On the Route to the Photogeneration of Heteroaryl Cations. the Case of Halothiophenes

Article abstract of DOI:10.1021/acs.joc.6b00978

2-Chloro-, 2-bromo-, and 2-iodothiophenes undergo photochemical dehalogenation via the triplet state. In the presence of suitable π-bond nucleophiles, thienylation occurs with modest yield from chloro and bromo derivatives (via photogenerated triplet 2-thienyl cation). Specific trapping by using oxygen along with computational analysis carried out by means of a density functional method support that, in the case of iodo derivatives, homolytic thienyl-I bond fragmentation occurs first and heteroaryl cations are formed by electron transfer within the triplet radical pair, thus opening an indirect access to such cations.

Full text of DOI:10.1021/acs.joc.6b00978

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Article
On the route to the photogeneration of
heteroaryl cations. The case of halothiophenes
Carlotta Raviola, Francesco Chiesa, Stefano Protti, Angelo Albini, and Maurizio Fagnoni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00978 • Publication Date (Web): 06 Jul 2016
Downloaded from http://pubs.acs.org on July 13, 2016
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On the Route to the Photogeneration of Heteroaryl
Cations. The Case of Halothiophenes
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a*
b
a*
a
a
Carlotta Raviola, Francesco Chiesa, Stefano Protti, Angelo Albini, and Maurizio Fagnoni
a
PhotoGreen Lab, Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia,
Italy.
b
Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
Abstract. 2ꢀChloroꢀ, bromoꢀ and iodothiophenes undergo photochemical dehalogenation via the
triplet state. In the presence of suitable πꢀbond nucleophiles, thienylation occurs with modest yield
in chloroꢀ and bromoderivatives (via photogenerated triplet 2ꢀthienyl cation). Specific trapping by
using oxygen along with computational analysis carried out by means of a density functional
method support that in the case of iododerivatives homolytic thienylꢀI bond fragmentation occurs
first and heteroaryl cations are formed by electron transfer within the triplet radical pair, thus
opening an indirect access to such cations.
Table of contents.
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INTRODUCTION
The mild conditions of transition metal catalyzed crossꢀcoupling arylations have been the basis of
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the enormous success of this class of reactions. Transition metal catalytic reactions are generally
depicted as involving oxidative addition of the starting compound to the metal that imparts an
electrophilic character to the reactive complex, thus enabling the reaction with both n and πꢀ
nucleophiles (NuE in Scheme 1, path a). Metalꢀfree alternatives conserving mild conditions are still
2
a challenge but photochemical reactions have proved to give a significant contribution to this
3
field. Indeed, the high energy of excited states makes possible to confront the barrier of the ArꢀX
bond cleavage process and to generate convenient intermediates (e.g. aryl radicals or aryl cations)
4
5
for organic synthesis. For example, our research group have developed photoꢀS 1arylations
N
3
+
3
through triplet phenyl cations ( Ar ) by photoheterolysis of the triplet state of phenyl halides ( Arꢀ
5
6
6a
7
X), sulfonates, phosphates and sulfates. Contrary to their singlet counterpart, which behave as
5
unselective electrophiles, triplet cations attack selectively πꢀnucleophiles (NuE), thus leading to the
arylation of alkenes, alkynes and (hetero)aromatics (Scheme 1, path b).
Scheme 1. Ar-X Activation via Metal Catalysis (path a) and by Photochemical Means (path b)
Cat
Ar X
Ar
Cat
X
Cat
a
NuE
-EX
Ar
X
Ar-Nu
h
ISC
3Ar
b
3Ar+ X-
X
Cat = Transition metal catalyst
ISC = Inter System Crossing
NuE = n or -bond nucleophiles.
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These photochemical reactions are efficient when irradiating, in polar protic solvents, aryl chlorides
5
,8
substituted with strong (NH , NMe , OH, OMe, CH SiMe ) or mild (alkyl, SiMe ) electronꢀ
2
2
2
3
3
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donating groups. In highly ion stabilizing 2,2,2ꢀtrifluoroethanol (TFE), heterolysis of the ArꢀCl
10
bond can likewise take place in parent chlorobenzene or in 4ꢀchloroꢀbenzaldehydes and
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1
1
acetophenones when protected as 1,3ꢀdioxolanes. Recently, we demonstrated that the likelihood of
the photoheterolysis step was established through DFT calculations evaluating the geometry, the
3
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spin and charge distribution on the benzene ring of the aromatic in its triplet state ( ArX). Indeed,
the process is efficient where the triplet state showed an out of the plane deformation of the C atom
bringing the nucleofugal group and, after stretching the ArꢀX bond up to 4 Å, a negative charge
must develop on the leaving atom with only a small fraction of the spin density. Another key
3
parameter for the feasibility of the heterolytic step is the energy required for elongating the ArꢀX
ꢀ1 12
bond (< 27 kcal mol ).
We then deemed to extend this approach to the photogeneration of heteroaryl cations due to the
1
3
pivotal role that substituted heterocycles have in bioactive compounds and drugs. This is a
difficult task and only a couple of photoheterolytic cleavages were claimed to generate heteroaryl
1
4,15
cations as shown in Scheme 2.
An intriguing case was the photocyanation of substituted
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nitrothiophenes Ia,b and nitrofuran Ic (Scheme 2a). Another unusual leaving group was the
fluorine anion in the methoxylation of (±)ꢀNꢀformylꢀ4ꢀfluorotryptophan methyl ester (III) to give
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(±)ꢀNꢀformylꢀ4ꢀmethoxytryptophan methyl ester (IV, 45% yield, Scheme 2b).
Scheme 2. Rare Examples of Photogenerated Heteroaryl Cations
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One of the main drawback in dealing with heteroaryl cations is that in most cases these underwent
ring opening to more stable open chain cations. In fact, calculations showed that the heteroaryl
+
16a
cations deriving from the dediazoniation of adeninediazonium ion (V , Scheme 3a)
or
+
16b
cytosinediazonium ion (VII , Scheme 3b) were in equilibrium with the more thermodynamically
+
+
favored VI and VIII , respectively. Nonetheless, dediazoniation of some electronꢀrich five
+
membered heterocycles (see the case of pyrazolyl cation intermediate IX , Scheme 3c) has been
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postulated as a possible pathway for thermal formation of X via intramolecular arylation.
Scheme 3
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The obvious choice for photogenerating a heteroaryl cation was by photolysis of electronꢀrich five
membered heterocycles, in particular highly aromatic thiophenes. Shelf stable halothiophenes were
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selected in place of more delicate thienyl diazonium salts as the cation precursors. The
photosubstitution of thiophenes has been previously investigated mainly on derivatives bearing
conjugating and electronꢀwithdrawing substituents, such as nitro, carbonyl or carboxyl groups and a
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thienyl radical was invoked as the intermediate. Thus, as a first attempt to generate a triplet thienyl
cation, we decided to explore the photochemical behavior of 2ꢀhalothiophenes (ThꢀX, 1a-e, Chart
1
). A combined computational and experimental investigation was carried out and the results were
compared with those of an extended range of halobenzenes previously studied by our research
group.
Chart 1. Substrates Examined in the Present Work
RESULTS
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Computational Investigation. In order to clarify the course of the photoreaction a preliminary
computational study on thiophenes 1a-d was carried out. A detailed description of the theoretical
approach is available in the Supporting Information. Briefly, density functional theory (DFT) at the
(U)B3LYP/6ꢀ311+G(2d,p) level was adopted to optimize the absolute minimum of 1a-c as in our
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previous studies on phenyl halides. In the case of 1d, since the above basis set is not defined for
Iodine atom, a mixed set was employed, viz. 6ꢀ311+G(2d,p) for C, H, S atoms and LANL2DZ for
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the Iodine atom. Solvent effects (MeOH and C H bulk) were included at the same level of
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theory by singleꢀpoint calculations using the CPCM method (conductorꢀlike polarizable continuum
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model).
ꢀ1
3
The energy (in the 50ꢀ60 kcal mol range, see Table S2) of the triplet halothiophenes 1a-d in
methanol and in cyclohexane bulk was calculated. As it is apparent from Figure 1 all triplet states
were non planar and exhibited a marked out of the molecular plane displacement of the halogen
atom (X) and (to a lower degree) of the carbon atom (C
homolytic vs heterolytic character of the C
2
) bearing X (see also Figures S1ꢀS5). The
3
2
ꢀX bond cleavage in 1a-d was evaluated by stretching
12
6
the bond in the optimized configuration of these triplets up to 4 Å (MeOH and C H12 bulk) a
1
2
distance where the bond can be considered broken.
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a)
b)
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c)
d)
Figure 1. Geometries, ESP atomic charges, spin densities (in italics) (in parentheses after
elongation of ꢀX bond up to 4.00 Å) calculated in MeOH at the CPCMꢀ
UB3LYP/gen//UB3LYP/gen level of theory for: (a) 1a; (b) 1b; (c) 1c; (d) 1d.
C
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3
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3
3
2
The key parameters (ꢀE, that is the energy required to stretch C ꢀX bond up to 4.00 Å, charge and
spin density at the X atom after CꢀX bond elongation) are summarily indicated in Figures 2a,b and
reported in tabular way in the supplementary (See Table S5 in Supporting Information). The values
calculated for 5ꢀmethylꢀ2ꢀhalothiophenes and 5ꢀmethoxyꢀ2ꢀhalothiophenes were likewise reported
3
ꢀ1
for the sake of comparison. The barrier confronted decreased from 42 (for 1a) to 13 kcal mol (for
3
3
1d) in methanol bulk, with a much larger value in cyclohexane in the case of 1a, while the energy
3
involved in the ThꢀX bond stretching was independent of solvent polarity for the case of 1b-d [ꢀE
(
C H ) ≈ ꢀE(MeOH) in Figure 2a]. Since the presence of an electron donating group (Me, OMe)
6
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1
2
was found to favor ArꢀX heterolytic cleavage in aryl halides, the effect of EDG substituents (in 5ꢀ
position) was also investigated in that case. Notably, a decrement of the ꢀE required for the
cleavage was observed in methanol when moving from unsubstituted to 5ꢀmethoxyꢀ2ꢀ
halothiophene, except for the case of iodoꢀderivatives where such groups had no effect (Figure 2a).
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In protic solvent bulk elongation of the C ꢀX bond involved the localization of a full negative
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charge and a minor spin localization at the fluoro atom in 1a (see Figure 2b and S1b) fully
supporting heterolysis. With the other halides, however, charge localization was much lower and
spin density increased suggesting a shift from heterolysis to the homolysis of ThꢀX bond (See
figures 2b and S2ꢀS5). The effect on charge separation and spin localization of a methyl or a
methoxy group was negligible in fluoro and chlorothiophenes and small in bromo and iodo
analogues. In contrast, homolysis was exclusive for all of the examined halothiophenes in
cyclohexane (See Table S5 in Supporting Information).
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a)
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b)
Figure 2. (a) Calculated ꢀE in MeOH and in C
6
H12 Bulk. ♦ fluoroderivatives, ● chloroderivatives,
▲
bromoderivatives, ■ iododerivatives (halothiophene, 2-halo-5-methylthiophene, 2-halo-5-
methoxythiophene). (b) ESP charge distribution and spin density on the halogen (X, calculated in
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MeOH or C
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H
12 bulk). ♦ fluoroderivatives, ● chloroderivatives, ▲ bromoderivatives, ■
iododerivatives (halothiophene, 2-halo-5-methylthiophene, 2-halo-5-methoxythiophene).
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For the sake of completeness, calculations on 1a-d were also carried out by adopting the functional
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M06ꢀ2X (with def2TZVP as the basis set) which has been reported to be accurate in describing nonꢀ
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covalent interactions and bond dissociation processes. Solvation was carried out by using SMD
2
2
3
model. In this case, geometries of 1a-d at both the equilibrium and after stretching of the ThꢀX
bond up to 4 Å have been optimized in solvent (MeOH bulk). The results observed with this
method supported what already predicted by the former approach. Indeed, the ꢀE values obtained
are quite similar, while both spin and charge distribution (see Table S6 for further details)
3
confirmed the heterolytic nature of the ThꢀCl(Br) bond cleavage in 1b-c and the homolysis of the
3
ThꢀI bond in 1d. In the latter case, however, the ThꢀI bond in the equilibrium geometry resulted
already homolytically cleaved.
Photochemical results. 2ꢀfluorothiophene (1a) was not experimentally studied because the
ꢀ1
calculated barrier to cleave the ThꢀF bond resulted too high (42 kcal mol ). 2ꢀBromo, and 2ꢀ
23,24
iodothiophene (1c,d) are known to undergo reductive dehalogenation upon irradiation
whereas
the photochemistry of 2ꢀchlorothiophene (1b ) is so far unexplored. Whether a diagnostic heteroaryl
cation intermediate was formed was investigated by irradiation in the presence of
25
allyltrimethylsilane (ATMS, 4). Some significant data, concerning the irradiation of 1b-d at a
fixed time (6 h, 254 nm or 310 nm (for 1d) centered lamps) are reported in Table 1. A base
(caesium carbonate) was required in the experiments carried out in MeOH or TFE in order to avoid
the formation of some filming on the walls and to buffer the acidity released. Reduction to
thiophene 2 and arylation to allylthiophene 5 are the only observed pathways. 5 was formed in up to
ca. 50% yield in the case of 2ꢀiodothiophene 1d in MeCN (Scheme 4), for which the measured
quantum yield of photodecomposition (Φꢀ1) is 0.12 (0.34 in MeOH).
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Table 1. Products from the Irradiation of 2-Halothiophenes (1b-d) 0.05 M in the Presence of
Allyltrimethylsilane (1 M)
Products
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2
-Halothiophene
Solvent Conversion, %
a
(
yield %)
1b, X=Cl
MeCN
68
78
68
2, traces
5
, 10
2, 12
, 10
2, >5
, 10
b
1
b
MeOH
5
b
1b
TFE
5
1
c, X = Br
MeCN
100
95
5, 12
2, 27
b
1
c
MeOH
5
, 9
2, 9
, 16
b
1c
TFE
77
5
c
1
d, X = I
MeCN
67
5, 49
2, 41
5, 10
2, 20
b
1
d
MeOH
100
b
1
d
TFE
100
5
, 35
a
Yield based on the consumption of the 2ꢀhalothiophenes and determined by GC or GC/MS
b
c
2 3
analysis; Cs CO , 0.05 M added; Isolated yield.
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Since 2ꢀiodothiophene 1d gave allylated product 5 in a satisfactory yield, reactions in solvents and
in the presence of π nucleophiles were more extensively investigated for the case of 5ꢀmethylꢀ2ꢀ
iodothiophene (1e), analytically more expedient (Table 2).
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9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Product Distribution by Irradiation (310 nm, 6h) of 5-Methyl-2-Iodothiophene (1e)
(0.05 M) in Solvents and in the Presence of π−Bond Nucleophiles
Further
products
(yield %)
2
e
Conditions
Conversion, (%)
a
(
yield %)
a
Cyclohexane
100
27
79
100
95
86
98
62
72
19
3, 15
CH
3
COOMe
ꢀ
ꢀ
ꢀ
ꢀ
MeCN
MeOH
27
54
MeOH, Cs
TFE
CO
2
CO
3
0.05 M
100
73
b
2e’, 12
b
TFE, Cs
2
3
0.05 M
76
2e’, 12
b
TFE, Cs CO 0.05 M, O
88
2e’<5
2
3
2
3
, 43;
b
56
5e, <5 ;
C
6
H
12, 4 (1 M)
88
b
6
, <5
MeCN, 4 (1 M)
63
18
18
5e, 62
2
TFE, Cs CO
3
0.05 M
c
100
5e, 37
5e, <5
5e', <5
4
(1 M)
MeCN, 4' (0.2 M)
MeCN, 4'' (0.2 M)
65
62
62
13
ꢀ
b
7
(neat)
35
25
16
9e, 65
c
7
/TFE (1/3), Cs CO
2
3
0.05 M
9e, 48 ;
64
b
2
e’, <5
TFE, Cs
2
CO
1 M
3
0.05 M
c
90
10e, 44
8
b
2
e’, 8;
TFE, Cs
2
CO
3
0.05 M,
b
79
43
12e, <5 ;
1
1 0.2 M
b
13e, <5
a
b
Yield based on the consumption of 1e and determined by means of GC analyses. Detected by
c
GCꢀMS analysis. Isolated yield.
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In solvent, reduction was the main process also with iodide 1e, with best yields in cyclohexane
(with cyclohexyl iodide 3 as byproduct) and in methanol (with caesium carbonate). In TFE,
however, 5ꢀmethylꢀ2ꢀtrifluoroethoxythiophene 2e' was formed in up to 10% yield. The allylation in
the presence of 4 occurred with modest yield, at best in MeCN (62% yield). In contrast, the use of
allylsulfones 4' and 4'' afforded the corresponding allylthiophenes only in traces. Phenylation was
obtained both in benzene and in benzene/CF CH OH (1/3) mixture. A 40% arylation likewise,
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
3
2
occurred with mesitylene. On contrast hexamethylbenzene had a limited effect on the product
mixture, with a small amount of triene 12e and pentamethylbenzene 13e observed on the basis of
GC/MS analysis. In order to obtain mechanistic evidence, the effect of oxygen (saturated solution)
was tested, resulting in the quenching of both reductive alkylation and iodine substitution.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. Photolysis of 2-iodothiophenes (1d-e) in Solvents and in the Presence of π
Nucleophiles
H
Me
H
S
S
2
2e
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
I
Me
h
OCH CF3
2
S
Me
S
2
e'
3
12e
5, Y = H
5e, Y = Me
h
Solv-H
Y
S
h
+
Me
S
SiMe3
SiMe3
I
13e
Me6
6
4
11
Y
I
S
h
1d, Y=H
1e, Y=Me
h
5e (traces)
4'
R
R
SO Ph
2
R
h
R
Me
4''
S
COOMe
R
R
7, R = H
, R = Me
8
SO2
Me
9
e, R = H
10e, R = 2,4,6-Me
COOMe
SolvH = C H , CH CN, CH OH, CF CH OH
Me
6
12
3
3
3
2
S
5e' (traces)
DISCUSSION
In order to obtain a more complete picture, the same calculations carried out for 2ꢀhalothiophenes
were performed for 4ꢀhalotoluenes, 4ꢀhaloanisoles and 4ꢀhaloanilines, and are likewise reported in
Figure 3. It appears that 2ꢀhalothiophenes encounter the highest barrier to heterolytic fragmentation
in the series (independent of the medium, Figure 2a) even higher than 4ꢀhalotoluenes. On the
contrary, the barrier strongly decreases while the ESP charge at the halogen atom strongly increases
in the case of methoxy and aminobenzenes. When an heterolytic fragmentation is involved, the
charge on the halogen atom is close to ꢀ1 (see Figure 1a). Only fluorinated or chlorinated
thiophenes reach this region, along with all of the haloanilines and anisoles examined (see the lower
charge with the iodoanisole, though). Moreover, with thiophenes, introducing substituents had only
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a minor effect on barrier and charge localization (see also Figures 2a and 2b) On the other hand, the
presence of electron donating groups on benzene derivatives reduced the barrier in methanol, indeed
heterolysis was an exothermic process for chloro and bromoanilines, and encountered a low barrier
with the other 4ꢀhaloanilines and the 4ꢀhaloanisoles. It appears that with thiophene derivatives the
aryl cation was not sufficiently stabilized to make this path dominating (high energy barrier for Thꢀ
X cleavage when X = F, Cl and low ESP charge in the case of bromides and iodides, Figure 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
5
1
while this was the case for phenyl derivatives. Triplet cations, which have a π σ radical cation
structure, are more stabilized by electron donating substituents for sixꢀmembered aromatics with
respect to the corresponding fiveꢀmembered heterocycles such as thiophenes (and expectedly with
other electron rich heterocycles).
Figure 3. Energy required to stretch CꢀX bond up to 4.00 Å in the triplet state of some
(hetero)aromatic halides vs ESP charge distribution on X atom (calculated in MeOH bulk). ♦
fluoroderivatives, ● chloroderivatives, ▲ bromoderivatives, ■ iododerivatives (halothiophene, 4-
halo-N,N-dimethylanilines, 4-halotoluenes, 4-haloanisoles).
As shown in Figure 3, three groups of aromatic and heteroaromatic halides have been recognized on
the basis of the nature of the (Het)ArꢀX bond cleavage. In the group 1 a negative ESP charge (> ꢀ
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0.75) developed at the halogen atom, while only a small fraction of the spin density (< 10%, see
Table S5) became localized there, and heterolysis takes place with a small energy barrier (≤ 10 kcal
ꢀ1
mol ). These are necessary, but not sufficient conditions for the generation of an aryl cation. In fact,
with iododerivatives, heavy atom effects (e.g. in iodoanilines) may promote ISC to the ground state
and reducing the lifetime of the triplet excited state. Thus, a fast cleavage is mandatory to avoid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8a
ꢀ1
disexcitation. With less donating substituents (group 2), the barrier was higher (15ꢀ30 kcal mol )
with less charge (> ꢀ0.6) and more spin (10ꢀ20%) at the halogen. In this class the experimentally
observed outcome still involved phenylation reactions via photogenerated aryl cations deriving
from them, but only when irradiated in a protic, ionꢀsolvating solvent. Finally, in the group 3 the
required energy was relatively low but the charge at the halogen negligible, the spin larger (> 30%)
and homolysis took place as primary process.
Both experimental and computational data above support a mechanistic scheme depicted in Scheme
3
19b,c,26
5
, where halothiophene triplets 1b-e are the reacting states.
In fluorothiophenes, however,
that are expected to cleave heterolytically, the high barrier makes the process too slow to compete
with physical decay even if the ions would be stabilized in a polar medium (see Figures 2 and 3).
The process occurring in chloroꢀ and bromothiophenes 1b,c is an inefficient heterolytic cleavage of
3
+
the ArꢀX bond (Scheme 5, path a) to form the corresponding triplet thienyl cation ( 14 , see
structure in Figure S6). On the contrary, iodothiophenes 1d,e underwent a photohomolytic CꢀX
bond cleavage (paths b,c), a thermodynamically viable process (Figure 2). Thus, a triplet radical
•
• 3
27,28
3
+
pair [14 X ] was generated
rather than cation 14 . Diffusional separation of the radical center
•
•
29
•
formed a solvated radical pair [14 X ] (path d). The 2ꢀthienyl radical (14 ) is the intermediate
solv
involved both in the reduction to thiophenes 2 and 2e (path e) and addition to πꢀnucleophiles in
nonꢀhydrogen donating solvents (path f, see also the experiment in benzene, Table 2).
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Scheme 5. Pathways and Intermediates Involved in the Photochemistry of Halothiophenes 1b-e
1. h
2. ISC
1. h
2. ISC
3
3
a
+
S
14
X-
Y
Y
I
Y
X
Y
S
31
S
1b-e
X = Cl, Br
Inefficient
X = I b
3
+
d,e
c
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
3
d
Solv-H
e
.
.
.
.
Y
H
.
I
I
S
S
Y
S
.
. .
2, 2e
3
[
14 X ]
[14 X ]
solv
Polar solvent
g
ET
NuE
f
3
NuE, - E+
+
I-
Y
Y
Nu
S
h
S
5, 9-10, 12-13
31
4+
ISC i
1
CF CH OH
3
2
H C
3
OCH CF3
2
S
+
Y
S
2e'
1
14+
NuE = allyltrimethylsilane,
benzene,
Y = H, Me
mesitylene
hexamethylbenzene
3
The homolytic cleavage of the ThꢀX bond in 1d,e was supported by experimental evidence as the
specific quenching of the radical by oxygen, the formation of iodopropylsilane 6 from alkene 4 and
the formation of iodocyclohexane 3. On contrast, the role of aryl radicals in arylations in polar
solvents is excluded, since the presence of typical radical traps namely allyl phenyl sulfone 4' or
30
sulfone 4'' did not lead to appreciable amounts of allylated derivatives (Table 2). Furthermore, the
products of the reaction with allyltrimethylsilane and those with hexamethylbenzene are typical
markers of a triplet aryl cation and are best rationalized as resulting from electron transfer (ET)
•
• 3
3
+
within the thienyl and halogen radical pair [14 X ] . This leads indirectly to ion 14 (Scheme 5,
1
0,31
32
path g)
which is trapped by πꢀbond nucleophiles to give the arylated products (path h). The
formation of aryl cations from an ET mechanism within a radical pair has been sparsely
28,31b,33
documented, providing that it takes place in a high polar medium (e.g. water).
Notice further
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
that 5ꢀuracyl and 5ꢀcitosyl cations have been invoked when investigating the reactivity of 5ꢀ
34
35
fluorouracile and 5ꢀbromocitosine respectively, where the heteroaryl radical intermediate was
α
34,35
oxidized by the radical cation of N ꢀacetylꢀLꢀtryptophan Nꢀethylamide.
More relevant to the
present case, the formation of the parent triplet phenyl cations from the corresponding aryl radical
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10
has been previously postulated in the photodechlorination of chlorobenzene. The formation of a
small amount of trifluoroethoxythiophene (2e’) in TFE is best justified via ISC from triplet to
1
+
36
singlet thienyl cation ( 14 , Scheme 5, path i). Despite calculations support that triplet thienyl
ꢀ1
cations are slightly more stable than the corresponding singlets (by 8ꢀ10 kcal mol , Figures S6ꢀ
34
S10), such small energy difference may be overestimated, as previously observed. Indeed,
solvolysis to 2e’ took place as a minor process and is fully suppressed when a reactive πꢀbond trap
3
+
is used, supporting that singlet cation arises from the formerly generated 14 .
In conclusion, the generation of triplet phenyl cations from halobenzenes is a highly efficient
process, which is hardly extended to thiophenes. However, we demonstrated that heteroaryl cations
are formed from thienyl iodides in polar and protic solvents via a homolytic cleavage of the ThꢀI
bond followed by intramolecular electron transfer within the photogenerated triplet radical pair. The
cleavage occurs with reasonable efficiency (see Table 1ꢀ2), though solvation of the radical pair
before ET competes significantly, making reactions less clean. This work suggests that access to
aryl cations is viable also via paths different than cleavage of the PhꢀX bond encountered in
electronꢀdonating phenyl halides and further shows that a simply implemented functional method
allows to predict the viability of either type of cleavage (homolytic or heterolytic) for a specific
case.
EXPERIMENTAL SECTION
1
13
Materials and Methods. H NMR spectra were recorded with a 300 MHz spectrometer, while C
NMR spectra were recorded with a 75 MHz spectrometer. The attributions were made on the basis
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13
of H and C NMR, as well as DEPTꢀ135 experiments; chemical shifts are reported in ppm
downfield from TMS. GCꢀMS analyses were carried out using a GCꢀDSQ single quadrupole
GC/MS system. A Rtxꢀ5MS (30 m × 0.25 mm × 0.25 ꢁm) capillary column was used for analytes
ꢀ1
separation with helium as carrier gas at 36 mL min . The injection in the GC system was performed
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
in split mode and the injector temperature was 250 °C. The GC oven temperature was held at 40°C
ꢀ1
for 6 min, increased to 250 °C by a temperature ramp of 10 °C min and held for five min. The
transfer line temperature was 280 °C and the ion source temperature 250 °C. For 2 mass spectral
analyses were carried out in SIM mode, monitoring m/z 84, 58, 45 at the same time. To improve the
quality of the integration of the peaks of interest the Base Peak function was applied to the
chromatogram. This action afforded a new chromatogram that showed only the signals with m/z 84
’
’
as base peak. On contrast for 2e , 5e , 6, 12e, 13e mass spectral analyses were carried out in full
scan mode.
2
ꢀHalothiophenes 1a-1d, thiophene (2), 2ꢀmethylthiophene (2e) and all of the employed πꢀbond
nucleophiles were commercially available and used as received. 5ꢀmethylꢀ2ꢀiodothiophene (1e) was
37
obtained by iodination of 2e. 2ꢀ(Tosylmethyl)acrylate (4”) was synthesized according to a
38
literature procedure.
Photochemical experiments. The photochemical reactions were performed by using nitrogenꢀ
purged solutions in quartz tubes in a multilamp reactor fitted with ten 15 W Hg phosphor coated
lamps (emission maximum 310 nm) or 4×15 W Hg lamps (emission centred at 254 nm). The
reaction course was followed by GC analyses and the products formed were identified and
quantified by comparison with authentic samples. Workup of the photolytes involved concentration
in vacuo (80ꢀ100 Torr) and chromatographic separation. Solvent of HPLC purity were employed in
the photochemical reactions. Quantum yields were measured at 254 nm (1 Hg lamp, 15W). The
amount of 2ꢀmethylthiophene (1e) and iodocyclohexane (3) was determined by GC analysis on the
+
basis of calibration curves by comparison with commercial standard. Products 2 (m/z: 84 (M , 100),
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
’
+
’
+
58 (38), 45 (32)), 2e (m/z: 196 (M , 72), 113 (96), 85 (68)), 5e (m/z: 196 (M , 100), 136 (94), 111
+
+
(
(
(
34)) 6 (m/z: 185 (34), 115 (16),72 (100)), 12e (258 (M , 30), 161(100)), 13e (245 (M , 100), 229
98)) were determined by means of GCꢀMS analyses. In a typical experiment, a solution of 1b-e
1.5 mmol, 0.05M), a πꢀbond nucleophile (1.0 M except where otherwise indicated), Cs CO (0.05
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
M, 1.5 mmol except where indicated) in the chosen solvent (30 mL) was nitrogen purged in quartz
tubes and irradiated. The reaction course was followed for GC analysis. The photolyzed solutions
were concentrated in vacuo (80ꢀ100 Torr) and purified by column cromatography.
2
-(2-Propenyl)thiophene (5). From 166 ꢁL (0.05 M, 1.5 mmol) of (1d), 4.77 mL (1M, 30 mmol) of
allyltrimethylsilane (ATMS) in 30 mL of MeCN, irradiated at 310 nm for 6 hours (67%
consumption of 1d). Purification by column chromatography (aluminium oxide neutral; eluant:
pentane) afforded 61 mg of 5 (oil, 49% yield based on the consumption of 1d). Spectroscopic data
39
7 8
of 5 were in accordance with the literature. Anal. Calcd for C H S: C, 67.69; H, 6.49. Found: C,
67.7; H, 6.5.
2-Methyl-5-(2-propenyl)thiophene (5e). From 181 ꢁL (0.05 M, 1.5 mmol) of 1e, 489 mg (0.05 M,
.5 mmol) of Cs CO , 4.77 mL (1M, 30 mmol) of allyltrimethylsilane in 30 mL of TFE, irradiated 6
1
2
3
hours (100% consumption of 1e). Purification by column chromatography (aluminium oxide
neutral; eluant: pentane) gave 77 mg of 5e (oil, 37% yield). 2ꢀmethylꢀthiophene (2e) was likewise
1
formed in 18% yield (determined on the basis of calibration curve). 5e: H NMR (CDCl ) δ 2.45 (s,
3
13
3
H), 3.50ꢀ3.55 (d, 2H, J = 6.6 Hz), 5.10ꢀ5.20 (m, 2H), 5.95ꢀ6.10 (m, 1H), 6.55ꢀ6.60 (m, 2H); C
NMR (CDCl
140.3; IR (KBr)
Found: C, 69.5; H, 7.3.
3
) δ 15.1 (CH ), 137.9,
3
), 34.6 (CH
2
), 115.8 (CH), 124.1 (CH), 124.7 (CH), 136.8 (CH
2
ꢀ1
ν
max 2921, 1638, 1420, 909, 790 cm . Anal. Calcd for C H10S: C, 69.51; H, 7.29.
8
2
-Methyl-5-phenylthiophene (9e). From 181 ꢁL (0.05 M, 1.5 mmol) of 1e, 489 mg (0.05 M, 1.5
mmol) of Cs
2
CO
3
, 7.5 mL (2.8M, 0.1 mmol) of benzene in 30 mL of TFE, irradiated 6 hours (64%
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consumption of 1e). Purification by column chromatography (silica; eluant: hexane) gave 80 mg of
40
9
e (white solid, 48% yield based on the consumption of 1e), mp = 42ꢀ43°C , lit. = 39ꢀ41°C).
Compound 2e was likewise formed in the reaction (25% yield based on the consumption of 1e and
determined on the basis of calibration curve). GCꢀMS analyses revealed also the presence of 2ꢀ
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
(
3,3,3ꢀtrifluoroethoxy)ꢀ5ꢀmethylthiophene (< 5%). Spectroscopic data of 9e were in accordance
41
with the literature. Anal. Calcd for C11H10S: C, 75.82; H, 5.78. Found: C, 75.8; H, 5.8.
2
-(2,4,5-Trimethylphenyl)-5-methylthiophene (10e). From 181 ꢁL (0.05 M, 1.5 mmol) of 1e, 489
mg (0.05 M, 1.5 mmol) of Cs CO , 4.17 mL (1 M, 30 mmol) of mesitylene in 30 mL of TFE,
2
3
irradiated 6 hours (90% consumption of 1e). Purification by column chromatography (silica; eluant:
hexane) gave 129 mg of 10e (colorless oil, 44% yield based on the consumption of 1e. Compound
2e was also formed in the reaction (16% yield based on the consumption of 1e and determined on
1
the basis of calibration curve). 10e: HNMR (CDCl
3
) δ 2.20 (s, 6H), 2.40 (s, 3H), 2.55ꢀ2.60 (d, 3H,
13
J = 0.9 Hz), 6.60ꢀ6.65 (d, 1H, J = 3.5 Hz), 6.75ꢀ6.80 (m, 1H), 6.97 (s, 2H). C NMR (CDCl ) δ
3
15.2 (CH
39.4. IR (KBr)
C, 77.7; H, 7.4.
3
), 20.6 (CH
3
), 21.0 (CH
3
),124.9 (CH), 126.1 (CH), 127.9 (CH), 131.4, 137.5, 138.2, 139,
ꢀ1
1
ν
max 2911, 1454, 845, 791 cm . Anal. Calcd for C14
H16S: C, 77.72; H, 7.45. Found:
AUTHOR INFORMATION
Corresponding Authors: Dr. Carlotta Raviola. Dr. Stefano Protti
E-mail: carlotta.raviola01@universitadipavia.it, stefano.protti@unipv.it
*
Acknowledgments
We thank Dr. Stefano Crespi, Dr. Davide Ravelli (University of Pavia) and Dr. Oreste Piccolo for
fruitful discussion.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
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Absorption parameters measured for compounds 1b-1e; H and C NMR spectra of compounds 1e,
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, 5e, 9e, 10e; details of the calculations on intermediates.
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