Microwave-Assisted 1,3-Dipolar Cycloaddition of Azomethine Ylides to [60]Fullerene: Thermodynamic Control of Bis-Addition with Ionic Liquids Additives

Article abstract of DOI:10.1002/ejoc.202100546

The cycloaddition of azomethine ylides to [60]fullerene (C₆₀) has been studied in ortho-dichlorobenzene (o-DCB) by evaluating the impact of an ionic liquid (IL) additive. The solvent effect has been addressed by evaluating the activation parameters of the cycloaddition and the boosting effect of the microwave (MW) induced dielectric heating. The IL additive plays a twofold role of stabilizing the dipolar ylide intermediate and favoring the retro-cycloaddition at high temperature regime. Under the conditions explored, a combined kinetic and thermodynamic preference favors the selective formation of trans bis-fulleropyrrolidine regioisomers, in agreement with the DFT computational analysis.

Full text of DOI:10.1002/ejoc.202100546

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Microwave assisted 1,3-dipolar cycloaddition of azomethine
ylides to [60]fullerene: thermodynamic control of bis-addition with
ionic liquids additives
Authors: Estefanía M. Martinis, Alejandro Montellano, Andrea Sartorel,
Mauro Carraro, Maurizio Prato, and Marcella Bonchio
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100546
Link to VoR: https://doi.org/10.1002/ejoc.202100546
01/2020

10.1002/ejoc.202100546
European Journal of Organic Chemistry
FULL PAPER
Microwave assisted 1,3-dipolar cycloaddition of azomethine
ylides to [60]fullerene: thermodynamic control of bis-addition
with ionic liquids additives
Estefanía M. Martinis,[a,b] Alejandro Montellano,[c] Andrea Sartorel,[a] Mauro Carraro*,[a]
Maurizio Prato*,[c,d,e] Marcella Bonchio*[a]
Dedicated to Professor Franco Cozzi on the occasion of his 70th birthday
[a]
Dr. E. Martinis, Prof. M. Carraro, Prof. A. Sartorel, Prof. M. Bonchio
Department of Chemical Sciences, University of Padova, and ITM-CNR
Via Marzolo, 1, 35131 Padova, Italy
E-mail: marcella.bonchio@unipd.it, mauro.carraro@unipd.it
Dr. E. Martinis
Faculty of Engineering - National University of Cuyo - National Scientific and Technical Research Council
Centro Universitario, M5502JMA, Mendoza, Argentina
Dr. A. Montellano, Prof. M. Prato
[b]
[c]
Department of Chemical and Pharmaceutical Sciences, University of Trieste
Via Giorgieri 1 - 34127 Trieste, Italy
E-mail: prato@units.it
[d]
[e]
Prof. M. Prato
Center for Cooperative Research in Biomaterials (CIC biomaGUNE),
Basque Research and Technology Alliance (BRTA)
Paseo de Miramón182, 20014 Donostia San Sebastián, Spain
Prof. M. Prato
Basque Foundation for Science
Ikerbasque, Bilbao 48013, Spain
Supporting information for this article is given via a link at the end of the document
Abstract: The cycloaddition of azomethine ylides to [60]fullerene
(C60) has been studied in ortho-dichlorobenzene (o-DCB) by
evaluating the impact of an ionic liquid (IL) additive. The solvent
effect has been addressed by evaluating the activation parameters
of the cycloaddition and the boosting effect of the MW induced
dielectric heating. The IL additive plays a twofold role of stabilizing
the dipolar ylide intermediate and favoring the retro-cycloaddition at
high temperature regime. Under the conditions explored, a combined
kinetic and thermodynamic preference favors the selective formation
of trans bis-fulleropyrrolidine regioisomers, in agreement with the
DFT computational analysis.
of ILs is aimed at addressing the replacement of hazardous
volatile organic solvents, being instrumental for fast and
selective MW-heating by ionic conduction, with negligible vapor
pressure and safer protocols.[8]
CH3
N
CH3
N
R1
R1
n
R1CHO
CH3NHCH2COOH
R1CHO
CH3NHCH2COOH
solvent
MW
solvent
MW
7 N
N
-
[BF4
]
Solvent: o-DCB or o-DCB:IL=3:1
IL=
Introduction
FP 1
FP 2
R1
R1
=
CH3
Fullerene functionalization by the azomethine ylide
H
cycloaddition,
yielding
fulleropyrrolidines
(FPs),[1] has
=
significantly contributed to the synthesis of new molecular
materials for transformative research in strategic fields, including
solar energy conversion and nanomedicine.[2] FPs synthesis
tolerates many functional groups and can be accelerated by
microwave (MW) irradiation.[3,4] In this case, toluene, benzene or
o-dichlorobenzene (o-DCB) have been used as solvents,
whereby the latter displays a relatively higher boiling point and
medium MW-absorbing properties (with a tangent loss, tan  =
0.280, higher than that of water, tan  = 0.123).[5] Moreover, we
have previously described the preparation of FPs in a mixture of
ionic liquids (ILs) and o-DCB, showing that higher reaction rates
and conversions can be achieved in such conditions.[6,7] The use
Scheme 1 Azomethine ylide cycloaddition to [60]fullerene yielding mono- and
poly-adducts (FPs and 2) by reacting heptaldehyde or formaldehyde
respectively, under MW irradiation, in o-DCB/IL mixtures.
1
In this work, we have investigated the effect of MW irradiation on
the cycloaddition of azomethine ylides to [60]fullerene, in o-
DCB/IL mixtures (Scheme 1), in order to address the thermal
effect of MW-irradiation on reaction rates and selectivity. When
the 1,3-dipolar cycloaddition is carried out on the fullerene
sphere, indeed, not only the mono-adduct (m-FP) is obtained,
but a complex mixture of poly-adducts (p-FP) can also form at
1
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푙푛
(푘표푏푠/푇) = −
+ ln(
)
10.1002/ejoc.202100546
European Journal of Organic Chemistry
FULL PAPER
higher fullerene conversion. Thus, 8, 46 and 262 FP
regioisomers can be expected for symmetrical addends
respectively for the bis, tris and tetrakis- addition at the fullerene
core.
Table 1. Reaction rate and conversion, observed during the reaction of
[60]fullerene with sarcosine and heptaldehyde in o-DCB and o-DCB:IL 3/1 v/v.
% Conv.[c]
[a]
Robs / Ms-1
Entry
Solvent
T (K)
(kobs ×105/ s-1) [b]
5 min
60 min
FP bis-adducts, in particular, are of great interest in a wide
number of applications in materials science.[9] However, their
isolation and purification may be difficult and time-consuming. In
this context, several approaches have been developed to
increase the selectivity of bis-addition to the fullerene core.[10]
While fullerene cyclopropanation has been successfully
controlled with tether‐directed covalent methods, supramolecular
masks or photo-triggers,[11] to the best of our knowledge, there
are no precedent reports on how to direct and optimize the bis-
addition selectivity during FPs synthesis.
Our results address: (i) the impact of MW-assisted heating
on the cycloaddition kinetics and selectivity in o-DCB and IL
containing media; (ii) optimization of the synthetic protocol
towards the bis-substitution of the fullerene core; (iii) DFT
calculations to interrogate mechanism and the thermodynamic
drivers leading to stable FP bis-adducts.
1
2
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
IL 25%
IL 25%
IL 25%
IL 25%
IL 25%
IL 25%
343
363
383
403
423
443
343
363
383
403
423
443
0.19 (2.7)
0.40 (5.7)
0.83 (7.7)
1.42 (20.3)
2.51 (35.8)
3.77 (53.8)
1.0 (14)
1
2
5
10
38
45
50
52
12
48
58
82
86
88
3
4
4
6
5
11
16
4
6
7
8
2.1 (29)
9
9
5.4 (78)
24
39
59
64
10
11
12
9.1 (130)
13.7 (196)
17.3 (247)
Results and Discussion
The reactivity of [60]fullerene with sarcosine and
heptaldehyde was initially used as a benchmark reaction to
screen the influence of the synthetic conditions. In particular, we
focused on the use of MW-activated IL phases to accelerate the
azomethine ylide cycloaddition and control the formation of
fullerene poly-adducts, p-FP 1 (Scheme 1).
[a] In all reactions: [60]fullerene 7 mM; sarcosine 14 mM, heptaldehyde 28 mM.
Entries 1 – 6: reaction performed in 1 mL o-DCB; entries 7 – 12: reactions
performed in 0.8 mL with ratio o-DCB/IL 3/1 v/v; [b] Robs = initial reaction rates
calculated from a linear regression at conversion < 20%); kobs is the first order
rate constant obtained by dividing Robs for the initial concentration of
[60]fullerene, equal to 7 mM. [c] [60]fullerene conversion monitored by HPLC
analysis.
IL nature and content, as well as [60]fullerene concentration
were shown to affect both the yield and the selectivity of the
reaction.[7] In particular, long chain ILs are effective to improve
fullerene dispersion. Therefore, a 1-methyl-3-n-octyl imidazolium
tetrafluoroborate (OmimBF4): o-DCB = 1:3 mixture was used to
The experimental kinetics show the progress of [60]fullerene
cycloaddition, which generally occurs with consecutive formation
of m-FP 1 and p-FP 1 products (Figures S1-S12).
A typical kinetic trace is reported in Figure 1a for the reaction
carried out at 423 K (entry 5 in Table 1) in o-DCB, showing a
[60]fullerene conversion up to 58% in 2h, with formation of m-FP
1 (35%) and a mixture p-FP 1 (23%). When IL is added to the
solvent phase, the cycloaddition kinetics is remarkably faster so
that formation of p-FP 1 becomes prevalent above 400K
(Figures S10-S12). In Figure 1b is reported the corresponding
kinetic trace for the reaction with IL additive, at the same
temperature (423 K), showing the prevalent formation p-FP 1
(52 %) vs m-FP 1 (39%) in 60 min. Noteworthy, the IL additive
leads to a 4-fold increase of the reaction rate with respect to the
control reaction in pure o-DBC at 443 K (Robs=17.3 and3.77
mol L-1 s-1, respectively), with [60]fullerene conversion rising up
to 64% in 5 minutes (Table 1, entry 12 vs entry 6).
prevent
clustering/aggregation
phenomena,
and
the
[60]fullerene concentration was set to ensure its complete
solubilization, while yield optimization was explored as a function
of the relative ratio between azomethine ylide precursors,
sarcosine and heptaldehyde. A faster conversion of pristine
[60]fullerene to m-FP 1 was thus observed at a fullerene
concentration of 7 mM, in the presence of two and four
equivalents of sarcosine and heptaldehyde, respectively.
ILs are known to play a role in the stabilization of the
incipient 1,3-dipole intermediate, however favoring cyclo-
reversion[6,12-14] under MW-induced dielectric heating. Indeed,
the cyclo-reversion of FPs can be readily achieved in pure ILs
under MW irradiation by unlocking the pyrrolidine ring to back-
release pristine [60]fullerene.[6] Noteworthy, when o-DCB is
introduced as a co-solvent, retro-cycloaddition is remarkably
slowed down, which provides a facile control over the process
reversibility giving access to a thermodynamic equilibration of
the reaction.
The Eyring plot in Figure 2 reports the dependence of the
reaction kinetic constant (kobs) on the temperature conditions
(Table 1), according to the following equation:
∆퐻‡ 1 ∆푆‡
+
퐾푘퐵
ℎ
푅
푇
푅
The effect of the temperature on the reaction was initially
investigated under conventional heating, in a temperature range
between 343 and 443 K, in the absence of MW irradiation, using
o-DCB, either alone or with the IL additive, as the solvent phase.
Table 1 collects the first order rate constants (kobs) obtained for
[60]fullerene conversion under the explored reaction conditions
(Scheme 1).
where H‡ and S‡ are the enthalpy and entropy of activation,
respectively, T is the reaction absolute temperature, R is the gas
constant (1.986 Kcalmol-1), K is the transmission coefficient
(assumed to be 1), kB = Boltzmann constant, h = Planck
constant.
2
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10.1002/ejoc.202100546
European Journal of Organic Chemistry
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circles). MW-induced Tcalc (Table 2) were extrapolated from this graph (light
grey and red circles).
a)
In all cases, kobs values are obtained considering a first order
kinetics for the [60]fullerene reactant, in agreement with the
experimental concentration–time profiles and consistent with the
generally accepted mechanistic scheme (Table 1 and Scheme
S1 in Supplementary Information).
Inspection of graphs in Figure 2 shows the line slopes (ca.
4200 K-1) yielding similar values of activation enthalpy, H‡ =
8.4±0.2 and 8.0±0.8 Kcalmol-1 ascribed to o-DCB and o-DCB/IL
solvent conditions, respectively. Similarly, the activation
entropies are calculated from the graph intercepts, showing
large negative values, that turn out to be slightly mitigated by the
addition of the IL additive (S‡ = -55.2±0.5 and -52.3±1.7 calK-
1mol-1 for o-DCB and o-DCB/IL). The almost identical enthalpy
activation barriers together with the negative activation entropy
are consistent with
a concerted 1,3-dipolar cycloaddition
b)
mechanism. The rate enhancement, observed in the presence of
ILs, is therefore explained by a less negative activation entropy
in the presence of ILs, due a favorable desolvation of the cyclic
transition state with respect to the zwitterionic azomethine ylide
reagent (Scheme S1).[15]
With the aim to exploit the ILs ionic phase as excellent MW-
absorbers, the reaction was performed under MW irradiation (50
W), flowing compressed air to avoid possible overheating effects
(Table 2).
Table 2. Rate, [60]fullerene conversion to m-FP 1, and selectivity ratio,
observed for the MW-assisted reaction of [60]fullerene with sarcosine and
heptaldehyde in o-DCB and o-DCB:IL=3:1.
Conv. (%)
C60
m-FP 1
Sel
Robs M s-1)
Tcalc
[a]
Figure 1. Kinetic traces of [60]fullerene conversion to m-FP 1 and p-FP 1
during 1,3-dipolar cycloaddition of sarcosine and heptaldehyde in 1 mL of o-
DCB (a) or 0.8 mL of o-DBC/IL 3/1 v/v (b), at 423K. [60]fullerene 7 mM;
sarcosine 14 mM, heptaldehyde 28 mM. Data are connected with continuous
#
Solvent
[b]
[d]
(%)[c]
(kobs ×105/ s-1)
(K)[e]
1
o-DCB
9
6.6
4
1
2.2 (31)
419
471
2
IL 25%
65
31.7
40.1 (573)
[a] In all reactions: [60]fullerene 7 mM; sarcosine 14 mM, heptaldehyde 28 mM.
50 W power applied under magnetic stirring and simultaneous cooling by
compressed air at 40 psi. Entry 1: reaction performed in 1 mL o-DCB; entry 2:
reaction performed in 0.8 mL o-DCB/IL 3/1 v/v. [b] [60]fullerene conversion
monitored by HPLC analysis after 5 min. [c] % of m-FP 1 monitored by HPLC
analysis after 5 min. [d] Selectivity ratio, calculated as m-FP 1/ p-FP 1 ratio. [e]
temperature extrapolated from the Eyring plot in Figure 2.
MW-assisted kinetics were instrumental to address the
temperature conditions operating under MW induced dielectric
heating. The operating temperature can be determined indirectly
by extrapolation of the Eyring plot in Figure 2 (Tcalc in Table
2).[16,17]
The combined use of IL and MW is responsible for a
remarkable initial rate acceleration, reaching up to 40.1 M s-1
(Figure S13). This kinetic effect (kobs
=
573 x10-5 s-1)
corresponds to a temperature read-out Tcalc= 471 K, as provided
by the Eyring linear relationship in Figure 2 (light red circle). With
respect to the control reaction, performed in pure o-DCB and
under analogous MW irradiation power, the IL additive leads to a
ca. 20-fold rate acceleration, which is explained considering a
poor dielectric heating of the pure o-DCB solvent (Tcalc= 419 K,
lines for a better visualization.
Figure 2. Eyring plot for the reaction performed under conventional heating
conditions, in o-DCB (black circles) and in the presence of 25% OmimBF4 (red
3
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10.1002/ejoc.202100546
European Journal of Organic Chemistry
FULL PAPER
light grey circle in Figure 2). Despite the MW-induced boosting
effect, [60]fullerene conversion levels off at 65% (Figure S13
and Table 2) with formation of both m-FP 1 and p-FP 1 in ca 1.1
ratio (Table 2). While the evolution to poly-substituted products
is expected to increase at higher [60]fullerene conversion
(Figure 1 and Table 2), the observation of a limiting plateau yield
is likely ascribed to the equilibrium regime involving the
thermally activated retro-cycloaddition. This latter is effective in
the presence of the IL additive and likely occurs at all the
fulleropyrrolidine sites.
To further explore the effect of the thermodynamic control on
the cycloaddition products, we turned our attention to the
regioselectivity of the 1,3-dipolar cycloaddition obtained with
sarcosine and formaldehyde as a model reaction, yielding FPs 2
(Scheme 1).[18] In particular, the N-methyl unsubstituted
azomethine ylide generated from formaldehyde rules out the
formation of additional bis-FP 2 stereoisomers and minimizes
the steric hindrance of a second pyrrolidine ring installed on the
C60 scaffold.[19]
p-FP 2 turns out to be dominant (56%), hampering the isolation
of desired bis-functionalized products (Figure 4, trace a). A
similar product distribution is also obtained under conventional
heating conditions.
Noteworthy, the introduction of the ionic liquid additive
combined with MW-induced dielectric heating was crucial for the
simplification of the product profile. At shorter irradiation time (<
5 min), [60]fullerene conversion remains below 60%, which limits
the formation of p-FP 2, while enhancing the production of m-FP
2 (46%) and of bis-FP 2 where the preferential selectivity
towards trans and equatorial regioisomers is confirmed (54%)
(Figure S14b and Figure 4, trace b). The selective formation of
trans and equatorial regioisomers at short reaction time, is
indicative of a marked kinetic preference, regulated by steric
hindrance that favors the bis-functionalization at the equatorial
or sub-hemisphere distal positions.[19]
1,3 dipolar cycloaddition on [60]fullerene can involve 30
reactive double bonds, shared by condensed [6,6] cycles, so
that after installation of the first pyrrolidine ring, 8 isomeric bis-
adducts can be formed, either located on the same C60
hemisphere with respect to the first functionalization (three cis
isomers), in the opposite one (four trans isomers), or at the
equatorial positions (1 eq isomer) (Figure 3).[19]
Figure 4. Histogram plot illustrating the % composition of the reaction mixtures
obtained with 14 mol of [60]fullerene, 56 mol of formaldehyde and 28 mol
of sarcosine, irradiated at 12 W in (a) 2 mL of o-DCB, >10 min (1 step o-DCB,
blue columns) or (b) in 1.5 mL of o-DCB and 0.5 mL of OmimBF4, 5 min (1
step o-DCB/IL, orange columns). Yellow columns (c) are referred to an ylide
precursors-free mixture, obtained from the reaction in o-DCB, after
thermodynamic equilibration in 1.5 mL of o-DCB and 0.5 mL of OmimBF4,
upon 5 min irradiation (2 step o-DCB/IL). In all cases, % are based on
chromatographic peak areas by assuming a similar response factor for all
compounds.
To verify a converging thermodynamic control over the
equilibration of bis-fulleropyrrolidine regioisomers, we designed
a two-stage/follow-up experiment. In the first stage, a crude
reaction mixture was obtained under MW irradiation (12 W, <10
min) in pure o-DCB and purified from the unreacted ylide
precursors. The “purified” crude was then irradiated again, in a
second stage (12 W for 5 minutes), using a o-DCB:IL=3:1
solvent phase. HPLC analysis confirmed that the initial mixture
(Figure 5a), containing the unreacted [60]fullerene and
Figure 3. Isomeric bis-fulleropyrrolidines (bis-FP 2) and their relative Gibbs
free energy (see main text).
With the aim to tune the selectivity of the bis-cycloaddition,
MW-irradiation was optimized at an applied power of 12 W, and
the product profile was monitored via HPLC analysis, by
identification of the single analytes specifically attributed to m-FP
2 and to trans-, cis- and equatorial bis-fulleropyrrolidines
(Figures S14 and attributions in Table S1), while considering the
remaining peaks as an overall signature of further [60]fullerene
poly-functionalization. Using pure o-DCB as solvent, a complex
mixture of fulleropyrrolidines readily forms in solution after ca. 10
min irradiation (Figure S14a). Analysis of the product profile
reveals that [60]fullerene conversion (> 80%) leads to the
formation of m-FP 2 (13%) together with seven bis-FP 2
regioisomers (31%) where trans-bis-fulleropyrrlidines are the
prevalent isomers (23%). In this reaction, a mixture of ill-defined
fulleropyrrolidine products (m-FP 2, and seven bis-FP
2
regioisomers),[20] evolved in the second stage, under
thermodynamic re-equilibration. The resulting product profile
shows an increased conversion of [60]fullerene (up to 95%) that
occurs by consuming the trans-4, cis 1-3 and eq isomers while
leading to the preferential formation of trans-1, trans-2, trans-3
bis-FP 2 regioisomers (Figure 4, trace c and Figure 5b). The
further progress of the 1,3 dipolar cycloaddition, without
4
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10.1002/ejoc.202100546
European Journal of Organic Chemistry
FULL PAPER
recharging the ylide precursors (Scheme 1), is indicative of a
reversible reaction pathway under thermodynamic control.
m-FP
trans-1
trans-2
trans-3
trans-4
a)
C60
eq
cis-2
cis-1
t / min
b)
m-FP
trans-1
trans-2
trans-3
C60
Figure 6. Representation of frontier molecular orbitals of m-FP 2 (LUMO,
LUMO+1 and LUMO+2) and of ylide (HOMO).
t / min
Figure 5. HPLC profile of (a) a mixture of [60] fullerene monoadduct (m-FP 1)
and bis-adducts obtained from a reaction of 14 mol of fullerene, 56 mol of
formaldehyde and 28 mol of sarcosine irradiated at 12 W in 2 mL of o-DCB
(<10 min) and (b) of the mixture in (a) after irradiation (12 W for 5 min) in 1.5
mL of o-DCB and 0.5 mL of OmimBF4.
Geometry optimization of all the expected bis-FP 2 has been
performed with the aim to address their relative thermodynamic
stability. In all cases the calculated free energies (G) of the
diverse regioisomers are referred to the most stable equatorial
bis-FP 2 (eq, Figure 3).
Indeed, the LUMO-LUMO+2 molecular orbitals of m-FP 2
display an electron density distribution involving diverse [6,6]
bonds of the fullerropyrrolidine scaffold, which provides a
rational for a regioselective 1,3-dipolar cycloaddition controlled
by the frontier orbital coefficients of the interacting species
(Figure 6 and Table 3).[21]
According to the computational analysis, the higher energy
bis-FP 2 isomers display a cis-orientation (cis-1, cis-2 and cis-3)
with relative energy gap in the range G= +2.5 – 8.0 Kcal mol-1.
Because of the lower distortion of the fullerene scaffold, bis-FP 2
with a trans-orientation are more stable regioisomers, with
similar energy content (G below 1.5 Kcal mol-1, thus at the limit
of the significance value for this level of calculation).
To address reaction path and product distribution, we
performed DFT calculation at the b3lyp/6-311G level (see
Figures 3, 6, S15, S16).
The formation of bis-fulleropyrrolidines results from the
favorable interaction between empty orbitals of the m-FP 2 (in
particular, the LUMO, LUMO+1 and LUMO+2) and the HOMO of
the ylide reagent, with a calculated energy gap in the range
0.625 – 0.975 eV (14.4-22.5 Kcal mol-1, Figure 6 and Table 3).
Table 3. Frontier empty orbitals of m-FP 2, their difference in energy with
respect to the HOMO of the ylide reagent, and preferred bis-FP 2 regioisomers
localized on the [60]fullerene scaffold (minor regioisomers are indicated in
brackets deriving from a less favourable interaction of the orbital density), see
Figure 6.
These results are in good agreement with the regioselectivity
outcome observed under diverse heating conditions, indicating
that the trans- bis-FP 2 isomers are the dominant products,
formed under thermodynamic control, by unlocking the cyclo-
reversion of the high energy cis-isomers (Figures 4 and 5).
Frontier Orbital
of m-FP 2
Gap in energy with
HOMO of ylide / eV
Preferred bis-FP 2
regioisomers based on a
HOMO-ylide controlled
orientation
(Kcal/mol in brackets)
0.625 (14.4)
Conclusion
LUMO
cis-2, eq, trans-3
(cis-3)
The functionalization of [60]fullerene by azomethine ylide 1,3-
dipolar cycloaddition to fulleropyrrolidines has been performed
by the combined use of IL phases and MW dielectric heating.
The reaction of [60]fullerene with heptaldehyde and sarcosine as
ylide precursors has been considered as a benchmark system to
address the cycloaddition performance under conventional
heating and under MW irradiation. Here, the use of the IL
LUMO+1
LUMO+2
0.724 (16.7)
0.975 (22.5)
cis-1, eq, trans-2
trans-1, trans-4
(cis-3, trans-2, trans-3)
5
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10.1002/ejoc.202100546
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[2]
a) M. Prato, J. Mater. Chem. 1997, 7, 1097-1109; b) A. Montellano
López, A. Mateo-Alonso, M. Prato, J. Mater. Chem. 2011, 21, 1305-
1318; c) M. Prato, Top. Curr. Chem. 1999, 199, 173-187; d) A. Mateo-
Alonso, C. Sooambar, M. Prato, Org. Biomol. Chem. 2006, 4, 1629-
1637; e) A. Mateo-Alonso, D. M. Guldi, F. Paolucci, M. Prato, Angew.
Chem. Int. Ed. 2007, 46, 8120-8126; f) A.V. Mumyatov, A. E.
Goryachev, F.A. Prudnov, O.A. Mukhacheva, D.K. Sagdullina, A.V.
Chernyak, S.I. Troyanov, P.A. Troshin, Synth Met. 2020, 270, 116565;
g) R. Tao, T. Umeyama, K. Kurotobi, H. Imahori, ACS Appl. Mater.
Interfaces 2014, 6, 17313–17322; h) M.A. Faist, S. Shoaee, S.
Tuladhar, G.F.A. Dibb, S. Foster, W. Gong, T. Kirchartz, D. D.C.
Bradley, J.R. Durrant, J. Nelson, Adv. Energy Mater. 2013, 6, 744–752;
i) W. Huang, E. Gann, N. Chandrasekaran, S.K.K. Prasad, S.-Y. Chang,
L. Thomsen, D. Kabra, J.M. Hodgkiss, Y.-B. Cheng, Y. Yang, C.R.
McNeill, Adv. Energy Mater. 2017, 1602197; j) N. C. Miller, S.
Sweetnam, E.T. Hoke, R. Gysel, C.E. Miller, J.A. Bartelt, X. Xie, M. F.
Toney, M.D. McGehee, Nano Lett. 2012, 12, 1566–1570; k) J. K.
Sørensen, J. Fock, A. H. Pedersen, A. B. Petersen, K. Jennum, K.
Bechgaard, K. Kilså, V. Geskin, J. Cornil, T. Bjørnholm, M. B. Nielsen
J .Org.Chem. 2011, 76, 245-263.
additive allows a flash thermal activation induced by the efficient
MW absorption, which is responsible for
a 20-fold rate
acceleration of [60]fullerene conversion. Inspection of the
activation parameters by the Eyring relationship points to a
favourable stabilization of the zwitterionic azomethine ylide
reagent in the presence of ILs, which mitigates the negative
activation entropy expected for the evolution of the cyclic
transition state. Optimized conditions were then applied for the
regioselective formation of bis-FP 2 trans-regioisomers, as
observed for the reaction of [60]fullerene with a symmetrical
ylide generated in-situ from formaldehyde and sarcosine
precursors. In this case, the combined use of ILs additive and
MW irradiation is effective to unlock the reverse regime of retro-
cycloaddition, thus allowing a desirable thermodynamic control
of
the
product
distribution.
Controlling
[60]fullerene
functionalization by a proper choice of the solvent composition
and of the temperature conditions offers a straightforward tool to
exploit a convergent kinetic and thermodynamic control on the
cycloaddition selectivity.
[3]
[4]
a) F. Langa, P. de la Cruz, Comb. Chem. High Throughput Screen.
2007, 10, 766-782; b) F. Langa, P. de la Cruz in Microwaves in Organic
Synthesis Ed. A. Loupy, Wiley-VCH, and references therein.
a) P. de la Cruz, A. de la Hoz, F. Langa, B. Illescas, N. Martin
Tetrahedron 1997, 53, 2599-2608; b) S. Wang, J.-m. Zhang, L.-p. Song,
H. Jiang, S.-z. Zhu J. Fluorine Chem. 2005, 126, 349-353; c) J. Safaei-
Ghomi, R. Masoomi, RSC Adv. 2015, 20, 15591–15596; d) B. Jin, R.-F.
Peng, W.-N. Yang, K. Wang, B.-Q. Yuan, S.-J. Chu. Synth. Commun.
2010, 40, 580-586; e) J. Zhang, W. Yang, P. He, S. Zhu, S. Wang
Synth. Commun. 2005, 35, 89-96; f) F. G. Brunetti, M. A. Herrero, J. de
M. Muñoz, A. Díaz-Ortiz, J. Alfonsi, M. Meneghetti, M. Prato, E.
Vázquez, J. Am. Chem. Soc. 2008, 130, 8094-8100; g) E. Vazquez, F.
Giacalone, M. Prato Chem. Soc. Rev. 2014, 43, 58-69.
Experimental Section
General: Continuous microwave irradiation was carried out in a CEM-
Discover-Coolmate
mono-modal
microwave
apparatus,
with
simultaneous monitoring of irradiation power, pressure and temperature.
Compressed air was applied to improve the temperature control of the
reaction mixtures. All reactions were monitored by HPLC, using a
Shimadzu LC-10AT VP pump system, equipped with a UV detector
SPD–10A VP set at 340 nm. Phenomenex Luna and Cosmosil
Buckyprep columns (250 x 4.6 mm 5 μm particles) were used, with
toluene as eluent flowing at 1 mL/min.
[5]
[6]
[7]
V.G. Gude Microwave-mediated biofuel production. CRC Press. 2017,
p. 38.
I. Guryanov, Al. Montellano Lopez, M. Carraro, T. Da Ros, G. Scorrano,
M. Maggini, M. Prato, M. Bonchio Chem. Commun. 2009, 3940 – 3942.
I. Guryanov, F. M. Toma, Al. Montellano Lopez, M. Carraro, T. Da Ros,
G. Angelini, E. D’Aurizio, A. Fontana, M. Maggini, M. Prato, M. Bonchio
Chem. Eur. J. 2009, 12837 – 12845.
Procedure for the cycloadditions: Unless otherwise stated, 5 mg of
fullerene (7 mol) were dispersed upon sonication in a mixture of o-
dichlorobenzene (and ionic liquid), together with sarcosine (1.2 mg, 14
mol) and aldehyde (3.2 mg, 28 mol), in a closed glass test tube
containing 1 mL of solvent. Samples were diluted using toluene and
analyzed by HPLC.
[8]
[9]
a) Z. Yinghuai, S. Bahnmueller, C. Chibun, K. Carpenter, N. S.
Hosmane, J. A. Maguire, Tetrahedron Lett. 2003, 44, 5473-5476; b) Z.
Yinghuai, J. Phys. Chem. Solids 2004, 65, 349-353; c) R. R. Deshmukh,
J. W. Lee, U.S. Shin, J.Y. Lee, C.E. Song. Angew. Chem. Int. Ed. 2008,
47, 8615-8617.
DFT calculations have been performed with Gaussian 09 software.
Geometries have been optimized at the b3lyp/6-311G level in the gas
phase. Inclusion of a continuous pcm model for the solvent (water) did
not lead to significant changes in the relative energies of the bis-adducts
discussed in Figure 3.
F. Zhang, W. Shi, J. Luo, N. Pellet, C. Yi, X. Li, X. Zhao, T.J.S. Dennis,
X. Li, S. Wang, Y. Xiao, S.M. Zakeeruddin, D. Bi, M.Grätzel, Adv. Mater.
2017, 29, 1606806; b) T. Umeyama, H. Imahori, Acc. Chem. Res. 2019,
52, 2046 –2055.
[10] D. Sigwalt, F. Schillinger, S. Guerra, M. Holler, M. Berville, J.-F.
Nierengarten, Tetrahedron Lett. 2013, 54, 4241-4244.
[11] L. Đorđević, L. Casimiro, N. Demitri, M. Baroncini, S. Silvi, F. Arcudi, A.
Credi, M. Prato Angew.Chem. Int. Ed. 2021, 60, 313 –320.
[12] A. Alvarez, E. Ochoa, Y. Verdecia, M. Suárez, M. Sola, N. Martín J. Org.
Chem. 2005, 70, 3256-3262.
Acknowledgements
We thank Martino Gardan for preliminary investigation. Funding
from MIUR (PRIN Nanoredox, Prot. 2017PBXPN4) is gratefully
acknowledged. AS acknowledges Fondazione Cariparo for
funding (project SYNERGY, Progetti di Eccellenza 2018). This
work was performed under the Maria de Maeztu Units of
Excellence Program from the Spanish State Research Agency –
Grant No. MDM-2017-0720.
[13] O. Lukoyanova, C. M. Cardona, M. Altable, S. Filippone, A. Martín-
Domenech, N. Martín, L. Echegoyen Angew. Chem. Int. Ed. 2006, 45,
7430-7433.
[14] a) S. Filippone, M. Izquierdo Barroso, Á. Martín-Domenech, S. Osuna,
M. Solà, N. Martin, Chem. Eur. J. 2008, 14, 5198-5206; b) N. Martín,
M. Altable, S. Filippone, A. Martín-Domenech, L. Echegoyen, C.M.
Cardona Angew. Chem. Int. Ed. 2006, 45, 110-114.
Keywords: Fullerenes • Temperature effect • 1,3-dipolar
[15] T. Rispens, J. B. F. N. Engberts J. Phys. Org. Chem. 2005; 18, 908–
917.
Cycloaddition • Ionic Liquids • Microwaves
[16] P. K. Chen, M. R. Rosana, G. B. Dudley, A. E. Stiegman J. Org. Chem.
2014, 79, 7425–7436.
[1]
a) M. Maggini, G. Scorrano, M. Prato, J. Am. Chem. Soc., 1993, 115,
9798-9799; b) M. Prato, M. Maggini, Acc. Chem. Res. 1998, 31, 519-
526; c) N. Tagmatarchis, M. Prato, Synlett 2003, 6, 768-779.
[17] M. A. Frasso, A. E. Stiegman, G. B. Dudley Chem. Commun. 2020, 56,
11247-11250.
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10.1002/ejoc.202100546
European Journal of Organic Chemistry
FULL PAPER
[18] a) K. Kordatos, S. Bosi, T. Da Ros, A. Zambon, V. Lucchini, M. Prato J.
Org. Chem. 2001, 66, 2802–2808; b) S. Marchesan, T. Da Ros, M.
Prato J. Org. Chem. 2005, 70, 4706–4713.
[19] Y. Nakamura, K. O-kawa, J. Nishimura Bull. Chem. Soc. Jpn. 2003, 76,
865–882.
[20] Under thermal conditions, 1,3 dipolar cycloaddition to [60]fullerene
yields a product distributions that is similar to what observed under MW
irradiation in the absence of the IL additive (compare Figure 5a with
Figure 2 in ref 18b).
[21] M. Kissane, A. R. Maguire Chem. Soc. Rev. 2010, 39, 845–883.
7
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10.1002/ejoc.202100546
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
The 1,3-dipolar cycloaddition of azomethine ylides to [60]fullerene has been performed in the presence of ionic liquids and under
microwave (MW) dielectric heating. As confirmed by DFT calculations, a converging kinetic and thermodynamic control favors the
selective formation of the less sterically hindered and most stable bis-fulleropyrrolidine regioisomers.
Institute and/or researcher Twitter usernames: @nanomolcat @lab_carbon
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