Diels-Alder Cycloaddition of C60 with Photochemically Generated Hydroxy to o-quinodimethanes Governed by Steric Factors: A Mechanistic Study

Article abstract of DOI:10.1002/ejoc.201900859

Photoexcited o-alkyl-substituted benzaldehydes add to C₆₀through their photoenol reactive intermediates producing stable [4 + 2] fullerene adducts. A mechanistic approach for this reactivity of C₆₀ is provided, based mainly on intra-

Full text of DOI:10.1002/ejoc.201900859

A Journal of
Accepted Article
Title: A Mechanistic Study of the Diels-Alder Cycloaddition of C60 with
Photochemically Generated Hydroxy-o-quinodimethanes.
A facile functionalization governed by steric factors
Authors: Manolis M. Roubelakis, Nikitas G Malliaros, and Michael
Orfanopoulos
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900859
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10.1002/ejoc.201900859
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A Mechanistic Study of the Diels-Alder Cycloaddition of C60 with
Photochemically Generated Hydroxy-o-quinodimethanes.
A facile functionalization governed by steric factors
Manolis M. Roubelakis,[a]Nikitas G. Malliaros,[a]and Michael Orfanopoulos*[a]
Dedicated to the memory of Dr. Maria Hatzimarinaki
An alternative way whereby o-quinodimethanes that bear a
hydroxy group can be accessed from alkyl substituted
benzophenones was reported by Yang and Rivas.[9] More
specifically, they reported that when o-methylbenzophenone (1)
is photoirradiated in the presence of a dienophile such as
dimethyl acetylene-dicarboxylate (2), cycloadduct 3 is obtained
in good yield (Scheme 1). α-Hydroxy-o-quinodimethane isomer 4
is formed in situ as the reactive intermediate of this cycloaddition.
Abstract: Photoexcited o-alkylsubstituted benzaldehydes add to
C60through their photoenol reactive intermediates producing stable [4
+ 2] fullerene adducts. A mechanistic approach for this reactivity of
C60 is provided, based mainly on intra and intermolecular kinetic
isotope effects (KIEs) studies. It is demonstrated that the rotation of
Caromatic-Ccarbonyl single bond in the excited triplet state of o-alkyl
carbonyl compounds, is the rate determining step (rds), whereas C-
H(D) bond scission during the photoenolization step, occurs
relatively fast.
Introduction
Diels-Alder cycloadditions are among the most common
organic reactions that found application in the field of fullerene
chemistry.[1] Rigid s-cis dienes or dienes formed in situ in the
presence of [60]fullerene (C60) react smoothly with a [6,6] double
bond on the fullerene core leading to the corresponding
Scheme 1. Photochemical reaction between o-methylbenzophenone (1) and
dimethyl acetylene-dicarboxylate (2).
functionalized fullerenes, bearing
a
cyclohexene ring.[1]
It is well-established that UV irradiation of aromatic carbonyl
Especially, when o-quinodimethanes are used as dienes,
thermally stable adducts that do not revert back to the starting
materials (retro-Diels-Alder) are usually formed.[2-6] The high
stability of these compounds emanates from the aromatic
system generated in the final products. o-Quinodimethane
derivatives can be obtained as intermediates either from the
thermolysis of benzocyclobutenes,[2-4] or the SO2 extrusion of
sulfolenes or sultines,[5] or the iodide-induced 1,4-elimination of
compounds with alkyl substituents at the ortho position furnishes
a
class
of
reactive
intermediates,the
α-hydroxy-o-
quinodimethanes (or photoenols), through a process called
photoenolization.[10] Photoenolization mechanism is shown in
Scheme 2.[11-15]
Upon irradiation, the carbonyl group is excited to its singlet
state (S1), and then, fast intersystem crossing (ISC) furnishes the
excited triplet state (T1). This triplet state is the result of a n→π*
carbonyl excitation and is followed by an intramolecular γ-
hydrogen abstraction from the neighboring –CH2– group leading
to the formation of a triplet state 1,4-biradical intermediate
(Norish Type II reaction).[16] Eventually the biradical intermediate
decays to Z- and E-enols. Of these two isomers, Z-enols have a
very short lifetime (~100 ns) and rapidly convert back to the
initial carbonyl compound via a 1,5sigmatropic rearrangement.
On the other hand, E-enols have significantly larger lifetimes (a
few seconds) and their stereochemistry was confirmed by
trapping experiments.[10b]
1,2-bis-(bromomethyl)benzene
derivatives,[6]
or
pyrazine
derivatives,[7a] or cyclobutapyrimidines.[7b] The efficiency of o-
quinodimethane as the reactive intermediate in organic synthesis,
has been extensively reviewed by Martín and Segura.[8]
However, in some of the above methods the precursors are
not always easily available, whereas in some other, the
generation of the o-quinodimethane intermediates involves
rather high temperatures which can lead to undesirable side
reactions.
Although E-enols partially revert to the starting material,
also they can either undergo conrotatory ring closure forming
cyclobutenols or can be trapped by several dienophiles, such as
[60]fullerene, furnishing the corresponding [4+2] cycloaddition
products (Scheme 2).
[a]
Department of Chemistry, University of Crete
Voutes Campus, GR-71003
Heraklion, Crete, Greece
E-mail: morfanop@uoc.gr
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Later on, in contrast to the instability of compound 10, a
series of quite stable fullerene derivatives (12) were obtained
from the photolysis of commercially available o-tolualdehyde and
related carbonyl compounds in the presence of C60 (Scheme
5).[18] The successful preparation of these adducts not only
established a method that overcomes synthetic difficulties of
other reported methods in accessing o-quinodimethanes, but
also, due to the presence of the hydroxyl group on the
cyclohexene ring, provides the ability for further modification of
the initially formed [4+2] fullerene adducts.
Scheme 2. The photoenolization mechanism.
The first example of a cycloaddition reaction between α-
hydroxy-o-quinodimethanes and C60 was reported by Foote and
coworkers.[4] o-Quinodimethane (6) was thermally generated
from benzocyclobutenol (5) and reacted with C60 to give 1,9-
dihydrofullerene cycloadduct 7 (Scheme 3).
Scheme 5. Photochemical synthesis of [60]fullerene-o-quinodimethane
adducts bearing a hydroxy group.
Despite the usefulness and versatility of the above reaction
as well as the easiness in execution, its mechanism still remains
unknown. Here we report a mechanistic study of the title Dield-
Alder reaction based on the measurement of intra- and
intermolecular primary and secondary H/D kinetic isotope effects
(KIEs).
Scheme 3. Thermal cycloaddition of benzocyclobutenol with C60
.
In 1995, Tomioka and coworkers for the first time tried to
functionalize C60 with photochemically generated photoenol (9)
derived from o-methylbenzophenone (8) (Scheme 4).[17]
Scheme 6. Deuterated and non-deuterated substrates for the mechanistic
study of the photocycloaddition reaction between C60 and aromatic carbonyl
compounds.
o-Alkyl substituted benzaldehydes 13-d0, 14-d0, and 15-d0 and
their specifically deuterated counterparts 13-d3, 14-d2, 15-d3 and
15-d6, shown in Scheme 6, were utilized for the present study. At
this point it is useful to mention that although o-alkyl substituted
ketones can also undergo similar [4+2] cycloadditions with C60,
through their enol intermediates, in our study we only use
benzaldehydes since they react faster with C60 and provide
higher yields.
Scheme 4. Photochemical reaction of o-methylbenzophenone with C60
.
In this case, the anticipated cycloadduct 10 undergoes a facile
cleavage of the Cfullerene-Cbenzylicbond either by silica gel
chromatography, or upon heating in toluene, to produce 1-(2-
benzoylphenyl) methyl-1,2-dihydrofullerene (11).
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10.1002/ejoc.201900859
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of the [4+2] addition of dienes and C60, kinetic isotope effect
studies for the reaction between rigid s-cis dienes and C60,
showed that it proceeds through a concerted pathway via a
symmetrical transition state.[20]
Results and Discussion
Substrates 13-d0 and 14-d0 are commercially available.
Substrates 13-d3 and 14-d2 were prepared as depicted in
Scheme 7 (see SI for detailed experimental procedures and
spectroscopic data).
Based on this two-step reaction concept, two hypotheses
can be made concerning the rate limiting step:
a) If the rate determining step of the reaction is the first one
(i.e.photoenol formation),
a normal primary isotope effect
(kH/kD>1) is expected in all cases for both the intramolecular and
the intermolecular competitions. This would be the case since
the photoenolization step involves a substantial C–H or C–D
bond breaking in the transition state, and thus, according to the
kinetic isotope effect theory the lighter isotope is favored.[21]
b) If the rate determining step of the reaction is the second
one (i.e. [4+2] cycloaddition), that is, the step where
a
rehybridization of the carbon atoms that form the 6-member ring
from sp2 in sp3 takes place in the transition state, then in all
cases an inverse or close to unity α-secondary isotope effect is
expected (kH/kD ≤ 1).[22] Again, according to the theory of kinetic
isotope effects, an increase in the coordination number at the
reaction center leading to a more congested transition state
favors the sterically less demanding deuterium.[21,22]
Scheme 7. Synthesis of 13-d3 and 14-d2.
Compound 15-d0 was synthesized according to a literature
procedure following the route shown in Scheme 8.[19]
Irradiation of a mixture of C60 and a 3- to 5-fold excess of
substrate in benzene led to the formation of the corresponding
cycloaddition adducts. The reaction progress was monitored by
high performance liquid chromatography (HPLC) and the
resulting products were purified by column chromatography.
Intra- and intermolecular kinetic isotope effects were calculated
from the 1H NMR spectrum of the reaction products based on the
integrations of the suitable peaks corresponding to kH and kD
products (vide infra).
Scheme 8. Synthesis of substrate 15-d0.
First, treatment of o-tolualdehyde with lithium piperidide
forms the corresponding α-amino alkoxide which is then treated
with n-BuLi. In this intermediate alkoxide, the carbonyl group is
protected against nucleophilic attack while the presence of the
piperidine ring directs metalation at the 6-position due to
coordination of the nitrogen atom with the Li cation. Subsequent
alkylation with methyl iodide and hydrolysis provided 2,6-
dimethylbenzaldehyde (15-d0) in 50% yield, via a one-pot
reaction.
As an example, below we describe how we determined the
intermolecular kinetic isotope effect for the reaction between 13-
d0/13-d3 and C60. The reaction that takes place when a 3-fold
excess of an equimolar mixture of 13-d0/13-d3 is irradiated in the
presence of C60 is shown in Scheme 9.
Substrates 15-d3 and 15-d6 were also prepared in 48% and 50%
yields respectively, following the same procedure but using
deuterated methyl iodide (CD3I) instead of CH3I.For the
synthesis of 15-d6, the starting material was 13-d3.
According to Scheme 5, the formation of [60]fullerene-o-
quinodimethane adducts bearing a hydroxyl group seems to be a
two-step reaction: first the photoenolization step that furnishes
the intermediate o-quinodimethane and second the [4+2]
cycloaddition of the reactive diene intermediate to the dienophile
C60. The details of the photoenolization mechanism have already
been discussed above (Scheme 2). Concerning the mechanism
Scheme 9. Photocycloaddition of an equimolar mixture of 13-d0/13-d3 to C60
.
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In the two reaction products 16-d0 (kH) and 16-d2 (kD),
cyclohexene ring adopts a boat conformation and as a result, at
room temperature each product exists as a mixture of two
interconverting boat conformers A and E (Scheme 10).
shown in Scheme 6, were measured. The kH/kD determined
values are shown in Table 1. Notably, in the rest of the cases the
1H NMR spectra of the reaction products are much simpler since
for substrates 14 and 15 formation of a sole conformer is
thermodynamically favored (see SI).
Table 1. Intra- and intermolecular kinetic isotope effects.
[a]
Substrate
13-d0/13-d3
14-d0/14-d2
15-d3
kH/kD
Type
inter
inter
intra
inter
0.98 ± 0.04
0.63 ± 0.03
0.83 ± 0.03
0.65 ± 0.03
*
15-d0/15-d6
[a] Determination of kH/kD by integration of the proper 1H NMR signals of the
cycloaddition products.
*Toluene
The absence of a normal isotope effect (kH/kD> 1) dictates
that there is no C–H or C–D bond breaking in the rate
determining step of the reaction. Consequently, according to
hypothesis (a) discussed earlier, photoenolization of the o-alkyl
substituted benzaldehyde to the intermediate α-hydroxy-o-
quinodimethane (Scheme 5) cannot be the rate-limiting step of
the reaction.
Scheme 10.1ΗΝΜR spectrum (500 MHz, CDCl3/CS2) of the reaction products
from the intermolecular competition between 13-d0/13-d3.
Conformer Α possesses a pseudoaxial hydroxyl group,
while conformer E possesses a pseudoequatorial hydroxyl group
and they slowly exchange on the NMR time scale (Scheme 10).
These conformers (kH-Α and kH-Ε or kD-Α and kD-Ε) exhibit
The inverse isotope effects measured in all the cases,
initially could lead to the conclusion that it is the [4+2]
cycloaddition step that determines the reaction rate [hypothesis
(b)]. However, if this had been the case, similar values would
have been measured for the intermolecular competitions 13-
d0/13-d3 and 15-d0/15-d6 as well as for the intramolecular
competition in 15-d3. Therefore, it seems that there is another
factor that plays a more significant role in the reaction rate and
determines the kH/kD product ratio.
1
distinguishable H NMR chemical shifts, where one can observe
two different sets of peaks one for each isomer. On the other
hand, kH-Α and kD-Α protons (i.e.Hc and Hc′) as well as kH-Ε and
kD-Ε protons (i.e.Hf and Hf′) resonate at exactly the same
1
frequencies (Scheme 10). According to the integrations of the H
NMR peaks, the conformer ratio A/E for this specific substrate
was 4/6, in agreement with that reported in the literature.18
According to the spectrum displayed in Scheme 10 the
integrals of Hf, Hf′ and He absorptions for the E conformer can be
determined by solving the following equations:
The o-methylacetophenone
photoenolization mechanism
proposed by Small and Scaiano, is presented in Scheme 11.[14]
This mechanism is the same as the generic one discussed in
Scheme 2, however, at this point we would like to stress some
significant details. o-Methylacetophenone in its ground state
exists as a mixture of two conformers, syn and anti, in dynamic
equilibrium with each other. Upon irradiation, first the singlet and
eventually the triplet excited states of these conformers are
generated. Subsequently, the triplet state of the syn
conformation decays to a biradical via intramolecular hydrogen
abstraction from the γ position, whereas, the decay of the triplet
state of the anti-conformer is controlled by bond rotation since
first it has to convert to the syn conformation through an
irreversible bond rotation and then undergo hydrogen atom
Hf + Hf' = 2.02 (1)
He = Hf = 1.00 (2)
Thus, by combining equations (1) and (2), the product ratio 16-
d0/16-d2 can be easily determined. The ratio of these products,
which is the result of intermolecular isotopic competition between
13-d0 and 13-d3, is proportional to the kinetic isotope effect kH/kD.
Thus the ratio of the integrals of the signals Hf/ Hf' for both E
conformers, determines the isotope effect kH/kD = 0.98

0.04.
Identical result is obtained if instead of the peaks of the E
conformer we use those of the A conformer. Working the same
way, inter- and intramolecular KIEs for the rest of the substrates
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abstraction. As a result, the biradical is always formed in the syn
conformation, but then, the rotation barrier for the
interconversion between syn and anti biradicals is too low that
both enols are eventually formed.[14]
structures is planar, but instead, the carbonyl group is deflected
out of the plane of the benzene ring as a consequence of strain
in the ground state. Indeed, the MP2 6-311++G** calculation
method showed a 20.8o deflection of the carbonyl group out of
the plane of benzene (see SI, S19).
In 15-d3-I the oxygen atom is synto the –CH3 group while in 15-
d3-II is located synto the –CD3 group. The ratio of those two
conformers is different from unity since enhanced steric
hindrance in 15-d3-I (longer C–H bonds, bulkier methyl group)[22,
23]
as compared to 15-d3-II (shorter C–D bonds) makes it less
stable than 15-d3-II (Scheme 12). Thus, the 15-d3-II conformation
is more populated than the 15-d3-I and the same is the case for
the excited singlet and triplet states of the molecule as well as
the biradicals formed after the intramolecular hydrogen
abstraction.
Scheme 11.Photoenolization mechanism for o-methylacetophenone.
Wagner and co-workers have calculated rate constants for
both the intramolecular hydrogen abstraction (ke) and the
rotation around the Caromatic–Ccarbonyl bond (kr) for several o-alkyl
ketones in benzene and in tert-butyl alcohol.[11a] Thus, the
reaction rate for a hydrogen abstraction is on the order of 109 s-1,
while Caromatic–Ccarbonyl bond rotation is two orders of magnitude
slower (kr = ~ 107 s-1). Significantly, in their work they conclude
that the rotation around the Caromatic–Ccarbonyl bond in the excited
state is the rate determining step for the photoenolization of the
anti-conformer.
Scheme 12. Photochemical addition of 15-d3 with C60
.
Upon irradiation of the reaction mixture, excited triplet states
15-d3-I* and 15-d3-II* are generated and they undergo
enolization to give the corresponding enols (Scheme 12).
According to what we mentioned before, hydrogen abstraction in
15-d3-I* and 15-d3-II* should happen so fast that no
interconversion between these two triplets (via bond rotation)
can take place. 15-d3-I* leads exclusively to kH product whilst 15-
d3-II* gives exclusively kD (Scheme 12). Consequently, the 15-d3-
I*/15-d3-II* ratio determines the product ratio (kH/kD). The 15-d3-
I*/15-d3-II* ratio is proportional to the 15-d3-I/15-d3-II ratio of the
ground state. We can assume, without any significant error, that
the initial 15-d3-I/15-d3-II ratio is translated into the final kH/kD
product ratio. Such cases are known in the literature as non-
Curtin-Hammett cases.[24] Thus, according to the conclusion
made in the previous paragraph that 15-d3-II conformation is
more populated than the 15-d3-I, we conclude that the kD product
will be formed at a greater percentage than the kH. This is how
the significant inverse kinetic isotope effect (kH/kD = 0.83) can be
satisfactorily rationalized. In Scheme 13 the proposed energy
diagram of the reaction is presented. In this diagram, we want to
qualitatively show that the Caromatic–Ccarbonyl bond rotation barrier,
Accordingly, in the present study of the photocycloaddition
reaction, the rotation between Caromatic–Ccarbonylbond in the excited
triplet state of these carbonyl substrates occurs much slower
than γ-hydrogen abstraction. Therefore, it seems reasonable to
assume that the above mentioned bond rotation is the reaction
limiting step and dictates the kH/kD product ratio. In the following
paragraphs we will explain the isotope effects measured in this
study (summarized in Table 1) utilizing the above statement.
In the case of substrate 15-d3, its photochemical addition to
C60 can be described as shown in Scheme 12, following our
previous discussion (Scheme 11). 15-d3 in its ground state
consists of two conformers, 15-d3-I and 15-d3-II in
thermodynamic equilibrium that can lead to photoenolization
reaction products. Due to steric hindrance neither of those two
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i.e.15-d3-I to 15-d3-II interconversion, is significantly higher than
any other reaction barrier (photoenolization or [4+2]
cycloaddition) that leads to the final products.
point energy (ZPE) than those involving the corresponding C-D
bonds. In the case of a “crowded” transition state, this deference
increases, leading to an inverse remote steric isotope effect,
kH/kD<1.[22b] The inverse IE measured between 14-d0 and 14-d2
competition is similar to the one found between 15-d0 and 15-d6
(kH/kD = 0.63 and 0.65 respectively). These results indicate that
substrates 14 and 15 exhibit similar energy differences between
zero point energies and the corresponding transition states.
The close relation between the difference in the rotation
barriers of the protonated and deuterated species and the
isotope effect measured can be further corroborated by
substrate 13. In this case the isotope effect for 13-d0/13-d3 is
close to unity. Here, the steric hindrance is considerably
attenuated and the rotation barriers of 13-d0 and 13-d3 are
almost identical. That causes 13-d0 and 13-d3 to react with the
same rate. To conclude, the smaller the difference in the rotation
barrier between the two species the less inverse the isotope
effect is.
Scheme 13. The proposed energy versus reaction coordinate diagram for the
photocycloaddition reaction of 15-d3 with C60
.
In the case of the intermolecular competition between 15-d0 and
15-d6, rotation around the Caromatic–Ccarbonyl bond again plays a
crucial role in the ratio of the kH/kD and kD products, however, in
this case via a slightly different way.
The significant inverse H/D kinetic isotope effects measured
in most of the cases above were explained based on the
enhanced steric hindrance induced by a group of C–H bonds
compared to the shorter C–D bonds that causes conformational
changes within the molecule to decelerate. Such cases of
conformational kinetic isotope effects emanating from steric
restrictions are rare and are manifested only under conditions of
severe overcrowding. A few examples have been reported
previously.[25] Perhaps the most impressive example has been
reported many years ago by Mislow and coworkers.[25a] They
As we mentioned above, due to steric hindrance between
oxygen and –CH3 and –CD3 groups, the C=O double bond is out
of the plane of the aromatic ring. Upon excitation of the carbonyl
group in the singlet and then the triplet state, rotation around the
Caromatic–Ccarbonyl bond brings the oxygen in the vicinity of one the
–CH3 or –CD3 groups so that the molecule adopts the right
geometry that allows the excited carbonyl group to abstract a γ-
hydrogen or deuterium. The rotation barrier in 15-d0 is higher
than in 15-d6 because six C–H bonds induce larger steric
hindrance than six C–D bonds. Thus, rotation in 15-d6 occurs
faster than in 15-d0, and consequently, deuterated molecules
adopt faster the right geometry to give the abstraction reaction
faster than the protonated ones, that is, 15-d6 reacts faster than
15-d0 leading to the observation of a large inverse kinetic isotope
effect (kH/kD = 0.65).
observed
that
sterically
congested
9,10-dihydro-4,5-
dimethylphenanthrenes bearing two trideuteriomethyl groups
(Scheme 14) undergo racemization 1.16 times faster than their
nondeuterated counterparts in benzene at room temperature. In
this case, an inverse steric isotope effect was measured and
was found to be equal to kH/kD = 0.86 (Scheme 14).
The same is the case with the intermolecular competition of the
14-d0/14-d2 couple. Substrate 14 in its ground state exists mainly
in the anti conformation mentioned above for o-
methylacetophenone (Scheme 11). Caromatic–Ccarbonyl bond
rotation, similarly to compound 15, is faster in the deuterated
substrate (14-d2) than in the protonated one (14-d0) and as a
result, photoenolization reaction goes faster for 14-d2 and
therefore kD product forms faster than kH.
Scheme 14. Steric hydrogen isotope effect in the racemization rate of 9,10-
dihydro-4,5-dimethylphenanthrene.
Interestingly, in substrate 14 there is only one ortho substituent
(ethyl group) compared to substrate 15 which bears two ortho
methyl groups. Vibrations involving C-H bonds have higher zero
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a) Protection of the carbonyl group in o-bromobenzaldehyde.
Conclusions
o-Bromobenzaldehyde (2.5 g, 13.5 mmol), ethylene glycol (2 mL) and p-
TsOH (0.1 g) were mixed in 50 mL toluene and the mixture was refluxed
for 3 h. Next, an additional 4 mL of ethylene glycol were added and
heating was continued for an additional 14 h. Reaction progress was
monitored by gas chromatography (GC) where it was observed that after
the consumption of 85% of the starting material, the reaction practically
does not proceed any further. The mixture was cooled down at room
temperature and upon addition of diethyl ether (20 mL), was extracted
with NaOH 10% (45 mL) and with H2O (4 x 25 mL). The organic layer
was separated and dried over anhydrous MgSO4. Solvent evaporation
gave an oily mixture of the protected product and the starting material.
These two compounds were separated by column chromatography (SiO2,
hexane/ethyl acetate 20/1). Pure 2-(2-bromophenyl)-1,3-dioxolane was
isolated (2.07 g, yield = 67%). 1H NMR (500 MHz, CDCl3): δ = 7.62 (m,
2H), 7.36 (m, 1H), 7.25 (m, 1H), 6.13 (s, 1H), 4.18 (m, 2H), 4.11 (m, 2H).
To summarize, the rotation around the Caromatic–Ccarbonyl single
bond that, in the excited triplet state of o-alkyl carbonyl
compounds, is two orders of magnitude slower than the
intramolecular hydrogen abstraction, is the rate limiting step for
the photocycloaddition reaction of these compounds with C60.
Our findings here demonstrate that neither a C–H (or C–D) bond
breaking nor a change in hybridization from sp2 to sp3 is the rate
determining step of the reaction. The intramolecular hydrogen
abstraction during the photoenolization step and the subsequent
[4+2] cycloaddition proceed fast and efficiently. In fact, it is the
high efficiency of these processes that enables the formation of
the o-quinodimethane-C60 adducts. C60 in solution absorbs very
strong in the UV-Vis, while the photoenolizable species, i.e. the
aromatic carbonyl compounds, absorb only
a very small
b) Insertion of a trideuteriomethyl group in the aromatic ring of 2-(2-
bromophenyl)-1,3-dioxolane.
percentage of the incident light, however, this is still enough for
this transformation to take place.
2-(2-Bromophenyl)-1,3-dioxolane (2.07 g, 9.0 mmol) and dry THF (40
mL) were placed, under argon, in an oven-dried two-neck round-bottom
flask. The solution was cooled down to – 62 °C and then, 12.5 mL (20
mmol) of t-BuLi solution (1.6 M in hexane) was added dropwise with
vigorous stirring. The reaction mixture was stirred at – 62 °C for 40 min
until it adopts a yellow color, and subsequently, the temperature was
raised to 0 °C and CD3I (0.8 mL) was added dropwise. The reaction was
stirred at room temperature for 14 h and then, appropriate amount of
water was added at 0 °C until all the lithium salts (LiI, LiBr) precipitate
giving a transparent solution. Next, diethyl ether (30 mL) was added and
the mixture was washed with saturated NaCl solution. The organic layer
was collected and dried over anhydrous MgSO4. Solvent evaporation
furnished 2-(o-tolyl)-1,3-dioxolane-d3 (1.4 g, yield = 93%) that was used
in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ
= 7.56 (m, 1H), 7.3-7.21 (m, 2H), 7.20 (m, 1H), 5.99 (s, 1H), 4.17 (m, 2H),
4.07 (m, 2H).
Experimental Section
General Considerations. Proton and Carbon nuclear magnetic
resonance (1H NMR and 13C {1H} NMR) spectra were recorded on a
Bruker AMX-500 MHz spectrometer, in CDCl3 or CDCl3/CS2 solutions.
Chemical shifts are reported in ppm downfield from Me4Si, by using the
residual solvent peak as internal standard. High performance liquid
chromatography (HPLC) analyses were carried out on a Cosmosil 5C18-
MS-II (4.6 ID 250 mm) reverse phase column with detection at 310 nm.
A mixture of toluene/acetonitrile (50/50) was used as eluent at 1 ml/min
flow rate. TLC was carried out on SiO2 (silica gel F254). Flash column
chromatography was carried out on SiO2 (silica gel 60, SDS, 230-400
mesh ASTM). Evaporation of the solvents was accomplished with a rotary
evaporator or by high vacuum distillation.
All photochemical reactions were carried out in an ice bath using a
300 W Xenon Cermax lamp as the light source and a Pyrex filter (> 290
nm wavelength). The distance of the light source from the reaction vessel
was 13 cm.
c) Deprotection of the carbonyl group in 2-(o-tolyl)-1,3-dioxolane-d3.
2-(o-Tolyl)-1,3-dioxolane-d3 (1.4 g) and THF (40 mL) were placed in a
round-bottom flask and then, of HCl 3N (10 mL) was added. After stirring
at room temperature for 24 h, diethyl ether (40 mL) was added and the
solution was extracted with Η2Ο (50 mL). The organic layer was dried
over anhydrous MgSO4 and solvent evaporation furnishing the crude
product as oil. Purification with column chromatography (SiO2,
hexane/ethyl acetate 7/1) gave pure o-tolualdehyde-d3 (13-d3) (0.6 g,
yield = 58%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 10.26 (s,
1H), 7.79 (d, J = 7.6 Hz, 1H), 7.47 (dd, J = 11.80, 4.4 Hz, 1H), 7.36 (t, J =
7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ =
192.83 (s), 140.50 (s), 134.20 (s), 133.66 (s), 132.05 (s), 131.77 (s),
126.35 (s), 18.79 (septet, J = 19.25 Hz); HRMS (EI-Sector) m/z: [M+ H +
Na]2+ Calcd for C8H6D3NaO2+ 147.0734; Found 147.0803.
Diethyl ether and tetrahydrofuran were distilled over Na under N2, in
presence of benzophenone, prior to use. Benzene and dichloromethane
were distilled under N2 over Na and P2O5 respectively and stored over
pre-dried molecular sieves 4 Å for at least 24 h prior to use. Commercially
available reagents and solvents that didn’t need to be dry were used as-
received without further purification.
Substrate synthesis.
1. Synthesis of o-tolualdehyde-d3 (13-d3).
Starting from o-bromobenzaldehyde, 13-d3 was prepared according to the
following three steps:
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10.1002/ejoc.201900859
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2. Synthesis of o-ethyl-benzaldehyde-d2 (14-d2).
Starting from o-bromoacetophenone, 14-d2 was prepared according to
the following four steps:
g, yield = 49%). 1H NMR (500 MHz, CDCl3): δ = 10.26 (s, 1H), 7.79 (d, J
= 7.6 Hz, 1H), 7.47 (dd, J = 11.80, 4.4 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H),
7.25 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 192.83 (s),
140.50 (s), 134.20 (s), 133.66 (s), 132.05 (s), 131.77 (s), 126.35 (s),
18.79 (septet, J = 18.75 Hz); HRMS (ESI Orbitrap) m/z: [M + H - H2O]+
Calcd for C9H9D2+ 121,0986; Found 121,0980.
a) Reduction of o-bromoacetophenone with LiAlD4.
In an oven-dried two-neck round-bottom flask, LiAlD4 (0.17 g, 4 mmol)
was dissolved in dry diethyl ether (15 mL) under argon and the resulting
mixture was vigorously stirred for 15 min. Then, the flask was cooled
down to 0 °C and o-bromoacetophenone (2 g, 10 mmol) dissolved in dry
diethyl ether (15 mL) were added dropwise. The ice bath was removed
and the reaction mixture was stirred at room temperature overnight. After
that, the solution was cooled down to 0 °C and quenched with 1 mL of
H2O, 1 mL of NaOH 15% and 3 mL of H2O until all lithium and aluminum
salts precipitate as white solids. The solids were filtrated and the filtrate
was washed with NaHCO3 5%, brine and finally dried over anhydrous
MgSO4. The solvent was evaporated to give of 1-(2-
bromophenyl)ethanol-d1 (1.83 g, yield 90%). 1H NMR (500 MHz, CDCl3):
δ = 7.62 (m, 1H), 7.53 (m, 1H), 7.37 (m, 1H), 7.15 (m, 1H), 1.97 (br s,
OH), 1.50 (s, 3H).
d) Oxidation of 2-ethyl-benzylalcohol-d2 to 2-ethyl-benzaldehyde-d2
(14-d2) (Swern oxidation).[27]
In an oven-dried two-neck round-bottom flask, oxalyl chloride [(COCl)2]
(520 μL, 6 mmol) and dry dichloromethane (CH2Cl2) (15 mL) were mixed
under argon. The solution was cooled to – 78 °C and dimethyl sulfoxide
(DMSO) (570 μL, 8 mmol) dissolved in 15 mL of dry CH2Cl2 was added.
Reaction was stirred for 10 min and subsequently, 2-ethyl-benzylalcohol-
d2 (0.4 g, 3 mmol) dissolved in 10 mL of dry CH2Cl2 was added. The
resulting solution was stirred at – 78 °C for an additional 20 min and then,
triethylamine (Et3N) (3 mL, 22 mmol) was added. The reaction mixture
was then stirred at room temperature for 30 min. Water was added next,
and the aqueous phase was separated and washed with diethyl ether.
The two organic phases were combined together, washed with brine and
dried over anhydrous MgSO4. The solvent was removed in vacuo to give
b) Reduction of 1-(2-bromophenyl)ethanol-d1 with Et3SiD.[26]
In an oven-dried two-neck round-bottom flask, 1-(2-bromophenyl)ethanol-
d1 (1.2 g, 6 mmol) was dissolved in dry dichloromethane (20 mL) under
argon. The solution was cooled down to 0 °C and then, Et3SiD (1.9 mL,
12 mmol) was added dropwise followed by the addition of BF3/Et2O
solution (7.5 mL, 30 mmol). Subsequently, the reaction mixture was
stirred at room temperature for 1 h. During that time significant amount of
heat was released. The reaction was quenched at 0 °C by addition of
aqueous solution NaOH 10% (2.5 mL) under vigorous stirring. After 15
min., diethyl ether (50 mL) was added and the mixture was washed with
saturated NaHCO3 solution and finally with brine. The organic layer was
collected, dried over anhydrous MgSO4 and the solvent was evaporated
to give pure 2-ethyl-bromobenzene-d2 (1.1 g, yield = 99%). 1H NMR (500
MHz, CDCl3): δ = 7.55 (m, 1H), 7.26 (m, 2H), 7.07 (m, 1H), 1.24 (br s,
3H).
0.4
g of crude product which was further purified by column
chromatography (SiO2, hexane/ethyl acetate 8/1) to give 145 mg of 14-d2
1H NMR (500 MHz, CDCl3): δ = 10.28 (s, 1H), 7.83 (dd, J = 7.7, 1.4 Hz,
1H), 7.51 (td, J = 7.5, 1.5 Hz, 1H), 7.36 (td, J = 7.6, 1.1 Hz, 1H), 7.29 (d,
J = 7.7 Hz, 1H), 1.25 (s, 3H);13C {1H} NMR (125 MHz, CDCl3): δ = 192.40
(s), 146.99 (s), 133.95 (s), 133.50 (s), 131.75 (s), 130.22 (s), 126.37 (s),
25.04 (quintet, J = 20.00 Hz), 16.13 (s); HRMS (EI-Sector) m/z [M + H]+,
calcd for C9H9D2O+: 137.0935; Found 137.0930.
3. Synthesis of 2,6-dimethylbenzaldehyde-d3 (15-d3).[19]
Starting from the commercially available o-tolualdehyde (13-d0), 15-d3
was prepared in a one-pot reaction according to the following step:
In an oven-dried round-bottom flask, piperidine (0.28 g, 3.3 mmol) was
dissolved in dry benzene (10 mL) under argon. Then, n-BuLi solution (1.2
Μ in hexane) (2.8 mL, 3.3 mmol) was added dropwise and the solution
was stirred at room temperature for 15 min. Subsequently, ο-
tolualdehyde (13-d0) (0.36 g, 3 mmol) was slowly added and the resulting
mixture was stirred for 15 min. After the dropwise addition of n-BuLi
solution (7.5 mL, 9 mmol), the reaction was refluxed at 80 °C for 15 h.
The reaction mixture was cooled to room temperature, dry THF (10 mL)
was added, and then, methyl iodide-d3 (CD3I) (1.12 mL, 18 mmol) was
added dropwise at – 78 °C. The resulting mixture was stirred to room
temperature, poured into 50 mL of cold HCl 10% under stirring, extracted
with diethyl ether (60 mL), washed with brine and dried over anhydrous
MgSO4. The solvents were removed in vacuo to give the crude product
that was further purified by column chromatography (SiO2, hexane)
affording 2,6-dimethylbenzaldehyde-d3 (15-d3) (0.2 g, yield = 48%). 1H
NMR (500 MHz, CDCl3): δ = 10.65 (s, 1H), 7.35 (dd, J1 = J2 = 7.5 Hz,
1H), 7.11 (d, J = 7.5 Hz, 2H), 2.64 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
c) Preparation of 2-ethyl-benzylalcohol-d2(13-d2)
In an oven-dried two-neck round-bottom flask, 2-ethyl-bromobenzene-d2
(1.1 g, 6 mmol) was dissolved in dry THF (30 mL) under argon. The
reaction mixture was cooled to – 62 °C and tBuLi solution (C = 1.1 M in
hexanes) (11 mL, 12 mmol) was added dropwise to give the solution an
intense orange color indicative of the formation of the anion on the
aromatic ring (due to ortho metalation). The reaction was stirred at – 62
°C for an additional 30 min and then, formaldehyde (0.21 g, 7 mmol) was
added at 0 °C. Stirring was continued at room temperature for 40 min. At
the end, the orange color of the solution completely disappeared. The
reaction mixture was cooled to 0 °C and water was added to precipitate
lithium salts leaving a transparent solution. Next, diethyl ether (30 mL)
was added under vigorous stirring and the solution was extracted with
brine. The organic layer was separated, dried over anhydrous MgSO4
and the solvent was removed to obtain pure 2-ethyl-benzylalcohol-d2 (0.4
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10.1002/ejoc.201900859
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= 193.66 (s), 141.19 (s), 133.03 (s), 129.74 (s), 127.85 (s), 20.51 (s);
(after removing 13C absorptions of a small amount of the corresponding
acid); HRMS (EI-Sector) m/z: [M + H]+ Calcd for C9H8D3O+ 138.0998;
Found 138.0993.
Kinetic Isotope Effects Measurements
For the measurement of the kinetic isotope effects, the photochemical
reactions of C60 with either equimolar mixtures of 13-d0 and 13-d3, 14-d0
and 14-d2, 15-d0 and 15-d6 or substrate 15-d3 were realized according to
the method described above. The equimolar ratio of the deuterated and
nondeuterated counterparts was confirmed based on the 1H NMR spectra
of those mixtures.
4. Synthesis of 2,6-dimethylbenzaldehyde-d0 (15-d0).[19]
15-d0 was prepared in a one-pot reaction from 13-d0 following exactly the
same procedure described above for the synthesis of 15-d3. Methyl iodide
(CH3I) (1.12 mL, 18 mmol) instead of CD3I was used in this case,
whereas the quantities of all the other reagents remained the same. 15-d0
was isolated in 50% yield (0.2 g).1H NMR (500 MHz, CDCl3): δ = 10.63 (s,
1H), 7.32 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 2H), 2.61 (s, 6H).
As described in the main text, the kinetic isotope effects were
calculated from the ratio of the kH and kD products, determined from their
1H NMR spectra, that equals the kH/kD ratio of the rate constants. The
corresponding spectroscopic data are reported below (for the NMR
spectra and the structures of the fullerene adducts see the SI of this
paper).
5. Synthesis of 2,6-dimethylbenzaldehyde-d6 (15-d6).[19]
Intermolecular KIE from the competition in the 13-d0/13-d3 couple.
Both kH and kD products (see also scheme 9) appear as a mixture of the
A and E conformers. 1H NMR (500 MHz, CDCl3/CS2): δ = 7.96 (m, 1H of
kH-E and 1Η of kD-E), 7.80-7.50 (m, 3H of kH-E, 3H of kD-E, 4H of kH-A
and 4Η of kD-A), 6.51 (d, J = 6.5 Hz, 1H of kH-E and 1Η of kD-E), 6.38 (s,
1H of kH-A and 1Η of kD-A), 5.63 (d, J = 13.5 Hz, 1H of kH-A), 4.83 (d, J =
14 Hz, 1H of kH-E), 4.51 (d, J = 14 Hz, 1H of kH-E), 4.37 (d, J = 13.5 Hz,
1H of kH-A), 3.32 (d, J = 7 Hz, OH of kH-E and ΟΗ of kD-E), 3.14 (s, OH of
kH-A and ΟΗ of kD-A). The value of the KIE was calculated from the
integrations of the peaks from the E conformer at 6.51 ppm (kH + kD) and
at 4.83 ppm (kH). The result is the same if we use the peak integrations
from the A conformer.
15-d6 was prepared in a one-pot reaction from 13-d3 following exactly the
same procedure described above for the synthesis of 15-d3. o-
Tolualdehyde-d3 (13-d3) (0.37 g, 3 mmol) was used in this case instead of
13-d0, whereas the quantities of all the other reagents remained the
same. 15-d6 was isolated in 50% yield (0.21 g). NMR (500 MHz, CDCl3):
δ 10.65 (s, 1H), 7.35 (dd, J1 = J2 = 7.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 2H),
2.64 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 193.65 (s), 141.07 (s),
133.02 (s), 129.72 (s), 127.83 (s), 19.70 (septet, 2C, J = 20.00 Hz);
HRMS (EI-Sector) m/z: [M + H]+ Calcd for C9H5D6O+ 141.1187; Found
141.1181.
General method for the photochemical addition of ο-
alkylbenzadehydes with C60
C60 (18 mg, 0.025 mmol) was dissolved in 50 mL benzene in an oven-
dried round-bottom flask, and then, 3- or 5-fold excess of the
.
Intermolecular KIE from the competition in the 14-d0/14-d2 couple.
Both kH and kD products adopt only the E conformation. 1H NMR (500
MHz, CDCl3/CS2): δ = 7.96 (m, 1H of kH and 1H of kD), 7.72-7.62 (m, 3H
of kH and 3H of kD), 6.58 (d, J = 7 Hz, 1H of kH and 1H of kD), 4.70 (q, J =
7 Hz, 1H of kH), 3.23 (d, J = 7 Hz, OH of kH and OH of kD), 2.37 (m, 3H of
kH and 3H of kD). The value of the KIE was calculated from the
integrations of the peaks at 6.58 ppm (kH + kD) and at 4.70 ppm (kH).
a
deuterated carbonyl compound (or an equimolar mixture of deuterated
and non-deuterated substrate) was added. The resulting solution was
deaerated by bubbling a stream of argon through under continuous
stirring for 30 min in the dark. Removal of molecular oxygen is crucial
because in the presence of C60
,
which is
a highly efficient
photosensitizer,[28] singlet oxygen (1O2) can be generated. This species
can react easily either with the aromatic substrates or with C60 itself
leading to undesired oxygenated products. The reaction solution was
Intermolecular KIE from the competition in the 15-d0/15-d6 couple.
Both kH and kD products adopt only the A conformation. 1H NMR (500
MHz, CDCl3/CS2): δ = 7.58-7.48 (m, 2H of kH and 2H of kD), 7.41 (m, 1H
of kH and 1H of kD), 6.73 (m, 1H of kH and 1H of kD), 5.64 (d, J = 13.7 Hz,
1H of kH), 4.34 (d, J = 13.7 Hz, 1H of kH), 3.09 (br s, OH of kH and OH of
kD), 2.72 (s, 3H of kH). The value of the KIE was calculated from the
integrations of the peaks at 6.73 ppm (kH + kD) and at 5.64 or 4.34 ppm
(kH).
placed in an ice bath and irradiated with
a
xenon lamp
(VariacEimacCermax 300W). The distance of the light source from the
reaction vessel was 13 cm. The reaction progress was monitored with
high performance liquid chromatography (HPLC). The color of the
solution changed from deep purple to brown, indicative of the formation of
fullerene adducts. Irradiation of the sample was interrupted when roughly
40% of C60 was consumed, monitored by HPLC chromatography. Further
irradiation leads to an increase in the percentage of multiadducts. For
product isolation, most of the benzene was evaporated and the remaining
solution was column chromatographed (SiO2, toluene/hexane 4/1).
Unreacted C60 elutes first as a purple band and then follows the
monoadduct brown band. The latter band was collected and the solvents
were removed to give a brown solid.
Intramolecular KIE from the photocycloaddition of 15-d3 substrate
with C60
.
Both kH and kD products adopt only the A conformation. 1H NMR (500
MHz, CDCl3/CS2): δ = 7.58-7.48 (m, 2H of kH and 2H of kD), 7.41 (m, 1H
of kH and 1H of kD), 6.72 (m, 1H of kH and 1H of kD), 5.63 (d, J = 13.6 Hz,
1H of kH), 4.33 (d, J = 13.6 Hz, 1H of kH), 3.06 (br s, OH of kH and OH of
kD), 2.72 (s, 3H of kD). The value of the KIE was calculated from the
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10.1002/ejoc.201900859
European Journal of Organic Chemistry
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integrations of the peaks at 6.72 ppm (kH + kD) and at 5.63 or 4.33 ppm
(kH).
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Acknowledgements
The research work was co-funded by the Greek Ministry of
Education and the European Union through research and
education action program PYTHAGORAS II 2005 and
IRAKLITOS 2002.
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Supplementary Material:1H NMR spectra, 13C {1H} NMR spectra of all
new substrates. 1H NMR spectra of Diels-Alder cycloaddition products of
C60 with hydroxy-o-quinodimethanes.HRMS spectra of substrates 13-d3
and 13-d2. MP2 6-311++G** calculationmethod for the geometry of
substrate15-d3. Experimental details. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Keywords:C60-functionalization • Photoenolate • Cycloadditions
• Mechanism•Isotope Effects
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European Journal of Organic Chemistry
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FULL PAPER
Photoenol reactive intermediates
add to C60, producing stable
[4+2] fullerene adducts.
Photoenolates of [C60]Fullerene
Manolis M. Roubelakis, Nikitas G.
Malliaros, and Michael
Orfanopoulos*
A mechanistic approach for this
reactivity of C60 is provided,
based mainly on intra and
intermolecular kinetic isotope
effects (KIEs) studies.
Page No. – Page No.
A
Mechanistic Study of the Diels-Alder
Cycloaddition of C60 with Photochemically
Generated Hydroxy-o-quinodimethanes.
A
facile functionalization governed by
steric factors
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