra to determine these values. As noted in
Despite the reduced conversion rate for 2, 3, and 4, ex-
tended irradiation results in the formation of isolable quanti-
ties of various photoproducts. The most striking differences
in reactivity are seen in ketones 2 and 4, which exclusively
form the BCB and ACB photoproducts, respectively, in both
solution and aqueous suspension. In the case of mesityl de-
rivative 2, the selectivity for the BCB product is likely the
result of a very strong preference for benzylic hydrogen ab-
straction (step 3) due to lower BDE value such that the bi-
radical that would lead to the formation of the ACB photo-
products is never accessed, even in the solid state where the
geometric parameters predict a preference for adamantyl
hydrogen abstraction. By contrast, the deuteration experi-
ments for the ortho-isopropyl ketone 4 suggest that, at least
in solution, benzylic hydrogen abstraction occurs. However,
the absence of any BCB-4 in the photoproduct mixture indi-
cates that the radical recombination (step 6) does not occur.
This could be due to prohibitively large steric repulsion for
the dimethyl-radical recombination, such that return back to
4 via QDM-4 may be the only accessible pathway to this
biradical. Alternatively, the formation of QDM-4 may be
fast enough to preclude any conformer that would allow
radical recombination from ever being accessed. In either
case, the result is that hydrogen abstraction from the ada-
mantyl group (step 7) competes and enables the formation of
the ACB photoproducts.
Table 2, deuteration of 4 was not observed under these con-
ditions. However, modification of the solvent mixture to
include an acid catalyst to promote the proton-deuterium
exchange (8:1:1 MeCN-d3 : D2O : TFA-d) enabled deuter-
ation of the isopropyl group. A control experiment in which
an identical sample was not irradiated but allowed to stand
CHxD(3-x)
O
O
hν
OMe
OMe
9:1 MeCN-d3 : D2O
HyD(3-y)
C
x,y ∈ {1,2,3}
1
Figure 6. Partial H NMR spectrum of 3 with labeled peaks
normalized to the signal of the methylene unit before and after
irradiation in a degassed 9:1 MeCN-d3 : D2O solution. Integra-
tion values are labeled above each peak.
Interestingly, electronic excitation of adamantyl-4-
methoxy-2,6-dimethylacetophenone 3 produces both ACB
diastereomers as well as the BCB product. This implies that
5
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Table 3. Phosphorescence lifetimes and preexponential factors of ketones 1-5 at 77 K in methylcyclohexane glasses.
1
2
3
4
5
6
7
8
a
b
Ketone
A1
τ1 (ms) a
13.6
A2
τ2 (ms) b
38.4
τAve (ms) c
31
R2
1
2
3
4
5
0.56
0.98
0.97
0.80
0.57
0.44
0.02
0.03
0.20
0.43
0.99995
0.99770
0.99618
0.99661
0.99897
0.51
7.27
2.0
0.63
12.4
5.1
12.8
967
920
138
1092
955
aPreexponential factors and lifetimes of the short-lived components. bPreexponential factors and lifetimes of the long-lived components.
9
2
cAverage lifetime calculated from the equation τAve = (A1τ12 + A2τ2 ) / (A1τ1+A2τ2).20
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the various factors affecting hydrogen abstraction and radical
recombination balance, such that all possible Norrish-Yang
photoproducts are formed. Considering the similarity of the
solid state molecular structures of ketones 2 and 3, both with
methyl groups at their ortho-position, the substantial differ-
ence in photoproduct selectivity is very interesting. The abil-
ity of 3 to exhibit adamantane hydrogen abstraction in solu-
tion and in the solid sate must be the result of the change in
electronic structure imparted by the p-methoxy group. The
results of transient absorption spectroscopy experiments in
MeCN solution, discussed below, support this hypothesis.
While the lifetime of the T1 state of 2 was determined to be
<10 ns due to the lack of an observable transient, that of 3 is
480 ± 10 ns. The substantially longer T1 lifetime of 3 relative
to that of 2 reflects a lower reactivity that arises from a
greater contribution of the (π,π*) electronic configuration, as
documented for a number of acetophenone and benzophe-
none derivatives.21,22 The attenuated reactivity in the case of
3 appears to allow for a decrease in selectivity, as shown by
the formation of products from competing hydrogen abstrac-
tion at the adamantyl and aromatic methyl groups (Table 2).
However, the lack of observable transient species for both
ketones in the solid state indicates that reactions in the nano-
crystals are completed within the ca. 10 ns pulse.
It is also worth noting the difference in photochemical
selectivity observed between the solution and solid state
reactions for 3, with BCB favored in solution and ACB fa-
vored in the solid state. In solution, the enhanced conforma-
tional freedom enables preference for the thermodynamically
favored benzylic hydrogen abstraction. In the crystalline
solid, however, the ACB products are formed preferentially.
The geometric parameters listed in Table 1 suggest that the
adamantane γH atoms are better positioned for hydrogen
abstraction to occur (the carbonyl oxygen to γH distance is
shorter, and all angles are closer to the ideal values). Thus,
the more favorable geometry may be able to offset the ther-
modynamic preference for abstraction of the hydrogen atom
with lower BDE in order to form the ACB diastereomers as
the major photoproducts.
was no observable conversion of 5 by 1H NMR. Therefore, it
must be the case that the steric hindrance imposed by the
adamantane group prevents either the hydrogen abstraction
or the radical recombination step from occurring. Unfortu-
nately, the lack of a crystal structure of 5 prevents this hy-
pothesis from being further investigated by an analysis of the
geometry of the ground-state structure. However, if the mo-
lecular conformation in the crystal matches that of the calcu-
lated structure of 5 (SI), then the geometric parameters in
Table 1 predict that hydrogen abstraction should be possible,
supporting the hypothesis that steric effects are responsible
for the lack of photochemical reactivity.
Scheme 1
O
HO
hν
MeCN
6
7
Irradiation of ketone 6 in acetonitrile solution results in Norrish-
Yang cyclization. Compound 7 was isolated after dehydration of
the native photoproduct.
Phosphorescence Spectroscopy. The phosphorescence
spectra of ketones 1-5 were acquired at 77 K in methylcy-
clohexane glasses (Figures S36-S40). The emission onset in
each spectrum shows that all derivatives display similar tri-
plet energies (73.3-74.7 kcal/mol). However, the spectral
features observed for 4 and 5 indicate an excited state con-
figuration with mixed (n,π*) and (π,π*) character, while the
spectra for 1, 2, and 3 exhibit a vibrational resolution that is
typical of triplet ketones with a dominant (n,π*) configura-
tion. This qualitative analysis is supported by complex phos-
phorescence lifetime data, which could be fit well by a dou-
ble exponential function with short- and long-lived compo-
nents as indicated in Table 3. Also included in the table are
the weighted average lifetimes for each ketone, which were
shown to range from ca. 2 ms and 5 ms in the cases of ke-
tone 2 and 3, to almost 1 s in the case of ketones 4 and 5.
The results in Table 3 indicate that the T1 states of all of the
derivatives studied here have some (π,π*) character or that
states with the two configurations are close in energy.24,25,26
The dominant nature of the short-lived (n,π*) state in the
case of ketones 2 and 3 is interesting considering that they
do have strong electron donating substituents in their aro-
matic rings. This observation may be the result of a relative-
6
Ketone 5 was found to be photochemically inert under the
irradiation conditions used. This was surprising considering
that 2,4,6-tri-tert-butylacetophenone 6 has been shown to
form a cyclopentanol photoproduct upon irradiation in cy-
clohexane.23 This compound was synthesized and subjected
to the same irradiation conditions over 72 hours with an
equimolar sample of 5. This experiment yielded an isolable
quantity of the dehydrated photoproduct 7 from 2,4,6-tri-
tert-butylacetophenone after workup (Scheme 1), but there
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The Journal of Organic Chemistry
14
ly poor conjugation in their corresponding aromatic carbon-
9
6
3
0
0 ns
200 ns
400 ns
600 ns
800 ns
1000 ns
1
2
3
yls, which have dihedral angles of 81.6° and 85.2°, respec-
tively. By comparison, the dihedral angle between the plane
of the carbonyl and the plane of the aromatic group in the
case of 1 and 4 is 0.5o and 43.0°, respectively.
12
10
8
4
5
6
7
8
9
0
1000 2000 3000
Time (ns)
Transient Spectroscopy and Kinetics. Experiments were
conducted for each acetophenone derivative in both acetoni-
trile solution and in nanocrystalline suspensions using an LP
920 laser flash photolysis instrument from Edinburgh In-
struments modified with a one pass flow system using a
Quantel Brilliant b Nd:YAG laser with 266 nm output from
two sequential second harmonic generation modules. The
results for all LFP experiments are summarized in Table 4.
Representative transient absorption spectra obtained for a
solution of 3 and a nanocrystalline suspension of 4 are
shown in Figure 7 and Figure 8, respectively. All other tran-
sient absorption spectra that were acquired can be found in
Figures S69-S73. Some samples did not yield any observable
transient signal (fields labeled “N/A” in Table 4), suggesting
lifetimes that are shorter than the 10 ns pulse. Alternatively,
the transient species may not be generated in high enough
concentrations to be detectable. For solid state samples,
missing data points could also be the result of poor suspen-
sion quality (e.g., crystals that are too large, fast aggregation,
etc.). However, suspension characterization studies, includ-
ing DLS or SEM such as that shown in Figure 4 for samples
of each derivative (Figures S59-S63), help rule out this ex-
planation. With the exception of ketone 5, which contained
crystals of significantly larger average size, all suspensions
were amenable to transient absorption analysis.
6
4
2
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58
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60
0
300
350
400
Wavelength (nm)
450
500
Figure 7. Transient absorption spectrum of 3 (4-methoxy-2,6-
dimethyl ketone) in MeCN solution. The signal with λmax = 360
nm was assigned to the T1 state and shows a monoexponential
decay (inset) with τ = 480 ± 10 ns.
adamantyl and the ortho-methyl groups, which proceed
through two different biradicals, it is reasonable to assign the
observed transient to their common precursor. This assign-
ment implies that biradicals in solution do not accumulate,
but proceed rapidly towards product formation. Analogous
observations with the other ketone transients in solution led
us to assign all of them to the corresponding T1 states.
The nanocrystalline suspension of the di-isopropyl ketone
4 used for LFP experiments was identical to that used for
characterization by UV-Vis, DLS, and SEM. The transient
absorption spectrum acquired from its suspension is shown
in Figure 8. It exhibited a λmax at 390 nm with a relatively
long-lived monoexponential decay rate of τ = 1050 ± 40 ns.
The lack of an observable transient for this compound in
solution was attributed to rapid reactivity on the timescale of
the laser pulse, such that neither the T1 state of the ketone
nor the subsequent adamantyl biradicals can be detected in
solution. This interpretation implies that the lifetime of the
T1 state of 4 is extended by at least two orders of magnitude
from solution to the solid state, which is a more drastic ex-
ample of the behavior observed between solution and sus-
pension samples of ketone 1 (Figure S69 and S70), where
Table 4. Absorption maxima and lifetimes of transient
species in MeCN solution and nanocrystalline suspen-
sion.a
Nanocrystalline
MeCN Solution
Suspension
Ketone
Lifetime
(ns)
λmax
Lifetime
(ns)
λmax
(nm)
(nm)
810 ± 20
N/A
1
2
3
4
5
390
N/A
360
N/A
330
400
N/A
N/A
390
N/A
65 ± 2
N/A
5
0 ns
4
3
2
1
0
3.0
2.5
2.0
1.5
1.0
0.5
0.0
N/A
480 ± 10
N/A
500 ns
1000 ns
1500 ns
2000 ns
2500 ns
1050 ± 40
N/A
740 ± 50
0
1000 2000 3000
Time (ns)
aAll experiments were performed in triplicate. Lifetime values
correspond to the average of the three measurements, and error
ranges are reported as the sample standard deviation.
As an example, a 0.02 mg/mL solution of 3 in acetonitrile
was degassed by sparging with argon for 30 minutes, then
continuously pumped through the LFP flow-cell. The spec-
trum shown in Figure 7 was acquired, with a λmax at 360 nm
and a lifetime of τ = 480 ± 10 ns. This transient was assigned
to the T1 state of the ketone due to its similarity to previously
documented transients of this type,27–32 and the observation
that the lifetime is reduced as a function of increasing oxy-
gen concentration. Furthermore, considering that ketone 3
yields products arising from hydrogen abstraction from the
300
350
400
Wavelength (nm)
450
500
Figure 8. Transient absorption spectrum of 4 (2,4-diisopropyl
ketone) in nanocrystalline suspension. The signal with λmax
390 nm was assigned to the T1 state and shows a monoexponen-
=
tial decay (inset) with τ = 1050 ± 40 ns.
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the conformational restrictions imposed by the crystal lattice ter. Nanosecond transient absorption experiments were per-
1
2
3
4
5
6
7
8
attenuates the rate of hydrogen transfer from the triplet ex-
cited state.6
formed using an Edinburgh Instruments LP920 laser flash
photolysis spectrometer in conjunction with a Q-switched
Nd:YAG Brilliant b laser from Quantel with 266 nm output
wavelength, 5–8 ns pulse width, 1 Hz repetition rate, and
36–40 mJ pulse energy. Transient absorption detection is
based on a 450 W pulsed Xenon arc lamp, a Czerny-Turner
TMS300 monochromator, a Hamamatsu R928 photomulti-
plier detector, and a Tektronix TDS3012C digital oscillo-
scope. Transient absorption data was collected using the
L900 software package provided by Edinburgh Instruments,
then processed with Origin. Laser flash photolysis samples
were pumped through a 1 cm quartz flow cell mounted on a
custom-built sample holder at a rate of 2 mL/min with a
Masterflex L/S peristaltic pump. Samples for scanning elec-
tron microscopy (SEM) were deposited on silicon substrates
and sputter-coated with gold using a Hummer 6.2 sputtering
system. Samples were sputtered for 2 min., giving a ~10 nm
thick gold coating according to manufacturer specifications.
SEM samples were imaged using a JEOL JSM-6700F FE-
SEM instrument. Phosphorescence spectra were recorded
using an Edinburgh Instruments FLSP920 fluorimeter with a
µF 920H microsecond flashlamp emission source. Sample
irradiation for photoproduct analysis experiments was per-
formed in a photochemical reactor with a Hanovia 450 W
medium pressure mercury vapor lamp seated in a quartz
immersion well. Molecular mechanics and DFT calculations
were performed using the Spartan ’16 program.
CONCLUSION
Nanocrystalline suspensions enabled the acquisition of the
first solid state transient absorption spectrum of a compound
featuring competing photochemical reaction pathways.
While the lack of observable transients for other suspension
samples prevented a quantitative comparison of reaction
rates in the solid state, other mechanistic experiments and
product analysis helped to elucidate important details about
selectivity factors for the Norrish Type II reaction. It was
shown that when multiple Norrish-Yang photoproducts are
possible for a given substrate, many factors may affect the
reaction outcome. First, the HAT selectivity is determined by
geometric relationships between the carbonyl group and γH
atoms, the BDEs of the γH C-H bonds, and the T1 lifetime of
the ketone. Then, the radical recombination step is influ-
enced by conformational freedom of the biradical and the
steric effects associated with the approach of the biradical
toward recombination. If any of these factors is omitted from
consideration, then it is not possible to account for the pho-
toproduct distributions observed across all of the samples.
Therefore, it is necessary for all of them to be included in the
general framework for predicting outcomes of the Norrish
Type II reaction.
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General preparation of nanocrystalline suspensions.
Nanocrystalline suspensions of 1-5 were prepared by addi-
tion of an acetonitrile stock solution of the ketone into 0.04
mM cetyltrimethylammonium bromide (CTAB) in water
such that the final mixture contained 1% acetonitrile by vol-
ume and the indicated concentration of the ketone.
EXPERIMENTAL SECTION
General Remarks. Unless noted otherwise, all reagents
were used as received without further purification. Tetrahy-
drofuran was distilled from sodium with benzophenone indi-
cator. Dichloromethane was distilled from calcium hydride.
Acetonitrile, N,N-dimethylformamide, and methylcyclohex-
ane were used as received. All reactions were carried out in
oven-dried or flame-dried glassware under argon atmos-
2-(adamantan-1-yl)-1-(4-methoxyphenyl)ethan-1-one
(1): Synthesis of 1 was conducted as previously reported
with minor modifications.7 A 50 mL round-bottom flask was
charged with 1-adamantaneacetic acid (777 mg, 4.0 mmol),
dry DCM (16 mL), and DMF (10 drops). The solution was
stirred for 5 min., then oxalyl chloride (0.85 mL, 10.0 mmol)
was added dropwise over the course of 3 min. The solution
was stirred at room temperature for 1 hr., then the solvent
was removed to give the acid chloride as a pale yellow oil,
which was dissolved in 16 mL dry DCM and placed in an ice
bath. Aluminum trichloride (1.07 g, 8.0 mmol) was added
and the suspension was stirred for 10 min., followed by
dropwise addition of anisole (0.87 mL, 8.0 mmol). The reac-
tion mixture was stirred for 5 minutes at 0 °C and 90 minutes
at room temp, then poured into a 0.1 M HCl solution at 0 °C.
The mixture was extracted with DCM, dried over MgSO4,
and the solvent was removed. The crude product was puri-
fied by column chromatography (SiO2, 9:1 hexanes : ethyl
ether). Recrystallization from ethanol gave the product as a
white, crystalline solid (713 mg, 63 %). Rf = 0.38 (9:1 hex-
anes : ethyl acetate). m.p. 77-80 °C (lit.1 80-81 °C). IR
(powder): 2896, 1653, 1591, 1508, 1454, 1312, 1256, 1174,
1
phere. H and 13C{1H} NMR spectra for characterization of
synthetic targets and isolated photoproducts were acquired
on a Bruker Avance spectrometer at 500 MHz (1H) and 126
1
MHz (13C{1H}). H NMR spectra of photochemical reaction
product mixtures were acquired on a Bruker Avance spec-
trometer at 400 MHz. All chemical shifts are reported in
ppm on the δ-scale relative to the residual solvent signal as
reference (CDCl3 δ 7.26 and δ 77.16 for proton and carbon,
respectively, CD3CN δ 1.94 for proton and δ 118.26 for car-
bon). Coupling constants (J) are reported in hertz (Hz).
High-resolution mass spectrum data was recorded on a Q
Exactive Plus Hybrid Quadrupole-Orbitrap Mass Spectrome-
ter in positive ion mode. Melting point values were recorded
on a Melt-Point II apparatus. Infrared spectra were recorded
on a PerkinElmer Spectrum 100 spectrometer equipped with
a single reflectance diamond crystal universal ATR sampling
accessory. UV-Vis absorption spectra were recorded on an
Ocean Optics Flame-T spectrometer with the OceanView
software package. Dynamic Light Scattering (DLS) data
was collected using a Beckman-Coulter N4 Plus particle
analyzer. Powder X-ray diffraction patterns were measured
using a Panalytical X'Pert Pro X-ray Powder Diffractometer.
Single crystal X-ray diffraction data was collected on a
Bruker Smart ApexII CCD-single crystal X-ray Diffractome-
1
1144, 1017, 843, 821, 781, 770, 581, 535 cm-1. H NMR
(500 MHz, CDCl3): δ 7.94 (d, J = 9.0 Hz, 2H), 6.92 (d, J =
9.0 Hz, 2H), 3.87 (s, 3H), 2.66 (s, 2H), 1.94 (br s, 3H), 1.65
(m, 12H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 199.0,
163.4, 132.2, 130.9, 113.7, 55.6, 51.2, 43.2, 36.9, 34.1, 28.9
8
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ppm. HRMS (APCI, quadrupole-orbitrap) m/z: [M+H]+ cal-
culated for C19H25O2: 285.1849, found: 285.1838.
was purified by flash chromatography (SiO2, 39 : 1 hexanes :
1
2
3
4
5
6
7
8
ethyl acetate) and recrystallization from ethanol to give 3 as
a white, crystalline solid (45 mg, 14% yield). Rf = 0.48 (9:1
hexanes : Ethyl Acetate). m.p. 118–120 °C. IR (film): 2901,
2848, 1700, 1605, 1451, 1338, 1316, 1192, 1146, 982, 838,
2-(adamantan-1-yl)-1-mesitylethan-1-one (2): An equi-
valent amount of the acid chloride solution as described in
the synthesis of 1 was prepared in an identical manner. Alu-
minum trichloride (1.07 g, 8.0 mmol) was added and the
suspension was stirred for 10 min. Mesitylene (1.11 mL, 8.0
mmol) was added dropwise and the mixture was stirred for 1
hr. at 0 °C and 90 min. at room temperature. The reaction
mixture was poured into ice cold 0.1 M HCl solution, ex-
tracted with DCM, washed with brine, dried over MgSO4,
and evaporated to give the crude product as a yellow oil. The
crude product was purified by column chromatography
(SiO2, 4 : 1 hexanes : DCM). The resulting clear oil was
crystallized from cold hexanes to give 2 as a white, crystal-
line solid (828 mg, 70% yield). Rf = 0.58 (9:1 hexanes : ethyl
acetate). m.p. 69–72 °C. IR (film): 2879, 2845, 1694, 1612,
1449, 1336, 1212, 1149, 998, 980, 910, 850, 601, 526 cm-1.
1H NMR (500 MHz, CDCl3): δ 6.81 (s, 2H), 2.47 (s, 2H),
2.26 (s, 3H), 2.21 (s, 6H), 1.98 (br s, 3H), 1.75 (m, 12H)
ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 209.7, 140.6,
138.1, 132.5, 128.7, 57.6, 42.2, 37.1, 33.3, 28.8, 21.2, 19.2
ppm. HRMS (APCI, quadrupole-orbitrap) m/z: [M+H]+ cal-
culated for C21H29O: 297.2213, found: 297.2212.
1
551 cm-1. H NMR (500 MHz, CDCl3): δ 6.52 (s, 2H), 3.77
(s, 3H), 2.47 (s, 2H), 2.23 (s, 6H), 1.97 (br s, 3H), 1.73 (m,
12H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 209.4,
159.3, 136.4, 134.6, 113.3, 58.0, 55.3, 42.3, 37.1, 33.5, 28.8,
19.8 ppm. HRMS (APCI, quadrupole-orbitrap) m/z: [M]+
calculated for C21H28O2: 312.2084, found: 312.2088.
9
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32
33
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(adamantan-1-yl)-1-(2,4-diisopropylphenyl)ethan-1-
one (4): An equivalent amount of the acid chloride solution
as described in the synthesis of 1 was prepared in an identi-
cal manner. Aluminum trichloride (1.07 g, 8.0 mmol) was
added and the suspension was stirred for 10 min. 1,4-
diisopropylbenzene (1.51 mL, 8.0 mmol) was added drop-
wise and the mixture was stirred for 2 hrs. at 0 °C and 90
min. at room temperature. The reaction mixture was poured
into ice cold 0.1 M HCl solution, extracted with DCM,
washed with brine, dried over MgSO4, and evaporated to
give the crude product as a golden oil. The crude product
was purified by column chromatography (SiO2, 4 : 1 hexanes
: DCM). The resulting yellow oil was crystallized from cold
hexanes to give 4 as a white, crystalline solid (542 mg, 40%
yield). Rf = 0.58 (9:1 hexanes : ethyl acetate). m.p. 58–60
°C. IR (film): 2966, 2901, 2844, 1663, 1605, 1447, 1303,
2-bromo-5-methoxy-1,3-dimethylbenzene (8): Synthesis
of 8 was conducted as previously reported.33 A 100 mL
round-bottom flask was charged with 1-methoxy-3,5-
dimethylbenzene (2.83 mL, 20.0 mmol) and MeCN (20 mL).
The flask was placed on an ice bath. A solution of N-
bromosuccinimide (3.92 g, 22.0 mmol) in MeCN (30 mL)
was transferred to an addition funnel and added to the flask
over 10 min. The reaction was stirred at 0 °C for 2 hrs., then
poured into 100 mL H2O and extracted with hexanes. The
organic layers were dried over MgSO4 and evaporated to
give 8 as a pale yellow oil without further purification (3.78
g, 88% yield). Rf = 0.72 (hexanes). IR (film): 2953, 1586,
1468, 1408, 1320, 1195, 1162, 1077, 1018, 998, 853, 614
1
1283, 1255, 1062, 1017, 973, 846, 697, 600 cm-1. H NMR
(500 MHz, CDCl3): δ 7.36 (d, J = 8.0 Hz), 7.23 (d, J = 1.6
Hz, 1H), 7.05 (dd, J = 8.0, 1.6 Hz, 1H) , 3.39 (sept, J = 6.8
Hz, 1H), 2.91 (sept, J = 6.9 Hz, 1H) 2.64 (s, 2H), 1.94 (br s,
3H), 1.66 (m, 12H), 1.25 (d, J = 6.9 Hz, 6H), 1.24 (d, J = 6.8
Hz, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 206.2,
151.7, 147.7, 138.8, 127.9, 125.0, 123.1, 56.0, 43.0, 37.0,
34.3, 34.3, 29.5, 28.8, 24.5, 23.9 ppm. HRMS (APCI, quad-
rupole-orbitrap) m/z: [M+H]+ calculated for C24H35O:
339.2682, found: 339.2681.
1
cm-1. H NMR (500 MHz, CDCl3): δ 6.65 (s, 2H), 3.76 (s,
2-bromo-1,3,5-tri-tert-butylbenzene (9): Synthesis of 9
was conducted as previously reported.34 A 100 mL round
bottom flask with a reflux condenser was charged with 1,3,5-
tri-tert-butylbenzene (4.00 g, 16.2 mmol). Trimethyl phos-
phate (40 mL, 342 mmol) was added and the mixture was
heated to 70 °C. Bromine (1.66 mL, 32.5 mmol) was added
and the reaction was stirred at 70 °C for 26 hrs. The reaction
mixture was allowed to cool to room temperature, and the
orange suspension was poured into aqueous sodium thiosul-
fate solution (100 mL, 10% w/v) then extracted with hex-
anes. The organic layer was dried over MgSO4 and evapo-
rated to give a yellow solid. Recrystallization from ethanol
gave 9 as a pale yellow, crystalline solid (3.164 g, 69%
yield). Rf = 0.72 (hexanes). m.p. 169-171 °C (lit.3 167-169
°C). IR (powder): 2956, 1590, 1475,1396, 1362, 1241, 1216,
1011, 877, 739, 578 cm-1. 1H NMR (500 MHz, CDCl3): δ
7.41 (s, 2H), 1.59 (s, 18H), 1.32 (s, 9H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ 148.7, 148.6, 123.8, 121.8, 38.5, 35.1,
31.5, 31.1 ppm. HRMS (APCI, quadrupole-orbitrap) m/z:
[M]+ calculated for C18H29Br: 324.1447, found: 324.1447.
2-(adamantan-1-yl)-1-(2,4,6-tri-tert-butylphenyl)ethan-
1-one (5): A 50 mL round-bottom flask was charged with 1-
adamantaneacetic acid (597 mg, 3.07 mmol), DCM (10 mL),
and DMF (4 drops). Oxalyl chloride (0.66 mL, 7.7 mmol)
3H), 2.39 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
158.2, 139.2, 118.4, 114.0, 55.5, 24.2 ppm. HRMS (APCI,
quadrupole-orbitrap) m/z: [M]+ calculated for C9H11BrO:
213.9988, found: 213.9986.
2-(adamantan-1-yl)-1-(4-methoxy-2,6-dimethylphenyl)-
ethan-1-one (3): A 10 mL round-bottom flask was charged
with 1-adamantaneacetic acid (194 mg, 1.0 mmol). Dry
DCM (4 mL) and DMF (2 drops) were added, followed by
dropwise addition of oxalyl chloride (0.21 mL, 2.5 mmol).
The solution was stirred at room temperature for 2 hrs., then
the solvent was removed. A second 10 mL round-bottom
flask was charged with 8 (215 mg, 1.0 mmol) and dry THF
(2 mL), then cooled to -78 °C and charged with t-
butyllithium solution (1.2 mL, 1.7 M in pentane). The mix-
ture was stirred for 1 hr. at -78 °C, then allowed to warm to
room temperature. Dry THF (2 mL) was added to the acid
chloride, which was then cooled to -78 °C. The aryllithium
solution was then transferred by syringe to the acid chloride
solution over the course of 5 min. The reaction was stirred
for 70 min. at -78 °C, and 100 min. at room temperature.
Then, the mixture was quenched with H2O, extracted with
DCM, dried over MgSO4, and evaporated to give the crude
product as a dark orange oil (246 mg). The crude product
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was added dropwise to the solution, which was then stirred chromatography (SiO2, 49:1 hexanes : ethyl acetate) and
1
2
3
4
5
6
7
8
for 1 hr. The solvent was removed and the resulting residue
was redissolved in 10 mL THF. A 25 mL round-bottom flask
was charged with 9 (1.0 g, 3.07 mmol) and THF (10 mL),
then placed in a dry ice / acetone bath. The solution was
treated with n-butyllithium (2.5 mL, 2.5 M in hexanes) and
allowed to stir for 30 min. before warming to room tempera-
ture. Meanwhile, the acid chloride solution was placed in a
dry ice / acetone bath. Once the solution aryllithium solution
had reached room temp., it was transferred to the acid chlo-
ride solution dropwise via syringe, and the resulting mixture
was stirred for 3 hrs. Then, the reaction mixture was poured
into 0.1 M HCl, extracted with DCM, dried over MgSO4 and
evaporated to give the crude product as a brown oil. Upon
standing overnight, crystals had grown from the oil. The
crystals were washed with ethanol, then dissolved in DCM
and dried to give 133 mg off-white solid, which was passed
through a silica plug with hexanes as eluent then dried to
give 5 as a white, crystalline solid (75 mg, 6% yield). Rf =
0.75 (9:1 hexanes : ethyl acetate). m.p. 184–186 °C. IR
(film): 2963, 2902, 2848, 1703, 1601, 1454, 1393, 1363,
recrystallization from methanol to give 6 as a white solid (30
mg, 15% yield). Rf = 0.35 (19:1 hexanes : ethyl acetate).
m.p. 110-116 °C (lit.4 120.5-122 °C). IR (film): 2961, 1699,
1602, 1465, 1396, 1363, 1350, 1246, 1217, 1148, 879 cm-1.
1H NMR (500 MHz, CDCl3): δ 7.39 (s, 2H), 2.64 (s, 3H),
1.38 (s, 18H), 1.32 (s, 9H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 211.9, 149.5, 144.7 137.7, 122.9, 38.4, 37.3, 35.0,
33.1, 31.4 ppm. HRMS (APCI, quadrupole-orbitrap) m/z:
[M]+ calculated for C20H32O: 288.2448, found: 288.2451.
4,6-di-tert-butyl-1,1,3-trimethyl-1H-indene (7): A 20
mL screw-cap vial was charged with 15 mg 6 and 15 mL
MeCN. The solution was sparged with argon for 10 minutes,
then the vial was sealed with parafilm. The solution was
irradiated in the Hanovia photochemical reactor for 72 hours,
then the solvent was removed. Upon dissolving the resulting
solid in CDCl3, a significant change in TLC results indicated
that the CDCl3 promoted dehydration of the cyclopentanol
photoproduct to form 7, presumably due to trace HCl. Pre-
paratory TLC with hexanes as eluent enabled isolation of 7
as a white solid (2.4 mg, 17% yield). Rf = 0.32 (hexanes).
m.p. 102-104 °C. IR (film): 2955, 2865, 1610, 1458, 1396,
1362, 1253, 960, 875, 815 cm-1. 1H NMR (500 MHz,
CDCl3): δ 7.36 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H),
6.12 (q, J = 1.38 Hz, 1H), 2.44 (d, J = 1.43 Hz, 3H), 1.54 (s,
2H), 1.50 (s, 9H), 1.36 (s, 9H), 1.25 (s, 6H) ppm. 13C{1H}
NMR (126 MHz, CDCl3): δ 157.1, 147.1, 146.9, 144.6,
138.0, 136.1, 121.5, 116.5, 46.1 35.4, 34.9, 33.3, 31.7, 25.4,
21.1 ppm. HRMS (APCI, quadrupole-orbitrap) m/z: [M+H]+
calculated for C20H31: 271.2420, found: 271.2426.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1332, 1195, 978, 909, 731, 650 cm-1. H NMR (500 MHz,
CDCl3): δ 7.35 (s, 2H), 2.62 (s, 2H), 1.98 (br s, 3H), 1.82 (br
s, 6H), 1.72 (br s, 6H), 1.39 (s, 18H), 1.31 (s, 9H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 210.5, 149.0, 145.2,
137.6, 123.1, 60.8, 42.3, 37.8, 37.2, 34.9, 33.5, 33.4, 31.4,
28.8 ppm. HRMS (APCI, quadrupole-orbitrap) m/z: [M+H]+
calculated for C30H47O: 423.3621, found: 423.3615.
2,4,6-tri-tert-butylbenzoic acid (10): Synthesis of 10
was conducted as previously reported with minor modifica-
tions.23 A 50 mL round-bottom flask was charged with 9
(1.00 g, 3.07 mmol). THF (20 mL) was added and the flask
was cooled to -78 °C, then the solution was treated with n-
butyllithium (1.23 mL, 2.5 M in hexanes) and stirred for 30
min. Dry CO2 was then bubbled through the solution for 10
min., with the cold bath being removed after the first 5 min.
The reaction mixture was poured into a solution of 50 mL
H2O and 2 mL 2 M HCl, extracted with DCM, dried over
MgSO4 and evaporated to give the crude product as a white
solid, which was purified by flash chromatography (SiO2,
4:1 hexanes : ethyl acetate) to give 10 as a white powder
(871 mg, 97% yield). Rf = 0.0.35 (4:1 hexanes : ethyl ace-
tate). m.p. 292-294 °C (lit.4 291-293 °C). IR (film): 2959,
1694, 1603, 1459, 1390, 1363, 1287, 1218, 1165, 1083, 909,
878, 745 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.45 (s, 2H),
1.49 (s, 18H), 1.33 (s, 9H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 180.3, 150.9, 146.5, 127.7, 122.3, 37.2, 35.2, 32.4,
31.4 ppm. HRMS (APCI, quadrupole-orbitrap) m/z: [M+H]+
calculated for C19H31O2: 291.2319, found: 291.2308.
1-(2,4,6-tri-tert-butylphenyl)ethan-1-one (6): A 35 mL
round-bottom flask was charged with 10 (200 mg, 0.69
mmol), DCM (10 mL), and DMF (1 drop). Oxalyl chloride
(0.15 mL, 1.72 mmol) was added and the mixture (heteroge-
neous at the beginning due to limited solubility of 10 in
DCM) was stirred for 1 hr. The solvent was removed and the
resulting yellow solid was redissolved in 10 mL THF. The
flask was cooled to 0 °C and 0.46 mL 3 M MeMgBr solution
in diethyl ether was added. After 45 min., the reaction mix-
ture was poured into 10 mL 0.1 M HCl solution, extracted
with DCM, dried over MgSO4, and evaporated to give the
crude product as a white solid, which was purified by flash
General photoproduct isolation and photoproduct dis-
tribution determination. Photoproducts were isolated by
preparative TLC with 49:1 or 19:1 hexanes : ethyl acetate as
eluent. The photoproducts of ketones 1 and 2 were isolated
in their native form (trans-ACB-1, cis-ACB-1, and BCB-2).
However, cyclobutanols from ketones 3 and 4 transformed
into corresponding alkenes by water elimination upon chro-
matographic purification. In the case of ketone 4, a correla-
tion of 1H NMR spectra before and after purification showed
that trans-ACB-4 is isolated as the H2O elimination product
but cis-ACB-4 can be obtained in its native form. For ketone
3, only the elimination products were isolated. Relative per-
centages of trans-ACB-3, cis-ACB-3, and BCB-3 were de-
1
termined from crude H NMR spectra by integration of the
distinctive cyclobutanol methine proton of cis-ACB-3 at δ
2.90, the methoxy protons of trans-ACB-3 at δ 3.72, and the
cyclobutanol methylene protons of BCB-3 at δ 3.42 and δ
2.99. In all cases, relative percentages of photoproducts as
well as conversion percentages were determined by integra-
tion of characteristic signals of the starting material and pho-
1
toproducts in the crude H NMR spectra. Product distribu-
tions determined from this analysis for 1-5 after 10 minutes
and 2 hours of irradiation in both MeCN solutions and aque-
ous suspensions are shown in Table S1.
trans-ACB-1: 1H NMR (500 MHz, CDCl3): δ 7.36 (d, J =
8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.70 (d, J
= 10.9 Hz, 1H), 2.62 (br s, 1H), 2.38 (br s, 1H), 2.06 (d, J =
11.2 Hz, 1H), 1.99 (m, 1H), 1.81 (m, 5H), 1.59 (m, 3H), 1.50
(m, 2H), 1.39 (m, 2H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 159.1, 136.2, 129.2, 113.9, 81.7, 60.1, 55.4, 47.7,
45.9, 41.2, 38.1, 37.7, 30.91, 30.89, 29.9, 29.0, 28.3 ppm.
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HRMS (APCI, quadrupole-orbitrap) m/z: [M+H]+ calculated
ASSOCIATED CONTENT
1
2
3
4
5
6
7
8
for C19H25O2: 285.1849, found: 285.1839.
1
Supporting Information
cis-ACB-1: H NMR (500 MHz, CDCl3): δ 7.26 (d, J =
1
Spectroscopic H NMR and 13C{1H} NMR for all new com-
8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 2.91 (m,
1H), 2.36 (br s, 1H), 2.31 (m, 1H), 2.25 (d, J = 11.1 Hz, 1H),
2.20 (m, 1H), 2.11 (d, J = 11.1 Hz, 1H), 2.02 (m, 2H), 1.75
(m, 8H), 1.64 (s, 1H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 158.7, 142.0, 126.3, 113.9, 84.1, 55.49, 55.47,
48.5, 45.6, 41.2, 39.8, 38.3, 34.1, 32.4, 31.2, 30.1, 28.7 ppm.
HRMS (APCI, quadrupole-orbitrap) m/z: [M+H]+ calculated
for C19H25O2: 285.1849, found: 285.1838.
pounds and IR data compounds 1-10. Phosphorescence, UV-Vis
and transient absorption data along with characterization of
suspensions by DLS, SEM and PXRD for compounds 1-5. Pho-
toproduct distributions percentages for compounds 1-5 and pho-
tochemical deuteration experiments for compounds 2-4. Single
crystal X-ray thermal ellipsoid plots and crystallography data
for compounds 2-4. Calculated structure of compound 5. (PDF).
Single crystal X-ray structures for compounds 2-4 (CIF files).
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
BCB-2: H NMR (500 MHz, CDCl3): δ 6.80 (s, 1H), 6.78
(s, 1H), 3.56 (d, J = 14.3 Hz, 1H), 3.10 (d, J = 14.3 Hz, 1H),
2.30 (s, 3H), 2.27 (s, 3H), 2.02 (m, 2H), 1.96 (m, 3H), 1.85
(m, 3H), 1.69 (m, 9H), 1.53 (d, J = 14.7 Hz, 1H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 147.2, 141.5, 139.2,
131.6, 129.3, 121.6, 81.6, 50.8, 48.0, 43.8, 37.2, 34.3, 29.0,
22.1, 16.9 ppm. HRMS (APCI, quadrupole-orbitrap) m/z:
[M+H]+ calculated for C21H29O: 297.2213, found: 297.2201.
Elimination product of cis- and trans-ACB-3: 1H NMR
(500 MHz, CDCl3): δ 6.57 (s, 2H), 3.77 (s, 3H), 2.47 (m,
3H), 2.31 (m, 6H), 2.09 (m, 2H), 2.00 (m, 2H), 1.85 (m, 2H),
1.75 (m, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
157.8, 156.2, 138.2, 128.7, 122.1, 112.6, 55.1, 46.0, 43.1,
39.2, 37.0, 36.8, 31.5, 29.9, 21.1 ppm. HRMS (APCI, quad-
rupole-orbitrap) m/z: [M]+ calculated for C21H26O: 294.1978,
found: 297.1972.
AUTHOR INFORMATION
Corresponding Author
* mgg@chem.ucla.edu
Notes
ORCID:
Miguel A. Garcia-Garibay: 0000-0002-6268-1943
Vince M. Hipwell: 0000-0001-6297-241X
ACKNOWLEDGMENT
This work was supported by grants National Science Foundation
grants CHE-1855342, MRI-1532232 (solid state NMR), and
CHE-1048804 (solution NMR).
1
Elimination product of BCB-3: H NMR (500 MHz,
CDCl3): δ 6.57 (s, 1H), 6.52 (s, 1H), 5.35 (s, 1H), 3.77 (s,
3H), 3.66 (s, 2H), 2.28 (s, 3H), 2.00 (m, 3H), 1.76 (m, 6H),
1.71 (m, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
159.7, 146.0, 137.5, 133.9, 131.5, 128.7, 115.0, 105.3, 55.5,
42.9, 38.3, 36.9, 36.1, 28.6, 18.1 ppm. HRMS (APCI, quad-
rupole-orbitrap) m/z: [M]+ calculated for C21H26O: 294.1978,
found: 297.1989.
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Hz, 1H), 7.01 (dd, J = 8.0, 1.7 Hz, 1H), 3.38 (sept, J = 6.9
Hz, 1H), 2.87 (sept, J = 6.9 Hz, 1H), 2.85 (m, 1H), 2.57 (s,
2H), 2.08 (m, 2H), 1.97 (m, 2H), 1.89 (m, 2H), 1.78 (m, 4H),
1.69 (m, 2H), 1.24 (d, J = 6.9 Hz, 6H), 1.23 (d, J = 6.9 Hz,
6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 154.3, 147.2,
145.6, 132.6, 128.2, 123.3, 123.2, 123.1, 45.1, 42.7, 38.7,
37.3, 36.7, 34.1, 32.5, 29.7, 29.2, 24.0, 23.9 ppm. HRMS
(APCI, quadrupole-orbitrap) m/z: [M]+ calculated for C24H32:
320.2499, found: 320.2493.
̈
̈
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cis-ACB-4: H NMR (500 MHz, CDCl3): δ 7.17 (d, J =
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1.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 7.9, 1.9
Hz, 1H), 3.37 (sept, J = 6.9 Hz, 1H), 2.93 (m, 1H), 2.88
(sept, J = 6.9 Hz, 1H), 2.49 (s, 1H), 2.38 (br s, 1H), 2.33 (d,
J = 11.1 Hz, 1H), 2.29 (d, J = 11.1 Hz, 1H), 2.20 (m, 1H),
2.02 (m, 2H), 1.82 (m, 2H), 1.73 (m, 6H), 1.67 (br s, 1H),
1.25 (d, J = 6.9 Hz, 6H), 1.21 (d, J = 6.9 Hz, 6H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 148.2, 147.5, 142.9,
125.7, 125.1, 123.2, 85.1, 54.9, 49.9, 45.5, 41.0, 39.6, 38.1,
34.4, 33.9, 32.2, 30.9, 30.6, 28.7, 28.5, 24.7, 24.5, 24.02,
23.99 ppm. HRMS (APCI, quadrupole-orbitrap) m/z:
[M+H]+ calculated for C24H35O: 339.2682, found: 339.2693.
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OMe
HO
hν
Benzylic
H-abstraction
REACTION SELECTIVITY:
•BDEs of C-H bonds
•Reaction geometries
•Excited state lifetimes
Me
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OMe
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•Sterics of biradical intermediates
H
Adamantyl
H
H
H-abstraction
Reaction Cavity
in Crystal Lattice
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