Carlotta
Raviola
and
Maurizio
Fagnoni
*
PhotoGreen Lab, Department of Chemistry, V. Le Taramelli 12, 27100 Pavia, Italy. E-mail: fagnoni@unipv.it; Fax: +39 0382 987323; Tel: +39 0382 987198
First published on 4th December 2017
The site-selective cleavage of an Ar–X bond in polyhalogenated aromatics is an important tool in synthetic planning especially when more than one identical halogen atom is present. An alternative to the usual metal-catalyzed cleavage is represented by photochemistry although only a few examples have been reported. We then investigated the feasibility of the site-selective photodechlorination of some dichloroanisoles through a combined experimental and computational study. In the case of 2,4-dichloroanisole, selective detachment of the chlorine atom at the ortho position with respect to the OMe group was observed upon photohomolysis (in cyclohexane) or photoheterolysis (in MeOH) of the Ar–Cl bond. In the latter case, 5-chloro-2-methoxy-1,1′-biphenyl was exclusively formed upon reaction of the resulting phenyl cation with benzene. The substitution of an OH group for a OMe group was detrimental since a lower photoreactivity resulted with no improvement in the selectivity.
Only a few examples of photodehalogenation of dichloroanisoles have been reported in the literature. Irradiation of symmetrical 2,6-dichloroanisole and 3,5-dichloroanisole in methanol afforded monochlorinated products (2- and 3-dichloroanisoles, respectively) along with a modest amount of anisole.11,12 The case of unsymmetrical derivatives is more interesting. Indeed, the photolysis of 2,4-dichloroanisole and 2,3-dichloroanisole led to the selective cleavage of chlorine at the ortho position. In the former case the C2–Cl bond breakage was induced by a rhenium complex,13 while in the latter case simple irradiation in methanol led to a mixture of 3-chloroanisole and anisole.12
Thus, we decided to investigate in detail the photochemistry of all unsymmetrical dichloroanisoles (1–4, Scheme 2a). In particular, we studied their photochemical behavior in cyclohexane and MeOH upon irradiation at λ = 310 nm in order to assess whether a different selectivity may be observed when using two different photochemical activations. Indeed, we previously demonstrated that the photoinduced dechlorination of monochloroanisoles occurred from the first triplet excited state with two different mechanisms depending on the reaction solvent (homolysis in an apolar solvent and heterolysis in a polar one, Scheme 2b).8,14 This work was likewise supplemented by calculations aiming to rationalize the photoreactivity observed. Moreover, for the sake of comparison we also considered one dichlorophenol (5, Scheme 2a).
Scheme 2 (a) Dichloroaromatics tested in this study and (b) the effect of medium on the photoinduced cleavage of the Ar–Cl bond in 4-chloroanisole. |
Photochemical reactions were performed by using nitrogen-purged solutions in quartz tubes in a multilamp reactor fitted with ten 15 W phosphor coated lamps (emission centered at 310 nm) for irradiation. 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 and chromatographic separation by using silica gel. Solvents of HPLC purity were employed in the photochemical reactions. Quantum yields were measured at 254 nm (1 Hg lamp, 15 W).
2,3-Dichloroanisole (1), 2,5-dichloroanisole (2), 3,4-dichloroanisole (3), 2,4-dichloroanisole (4), 2,3-dichlorophenol (5), 3-chloroanisole (6), 2-chloroanisole (7), anisole (8), 4-chloroanisole (9), 2-chlorophenol (11), 3-chlorophenol (12), phenol (13) and benzene are commercially available.
The decomposition quantum yield (Φ−1) of phenyl chlorides 1–5 (10−2 M) was determined by irradiation in cyclohexane and MeOH at 254 nm in comparison with monochlorinated anisoles (Table 1). As for 2- and 3-chloroanisoles, they are consistently more reactive in cyclohexane than in MeOH contrary to 4-chloroanisole where the photoreactivity was comparable (Φ−1ca. 0.3). The presence of an additional chlorine atom in dichloroanisoles did not change significantly the photoreactivity and the order in cyclohexane is 3 > 1 > 4 > 2 and in MeOH it is 2 > 3 > 1 ≈ 4. Again the photoreactivity of 1–4 was very high in apolar solvents and higher than in MeOH where it is low (<0.11), except for the case of 2. Changing a methoxy group with a hydroxy group dramatically decreased the reactivity in cyclohexane and to a lower extent in MeOH (compare the values of Φ−1 for 1 and 5).
Substrate | Decomposition quantum yields (Φ−1)a | |
---|---|---|
Cyclohexane | MeOH | |
a Measured at 254 nm in a 10−2 M solution. The values of the monochlorinated anisoles were reported for the sake of comparison. | ||
2-Chloroanisole | 0.74 | 0.11 |
3-Chloroanisole | 0.70 | 0.30 |
4-Chloroanisole | 0.26 | 0.26 |
1 | 0.57 | 0.09 |
2 | 0.39 | 0.29 |
3 | 0.69 | 0.11 |
4 | 0.48 | 0.08 |
5 | 0.11 | 0.03 |
Irradiation experiments were carried out in cyclohexane and in methanol to induce (in analogy with 4-chloroanisole) a homolytic and a heterolytic cleavage of the Ar–Cl bond, respectively.8 No consumption of derivatives 1–5 was observed when irradiating the solutions covered with aluminum foil. 2,3-Dichloroanisole (1) was the first compound tested (Table 2) and irradiation of 1 in cyclohexane gave roughly an equimolar mixture of 3-chloroanisole (6) and 2-chloroanisole (7). Partial dechlorination of 6/7 to give anisole 8 occurred after 90 min of irradiation. GC analyses of the photolysate showed the presence of variable amounts of 1,1′-bi(cyclohexane) and chlorocyclohexane. On shifting to methanol, the reaction became more sluggish (64% consumption of 1 after 14 h) but again no selective ortho/meta dechlorination took place (Table 2).
Solvent | t irr (conversion %) | Products (yield %)b,c | ||
---|---|---|---|---|
6 | 7 | 8 | ||
a Irradiation carried out at λ = 310 nm with ten 15 W phosphor coated lamps on a 0.05 M solution of the dichloroaromatic in the solvent chosen. b Yields were determined by GC analysis. c In the experiments performed in cyclohexane, variable amounts of 1,1′-bi(cyclohexane) and chlorocyclohexane were detected by GC analysis. | ||||
Cyclohexane | 15 min (18) | 9 | tr. | — |
Cyclohexane | 30 min (39) | 15 | 14 | — |
Cyclohexane | 60 min (55) | 20 | 16 | — |
Cyclohexane | 90 min (79) | 27 | 21 | 8 |
MeOH | 3 h (16) | 5 | 6 | — |
MeOH | 7 h (32) | 11 | 12 | — |
MeOH | 14 h (64) | 15 | 17 | 13 |
The experiments were supplemented by computational studies with the aim to rationalize the site-selectivity of the photoreaction. DFT (Density Functional Theory) at the M06-2X/def2TZVP level of theory was adopted to optimize the relevant structures as in previous studies on related chloroaromatics.9 Solvent effects (C6H12 and MeOH bulk) were included at the same level of theory adopting the SMD model (see the ESI† for further details).16 The photodehalogenation was supposed to arise from the triplet state since Intersystem Crossing (ISC) is very efficient in aromatic halides.17–19 We then considered for our purpose the most stable triplets in apolar or polar solvents. In the case of 31, calculations showed that in cyclohexane (or in methanol) the absolute minimum is 31ortho (or 31′ortho in MeOH) with the chlorine atom in position 2 out of the plane of the aromatic ring (see Fig. S2 and S3 in the ESI†). The non-planarity of the triplet state is in fair agreement with previous findings on (hetero)aromatic monohalides.9,17 The corresponding 31meta/31′meta isomers (see Fig. S4 and S5†) were less stable by about 6 kcal mol−1 (see the data collected in Table 7). Thus, calculations showed that in both apolar and polar solvents there is a preference for the cleavage of the ortho Ar–Cl bond (Ar–Clortho). In order to evaluate the energy required to detach the Clmeta atom in 31meta (ΔEmeta) and the Clortho atom in 31ortho (ΔEortho), the Ar–Cl bond was elongated up to 3 Å, a distance where the bond can be considered broken. Comparable values were obtained for the two isomers in cyclohexane (ca. 15 kcal mol−1, Table 7) consistently higher than those in methanol (the difference between ΔEmeta and ΔEortho was ca. 8–10 kcal mol−1).9 The stretched structures in cyclohexane (31sortho) and in MeOH (31′sortho) of the most stable conformers are shown in Fig. 1a and Fig. 1b, respectively.
The homolysis of the Ar–Cl bond in cyclohexane was confirmed since the spin density was almost equally localized on C2 (52%) and on the chlorine atom (38%, Fig. 1a). In contrast, the heterolysis in MeOH was witnessed by the significant negative charge developed at the chlorine atom (−0.82, Fig. 1b).
In order to investigate a different ortho/meta preference with respect to the OMe group in the photodechlorination, we then irradiated 2,5-dichloroanisole (2, Table 3). Interestingly, different from the previous case, irradiation both in cyclohexane and in MeOH led to a preference for the release of the chlorine atom placed at the ortho position (6/7ca. 2:1 in the first case and ca. 3–4:1 in the second case). Although the rate of consumption of product 2 in cyclohexane seemed comparable to that of 1, the consumption of compound 2 in methanol was much higher (83% in 6 h). Computational results were similar to those obtained for 1 (Table 7), showing again a preference for the cleavage of the Ar–Clortho bond (see the structures 32sortho and 32′sortho in Fig. 2 and Fig. S6–S9† for the other minima) confirming the homolysis in cyclohexane and heterolysis in MeOH.
Solvent | t irr (conversion %) | Products (yield %)b,c | ||
---|---|---|---|---|
6 | 7 | 8 | ||
a Irradiation carried out at λ = 310 nm with ten 15 W phosphor coated lamps on a 0.05 M solution of the dichloroaromatic in the solvent chosen. b Yields were determined by GC analysis. c In the experiments performed in cyclohexane, variable amounts of 1,1′-bi(cyclohexane) and chlorocyclohexane were detected by GC analysis. | ||||
Cyclohexane | 10 min (18) | 9 | tr. | — |
Cyclohexane | 30 min (32) | 18 | 9 | — |
Cyclohexane | 60 min (54) | 27 | 13 | — |
Cyclohexane | 90 min (82) | 42 | 17 | 5 |
Cyclohexane | 120 min (88) | 49 | 18 | 10 |
Methanol | 1.5 h (36) | 29 | 6 | — |
Methanol | 3 h (62) | 45 | 14 | — |
Methanol | 6 h (83) | 60 | 17 | 5 |
The photochemistry of 3,4-dichloroanisole (3) gave an indication about the meta/para selectivity (Table 4). In cyclohexane, an almost complete consumption of 3 was achieved after 90 min. In this case the cleavage of the meta chlorine atom was preferred and, interestingly, no complete dechlorination took place even at such high conversion (ca. 95%). In methanol, despite the sluggish conversion, no product 6 was formed and the selectivity was complete for the meta position albeit a strong competitive further dechlorination operated here to form 8. Also in this case two minima were found: one with the meta chlorine atom (33meta) and the other with the para chlorine atom (33para) out of the plane of the aromatic ring. Unfortunately, these differed only by about 1 kcal mol−1 (Table 7) and so calculations were not able to give an indication on the selectivity of the reaction, although the Ar–Clpara bond was slightly preferred (see Fig. 3 and Fig. S10–13† for the other structures). As already reported for compounds 1 and 2, the energy calculated to detach the chlorine atom is higher in apolar solvents than in polar solvents (Table 7).
Solvent | t irr (conversion %) | Products (yield %)b,c | ||
---|---|---|---|---|
6 | 9 | 8 | ||
a Irradiation carried out at λ = 310 nm with ten 15 W phosphor coated lamps on a 0.05 M solution of the dichloroaromatic in the solvent chosen. b Yields were determined by GC analysis. c In the experiments performed in cyclohexane, variable amounts of 1,1′-bi(cyclohexane) and chlorocyclohexane were detected by GC analysis. | ||||
Cyclohexane | 5 min (14) | — | 8 | — |
Cyclohexane | 10 min (27) | — | 13 | — |
Cyclohexane | 15 min (34) | 5 | 17 | — |
Cyclohexane | 30 min (43) | 5 | 21 | — |
Cyclohexane | 60 min (78) | 8 | 34 | — |
Cyclohexane | 90 min (95) | 12 | 49 | — |
Methanol | 21 h (39) | — | 31 | 8 |
Methanol | 32 h (50) | — | 25 | 25 |
Methanol | 48 h (60) | — | 18 | 29 |
Methanol | 62 h (64) | — | 16 | 35 |
We then reasoned that since an ortho vs. meta preference was found in compound 2 and a meta vs. para preference was observed in derivative 3, a marked preference in the Ar–Cl cleavage from the ortho position in ortho/para dichlorinated anisole should be expected. This led us to consider 2,4-dichloroanisole (4) as a promising substrate for a site-selective cleavage. Interestingly, in cyclohexane, 4-chloroanisole (9) is the only photoproduct formed up to 79% conversion of 4 (Table 5). Further irradiation caused the conversion of 9 to anisole. In methanol, the reaction was still selective, albeit sluggish, and with a poor mass balance. In accordance with experimental data, calculations demonstrated both in cyclohexane and in methanol that the absolute minimum was that causing the Ar–Clortho cleavage (see Fig. 4 and Fig. S14–S17† for the other structures). The energy barrier for the Ar–Cl cleavage was similar in 34spara and 34sortho and higher in cyclohexane (ΔE ≈ 15–18 kcal mol−1) rather than in methanol (ΔE ≈ 5–7 kcal mol−1, Table 7).
Solvent | t irr (conversion %) | Products (yield %)b,c | ||
---|---|---|---|---|
7 | 9 | 8 | ||
a Irradiation carried out at λ = 310 nm with ten 15 W phosphor coated lamps on a 0.05 M solution of the dichloroaromatic in the solvent chosen. b Yields were determined by GC analysis. c In the experiments performed in cyclohexane, variable amounts of 1,1′-bi(cyclohexane) and chlorocyclohexane were detected by GC analysis. | ||||
Cyclohexane | 5 min (6) | — | 6 | — |
Cyclohexane | 10 min (30) | — | 13 | — |
Cyclohexane | 30 min (49) | — | 26 | — |
Cyclohexane | 60 min (79) | — | 40 | — |
Cyclohexane | 90 min (95) | — | 57 | 5 |
Cyclohexane | 120 min (100) | — | 59 | 18 |
Cyclohexane | 150 min (100) | — | 37 | 35 |
Methanol | 8 h (37) | — | 15 | — |
Methanol | 16 h (54) | — | 22 | — |
Methanol | 24 h (63) | — | 25 | — |
Methanol | 46 h (70) | — | 26 | 12 |
Having these positive results on 4, we tried to perform a selective arylation at the ortho position by photoheterolytic cleavage in polar solvents by using benzene as the nucleophile. Since the reaction is quite sluggish in MeOH and this solvent is known to efficiently react with phenyl cations by hydrogen atom transfer,8 we shifted to 2,2,2-trifluoroethanol (TFE) in the presence of acetone known to accelerate the conversion of aryl chlorides by energy transfer.14 The conversion was kept low in order to avoid competitive dechlorination of the resulting arylated product. Gratifyingly, photolysis of 4 in TFE in the presence of benzene (2 M) after 9 h cleanly gave methoxybiphenyl 10 in 45% yield (Scheme 3).
Scheme 3 Selective metal-free arylation of 2,4-dichloroanisole (4). Isolated yield based on 31% consumption of 4. |
As the last substrate tested, we considered 2,3-dichlorophenol (5) in order to see whether a free OH group may exert a positive effect on the site selective C–Cl cleavage with respect to the corresponding anisole 1. Disappointingly, the reactions required a long time to occur (up to 48 h) and in cyclohexane the reaction did not reach completion (Table 6). In both cases the observed selectivity was not so different from that observed in the case of 1 and a low mass balance was obtained in the case of cyclohexane. As already observed for compound 1 we found two minima: 35meta and the more stable 35ortho with the meta and ortho chlorine atoms out of the plane, respectively. Noteworthily, both in cyclohexane and methanol the shift from 1 to 5 slightly affected the energy barrier (see Fig. 5 and Table 7, Fig. S18–S21†).
Solvent | t irr (conversion %) | Products (yield %)b,c | ||
---|---|---|---|---|
11 | 12 | 13 | ||
a Irradiation carried out at λ = 310 nm with ten 15 W phosphor coated lamps on a 0.05 M solution of the dichloroaromatic in the solvent chosen. b Yields were determined by GC analysis. c In the experiments performed in cyclohexane, variable amounts of 1,1′-bi(cyclohexane) and chlorocyclohexane were detected by GC analysis. | ||||
Cyclohexane | 6 h (30) | 6 | 4 | — |
Cyclohexane | 14 h (63) | 5 | 3 | 5 |
Cyclohexane | 24 h (65) | 4 | 4 | 9 |
Methanol | 24 h (14) | 4 | 10 | — |
Methanol | 48 h (100) | 22 | 25 | — |
Structures | Solvent | ΔEconfa (kcal mol−1) | ΔEC–Clxb(kcal mol−1) | Spin density (ESP charge) at Clx atomc | Spin density (ESP charge) at Clx atomd |
---|---|---|---|---|---|
a Energy difference between the two conformers. The most stable conformers are given in bold. b Energy required to stretch the Ar–Clx bond up to 3 Å. c At equilibrium. d At 3 Å. | |||||
31meta | C6H12 | 5.7 | Clmeta = 15.6 | 8% (−0.12) | 49% (−0.02) |
31ortho | C6H12 | Cl ortho = 14.8 | 9% (−0.11) | 38% (−0.21) | |
3 1 ′ meta | MeOH | 5.9 | Clmeta = 10.6 | 8% (−0.15) | 4% (−0.91) |
3 1 ′ ortho | MeOH | Cl ortho = 8.1 | 10% (−0.19) | 7% (−0.82) | |
3 2 meta | C6H12 | 5.8 | Clmeta = 14.5 | 7% (−0.13) | 48% (−0.05) |
3 2 ortho | C6H12 | Cl ortho = 13.7 | 9% (−0.13) | 50% (−0.10) | |
3 2 ′ meta | MeOH | 5.6 | Clmeta = 3.9 | 7% (−0.16) | 4% (−0.91) |
3 2 ′ ortho | MeOH | Cl ortho = 6.6 | 9% (−0.20) | 7% (−0.83) | |
3 3 meta | C6H12 | 0.6 | Clmeta = 17.6 | 7% (−0.12) | 50% (−0.02) |
3 3 para | C6H12 | Cl para = 17.7 | 8% (−0.14) | 43% (−0.16) | |
3 3 ′ meta | MeOH | 1.1 | Clmeta = 7.3 | 7% (−0.16) | 4% (−0.91) |
3 3 ′ para | MeOH | Cl para = 7.5 | 8% (−0.21) | 5% (−0.89) | |
3 4 para | C6H12 | 2.6 | Clpara = 15.6 | 8% (−0.15) | 44% (−0.14) |
3 4 ortho | C6H12 | Cl ortho = 18.7 | 8% (−0.10) | 47% (−0.07) | |
3 4 ′ para | MeOH | 2.1 | Clpara = 5.0 | 8% (−0.21) | 5% (−0.90) |
3 4 ′ ortho | MeOH | Cl ortho = 7.2 | 8% (−0.15) | 5% (−0.90) | |
3 5 meta | C6H12 | 2.8 | Clmeta = 14.9 | 8% (−0.12) | 49% (−0.02) |
3 5 ortho | C6H12 | Cl ortho = 17.1 | 9% (−0.11) | 43% (−0.14) | |
3 5 ′ meta | MeOH | 3.6 | Clmeta = 8.8 | 8% (−0.17) | 4% (−0.90) |
3 5 ′ ortho | MeOH | Cl ortho = 8.7 | 10% (−0.19) | 6% (−0.87) |
As for the photoheterolytic cleavage in compounds 1–4 a further computational study was performed on selected phenyl cations. In accordance with 2-methoxyphenyl cations (1/319+), 314+, 315+, and 317+ showed a ring with a geometry close to a regular hexagon, while 115+ was planar with a cumulative double bond character at the C1–C2–C3 moiety (see Fig. 6b and Fig. S28–S31†). In contrast, 114+ and 117+ (see Fig. 6a and Fig. S29, S31†) were characterized by a puckering of the ring and a small out of plane displacement. For completeness we have also investigated the geometry of the corresponding radical 24˙ that was found to be planar (Fig. 6c and Fig. S32, S33†).
In particular, the isodesmic reaction reported in eqn (1) was adopted in solution (MeOH) to evaluate the (de)stabilization imparted by the methoxy group and chlorine atom with respect to the parent singlet phenyl cation (1Ph+, Fig. 7). The presence of an ortho-methoxy group on the parent phenyl cation (see cations 1,319+) exerted a great stabilization on the corresponding triplet 319+ and a slight destabilization on the singlet 119+. The chlorine atom, however, exerted a destabilization effect on cations 1,319+ (less than 8 kcal mol−1 for triplets and in the 7–17 kcal mol−1 range for singlets). The most important effect was observed in cation 14+ when the chlorine atom is adjacent to the cationic site (Fig. 7). At any rate, in each case the energy gap between the singlet and the triplet states was increased by the presence of the chlorine atom, the triplets being again the most stable cations.
(1) |
Fig. 7 Relative Gibbs free energies (see Tables S2 and S3 in the ESI†) of singlet (red) and triplet (blue) phenyl cations 14+, 15+, 17+, and 19+ in MeOH solution according to isodesmic reaction reported in eqn (1). |
For the sake of comparison, a computational investigation on the photohomolytic cleavage by forming the corresponding phenyl radicals was likewise carried out. The isodesmic eqn (2) was used in solution (C6H12) to evaluate the (de)stabilization imparted by the methoxy group and chlorine atom with respect to the parent phenyl radical (Ph˙, Fig. 8).
(2) |
Fig. 8 Relative Gibbs free energies (see Tables S4 and S5†) of phenyl radicals 21˙, 23˙, 24˙, and 26˙ in C6H12 solution according to isodesmic reaction reported in eqn (2). |
Computational data confirmed that even in dichloroanisoles and phenols the cleavage of the Ar–Cl bond takes place from the triplet state and it is homolytic in cyclohexane whereas it is heterolytic in methanol. Taking 2,4-dichloroanisole (4) as a model, both in C6H12 and in MeOH the C2 atom sticks out of the plane of the aromatic ring at the equilibrium and becomes planar after stretching of the Ar–Clortho bond up to 3 Å (see Fig. 4 and Fig. S14–S17†).
The elongation of the Ar–Clortho bond in cyclohexane resulted in a non-significant charge formation on the chlorine atom (−0.07) and the spin distribution is mainly localized at C2 (50%) and Cl atoms (47%) fully supporting the homolysis. In methanol, a marked charge separation (Cl −0.90) is apparent with a concomitant low spin localization on the chlorine atom (5%) in accordance with the formation of a triplet cation.
For the sake of comparison, we analyzed what is so far reported for the activation of the Ar–Cl bonds in compounds 1–5. The data are collected in Table 8. Five methods were described for the tentative selective cleavage of the Ar–Cl bond in compound 1 giving contrasting results. In fact, under Pd catalysis the reaction with a strong (PhMgBr, entry 1) or a weak (an aniline, entries 2 and 3) nucleophile gave preferentially the substitution at the 3 position in the former case and at the 2 position in the latter case. Moreover, disubstitution is an important competitive path (see again entry 1). Copper catalysis led to a complete disubstitution pattern in the reaction with Me3SiCl/Mg (entry 4) whereas in Ni catalyzed reaction with EtMgBr an almost exclusive preference for the 3 position resulted (entry 5). Pd catalyzed addition of PhB(OH)2 onto 1 was not selective leading to disubstitution (entry 6). Only one example was reported on the reactivity of compound 2 where Pd catalysis has a preference for the activation of the chlorine at position 3 (entry 7). Similarly, a poorly selective functionalization was found in compound 3 (entries 8–11, Table 8) in some cases depending on the nucleophile used (compare entries 9 and 10). Different conditions were tested in the Ar–Cl cleavage in compound 4 (entries 12–16). Here the disubstitution is a serious drawback even under electrolytic dechlorination (entry 14). Nevertheless, a complete regioselectivity at position 2 was reported in the cobalt catalyzed carboxylation (entry 15) and under irradiation in the presence of Cp*Re(CO)3 (entry 16). The presence of an OH group in phenol 5 is sufficient to drive a complete site-selectivity at position 2 (entry 17, Table 8) in the Pd catalyzed reaction with phenylacetylene.
Entry | Substrate | Coupling reagent | Conditionsa | Position selectivity (%) |
---|---|---|---|---|
a (a) Pd-PEPPSI-IPent (2 mol%), THF, 50 °C, 3 h. (b) [PdCl(η3-C3H5)]2 (1 mol%), ferrocenylpolyphosphine 1,2-bis(diphenylphosphino)-1-(diisopropylphosphino)-4-tertbutylferrocene (2 mol%), tBuONa (1.4 equiv.), toluene, 115 °C, 20 h. (c) Mg powder, CuCl, LiCl, 1,3-dimethyl-2-imidazolidinone, 55 °C, 17 h. (d) [Ni(triphos)Cl]PF6(triphos = bis(2-(diphenylphosphino)ethyl)phenylphosphine) (0.5 mol%), Et2O, 0 °C → reflux. (e) Pd(OCOCF3)2 (4 mol%), SPhos (8 mol%), K2CO3 (3 equiv.), 18-crown-6 (5 mol%), scCO2, 110 bar, 110 °C, 24 h. (f) NiCl2(dppbz) (5 mol%), toluene, rt, 22 h. (g) Electrolysis. (h) Co2(CO)8 (7.5 mol%), K2CO3, MeOH, 62 °C, 4 h. (i) hν (350 nm), hexane, 15 h. (j) PdCl2(CH3CN)2 (2 mol%), Cy-DHTP·HBF4 (4 mol%), t-BuOLi toluene, reflux, 45 min. | ||||
1 | 1 | PhMgBr | a20a | 2 (0), 3 (70), 2 + 3 (30) |
2 | 1 | C6H5NH2 | b20b | 2 (91), 3 (9), 2 + 3 (0) |
3 | 1 | 4-MeC6H4NH2 | b20b | 2 (83), 3 (17), 2 + 3 (0) |
4 | 1 | Me3SiCl | c20c | 2 (0), 3 (0), 2 + 3 (100) |
5 | 1 | EtMgBr | d20d | 2 (5), 3 (95), 2 + 3 (0) |
6 | 1 | PhB(OH)2 | e20e | 2 (0), 3 (0), 2 + 3 (100) |
7 | 2 | PhMgBr | a20a | 2 (0), 5 (21), 2 + 5 (79) |
8 | 3 | PhMgBr | a20a | 3 (0), 4 (12), 3 + 4 (88) |
9 | 3 | C6H5NH2 | b20b | 3 (50), 4 (50), 3 + 4 (0) |
10 | 3 | 4-MeC6H4NH2 | b20b | 3 (86), 4 (14), 3 + 4 (0) |
11 | 3 | Me3SiCl | c20c | 3 (0), 4 (0), 3 + 4 (100) |
12 | 4 | PhMgBr | a20a | 2 (0), 4 (30), 2 + 4 (70) |
13 | 4 | nC12H25MgBr | f20f | 2 (45), 4 (0), 2 + 4 (55) |
14 | 4 | — | g20g | 2 (13), 4 (0), 2 + 4 (87) |
15 | 4 | Methyl oxirane + CO (1 atm) | h20h | 2 (100), 4 (0), 2 + 4 (0) |
16 | 4 | Cp*Re(CO)3 | i13 | 2 (100), 4 (0), 2 + 4 (0) |
17 | 5 | j21 | 2 (100), 3 (0), 2 + 3 (0) |
As apparent from Table 8, the (catalytic) thermal Ar–Cl selective activation in compounds 1–5 is rather complex although scarce data are available for compound 2. The site-selectivity observed in compound 1 depends on the nucleophile used and it is never complete and the reaction is clean only when forming disubstituted products. The single case described for 2 points toward a meta selectivity although 79% of disubstituted product was also present. Again, in derivative 3 the reaction is not clean but meta adducts are preferred with respect to the para derivatives. The best results were found in the case of 4 where the ortho selectivity is exclusive in some cases. Interestingly, the presence of an OH group in place of a methoxy group increases dramatically the selectivity towards the ortho substitution (compare the case of dichlorinated 1 with 5).
The rationalization of the photochemistry observed in compounds 1–5 based on computational analysis is not trivial. In each of the solvents studied two possible triplet states are obtained. It is reasonable to assume that if the energy of one of the triplets is at least lower than 2 kcal mol−1 this should be the reacting excited state and the Ar–Cl cleavage should arise from it. It is interesting to note that calculations suggest a very similar selectivity in the homolytic and in the heterolytic cleavage. This means that in the excited state of compounds 1–5, the Ar–Cl bond cleaved is the same independent of the mechanism operating. This is in fair agreement with what was observed experimentally (see Tables 2–6).
In addition, in the case of compounds having a chloro atom at the ortho position (1–2, 4–5) this halogen is always the preferred leaving group of the reaction. As for compound 3 the cleavage of the chlorine at the para position is slightly preferred with respect to the meta position although the difference between the two most stable structures is very low (<1 kcal mol−1).
The steady-state experiments on compounds 1–5 pointed to a non-selective Ar–Cl cleavage in an almost unpredictable manner. A different site-selectivity was actually found in isomers 1 and 2 where in both cases the chlorine atoms were in the ortho and meta positions with respect to the methoxy group. In fact, in the first case the total absence of selectivity resulted in cyclohexane and in MeOH. In the latter case, however, the ortho cleavage is markedly preferred independent of the medium used. In compound 3, the meta cleavage was indeed preferred upon photohomolysis and exclusively upon photoheterolysis. In the latter case, however, the further dechlorination was too efficient and avoids any synthetic use of the process. The ideal case is that of compound 4 where the complete ortho activation and the limited formation of anisole allowed us to perform a clean site-selective arylation to obtain biphenyl 10.
Quite surprisingly, the selectivity obtained in the case of phenol 5 is very poor (as the photoreactivity) and not better than the corresponding methyl ether 1. This is in contrast to what is usually reported under metal-catalyzed conditions where the OH group usually exerts a marked effect in directing the reactivity toward the ortho position (see also Table 8).21,22–24
This work was funded by the CINECA Supercomputer Center, with the computer time granted by ISCRA projects (code: HP10CN4237 and HP10CBEIAU).
Footnote |
† Electronic supplementary information (ESI) available: Photophysical data, computational details and copies of 1H and 13C NMR spectra of the synthesized compounds. See DOI: 10.1039/c7pp00372b |
This journal is © The Royal Society of Chemistry and Owner Societies 2018 |