Sugar-Assisted Photogeneration of Didehydrotoluenes from

Article pubs.acs.org/joc

Sugar-Assisted Photogeneration of Didehydrotoluenes from Chlorobenzylphosphonic Acids Stefano Crespi, Stefano Protti, Davide Ravelli, Daniele Merli, and Maurizio Fagnoni* PhotoGreen Lab, Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy S Supporting Information *

ABSTRACT: Irradiation of the three isomeric chlorobenzylphophonic acids in aqueous buffer led to a pH-dependent photochemistry. Under acidic conditions (pH = 2.5), photocleavage of the Ar−Cl bond occurred and a phenyl cation chemistry resulted. Under basic conditions (pH = 11), a photoinduced release of the chloride anion followed by the detachment of the metaphosphate anion gave α,n-didehydrotoluene diradicals (α,n-DHTs), potential DNA cleaving intermediates. At a physiological pH (pH = 7.2), both a cationic and a diradical reactivity took place depending on the phosphonic acid used. It is noteworthy that the complexation exerted by a monosaccharide (glucose or methylglucopyranoside) present in solution induced an exclusive formation of α,nDHTs. The mechanistic scenario of the different photoreactivities occurring when changing the pH of the solution and the role of the various intermediates (phenyl cations, diradicals, etc.) in the process was studied by computational analysis.

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by the photoheterolytic cleavage of an Ar−Cl19 or an Ar−O bond (in aryl sulfonates or phosphates).22 Detachment of the trimethylsilyl cation from the obtained triplet phenyl cations 3 IIa−c then affords all of the three α,n-DHT isomers. It was proven that the efficiency of α,n-DHTs photogeneration was increased by shifting from neat alcohol to alcohol/water mixtures. Thus, both the fact that the generation of didehydrotoluenes was favored in the presence of water19,20,23 and the obvious interest in this solvent for medicinal applications prompted us to investigate chlorophenylacetic acids as α,n-DHT precursors. These compounds were completely water soluble under physiological conditions (pH = 7.2), and carbon dioxide acted as an efficient electrofugal group (Scheme 1b, left part).19 Under these premises, we were interested in investigating the possible effect of sugars in the photogeneration of α,n-DHTs via interaction with the aromatic precursors. We then focused our attention on the PO3H2 moiety as an electrofugal group (Scheme 1b, right part) on different grounds: (i) phosphonatebased compounds are widely present in biological systems;24 (ii) our approach has the additional advantage to release an innocuous phosphate anion in solution, and most importantly, (iii) the PO double bond in phosphonates/phosphates is known to form chelate complexes with sugars.25−27 Accordingly, this could assist the detachment of the (meta) phosphate group. Albeit the photoheterolytic cleavage of the CO bond in benzyl phosphates (ArCH2OPO2R2) is well documented,28 the analogous liberation of a metaphosphate group (PO3−) from benzyl phosphonates was rarely reported.29,30 The

INTRODUCTION Carbohydrates and sugars have an active role in a wide range of biological events (the so-called glycobiology).1 In particular, such derivatives are involved in the regulation of various functionalities within the cells via specific molecular recognitions.2,3 Sugars may bind lipids, proteins (e.g., lectins, which are responsible for erythrocytes agglutination and hemagglutination),3 and even DNA.2−4 Concerning glycopeptides, the binding exerted by the sugar moiety can increase the antimicrobial activity of natural compounds, as in the case of the antibiotic vancomycin.5 In some cases, a molecular recognition pattern is essential to ensure site selectivity of a drug or a prodrug.6 In enyne antibiotics, DNA complexes with the carbohydrate moiety of calicheamicin γ1 have been characterized.7 Furthermore, the carbohydrate residue (aminoglycoside) present in the neocarzinostatin (NCS) chromophore was found to heavily influence the efficiency of such a compound in DNA cleavage, though it was not considered determinant to impart the base specificity to the process.8 The cytotoxicity of enynes is due to the cycloaromatization of their polyenic moiety causing the in situ generation of aggressive didehydroaromatics such as p-benzynes and α,n-didehydrotoluenes (α,n-DHTs, n = 2−4).9−12 The latter intermediates (Scheme 1) are heterosymmetric diradicals (σ,π) formally resulting from the elimination of two hydrogen atoms from a toluene molecule.13,14 The meta isomer (α,3-DHT) is the only species thermally accessible, via the Myers−Saito cycloaromatization of enyne−allenes.9,15−18 Recently, our group has developed an alternative route to the Myers−Saito reaction based on a one-photon doubleelimination process starting from substituted benzyl silanes Ia−c, as illustrated in Scheme 1a.19−22 The process is initiated © 2017 American Chemical Society

Received: August 4, 2017 Published: October 11, 2017 12162

DOI: 10.1021/acs.joc.7b01963 J. Org. Chem. 2017, 82, 12162−12172

Article

The Journal of Organic Chemistry Scheme 1

The pKa values of the three isomeric chlorobenzylphosphonic acids were determined by means of potentiometric titration (Figure S1 and Table S1 in the Supporting Information). The pKa1 and pKa2 values for 1a−c were in the 2.32−2.94 and 7.40−7.46 range, respectively. These values are comparable with those reported for related phosphonic acids.32 With the pKa data in hand, it was possible to plot the molar fraction graph of the different protonated species of 1a (taken as a model) at different pHs (Figure 1, selected pHs were 2.5, 5,

process was favored only when applied to electron-poor aromatics such as nitrobenzylphosphonate ions III (Scheme 1c), where the peculiar, diradicalic structure of the excited state III* was suggested to play a crucial role in the fragmentation of the phosphonate ester.29,30 As a result of the CP bond cleavage, a benzyl anion and a metaphosphate anion were liberated, thus leading to toluene and phosphate anion upon reaction with water (Scheme 1c). We deemed that chlorobenzylphophonates 1a−c could be valid candidates for α,n-DHTs photogeneration (Scheme 2). Moreover, the presence of two acidic hydrogens in compounds 1a−c may allow for a tuning of the product distribution induced by a pH-dependent reactivity.

Figure 1. Molar fraction graph of the different protonated species of 1a at different pHs.

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7.5, and 11). In particular, it was found that at pH = 2.5, acid 1a was present as a 4:1 mixture of the fully protonated form (1a) and monoprotonated species 1′a. The latter form is the only species in solution at pH = 5, while at a physiological pH = 7.2, 42% of 1′a is in equilibrium with 58% of the completely deprotonated species 1′′a, that is the sole form present at pH = 11 (Figure 1). The photophysical properties of 1a−c (1′a−c/1′′a−c) at pHs = 2.5, 7.2, and 11 were minimally affected by the pH value, albeit the three isomers showed a higher ε in the fully deprotonated form at pH = 11 (Table S2). Generally speaking, the fluorescence quantum yields were very low (ΦF < 0.02) for all of the examined compounds, with the para isomer 1a showing the highest ΦF in the series, a trend often found in haloaromatics.33,34 The photochemical reactions were carried out by direct irradiation at 254 nm or under acetone sensitization at 310 nm22 in various reaction media, including neat MeOH, aqueous MeOH or MeCN, and an aqueous phosphate buffer solution at different pHs, namely 2.5, 5, 7.2, and 11 (see Tables 1−3). The photoproducts formed may be classified in two main families, namely chlorine-free products (4a−c and 5, Scheme 3) and phosphorus/ chlorine-free derivatives (products 6−12, Scheme 3). A set of photochemical experiments were first carried out on compounds 1a and 1b in MeOH and in different MeOH/water mixtures under basic conditions (5 × 10−3 M Cs2CO3) to investigate the photochemistry of the fully deprotonated forms 1′′a and 1′′b and to evaluate the effect of the presence of water. As a general trend, the reactions in methanol gave only phosphorus/chlorine-free products, viz. phenethyl alcohol 7, benzyl methyl ether 8, and bibenzyl 12, but increasing the amount of water dramatically drove the reaction to give phenols 4, benzylphosphonic acid 5 (only in the case of 1b in a MeOH/water 9:1 mixture), and benzyl alcohol 6. Thus, 7 was the main product in the irradiation of 1a

EXPERIMENTAL STUDIES

Chlorobenzylphosphonic acids 1a−c were prepared by a two-step synthesis, involving an Arbuzov reaction with triethylphosphite starting from the corresponding chlorobenzyl chlorides 2a−c, followed by hydrolysis of the diethyl esters 3a−c (Scheme 2).31

Scheme 2. Preparation of Chlorobenzylphosphonic Acids 1a−c

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The Journal of Organic Chemistry Table 1. Irradiation of 1a (5 × 10−3 M) for 1 h at 254 nm in Different Reaction Media yield (%)a conditions

Φ−1

pH

conversion (%)

2.5 5 7.2 11 2.5 7.2 11

95 100 100 100 98 94 74 77 100 100 100 100 100

b

MeOH MeOH−H2O 9:1b MeOH−H2O 1:9b MeOH−H2O 1:9b sensitizedc MeOH−bufferd 1:9b MeCN−bufferd 1:9b phosphate buffere

0.13 0.14 0.16 0.26

phosphate buffere sensitizedc

4a

5

6

11 35

7

8

32 33

trace

58 75

15 34 73 58 47

10

11

12 2 13

4 5 4

12 3

9

15

30 26 32 35 57

7

41 11

14 17 28

23 trace

3 6 9

Yields were based on consumed 1a (see Experimental Section). b5 × 10−3 M cesium carbonate was added. cAcetone (10% v/v) was used as a sensitizer. The irradiation was performed using 310 nm lamps for 1 h (see Supporting Information). dPhosphate buffer 0.05 M, pH = 7.2. e Phosphate buffer 0.05 M. a

Table 2. Irradiation of 1b (5 × 10−3 M) for 1 h at 254 nm in Different Reaction Media yield (%)a conditions MeOHb MeOH−H2O 9:1b MeOH−H2O 1:9b MeOH−H2O 1:9b sensitizedc phosphate bufferd

Φ−1

0.08 0.12 0.10

phosphate bufferd sensitizedc

pH

conversion (%)

2.5 7.2 11 2.5 7.2 11

61 95 100 100 65 83 68 100 100 100

4b

5

2 44

6

8

15 25 30 6 6

89 62 72 34 4

44 39

9

10

11 71 5 3

5

7 38 43

11 8 4

a Yields were based on consumed 1b (see Experimental Section). b5 × 10−3 M cesium carbonate was added. cAcetone (10% v/v) used as a sensitizer. The irradiation was performed using 310 nm lamps for 1 h. dPhosphate buffer 0.05 M.

Table 3. Irradiation of 1c (5 × 10−3 M) for 1 h at 254 nm in Phosphate Buffer yield (%)a conditions phosphate bufferb

phosphate bufferb sensitizedc

Φ−1

pH

conversion (%)

4c

0.07 0.11 0.11

2.5 7.2 11 2.5 7.2 11

65 83 68 100 100 100

56 33 38 40 2

5

47 9

6

9

12

10 30 3 12 13

8 14 18

trace 3 8

a Yields were based on consumed 1c (see Experimental Section). bPhosphate buffer 0.05 M. cAcetone (10% v/v) was used as a sensitizer. The irradiation was performed using 310 nm lamps for 1 h.

in MeOH and in MeOH/water 9:1 mixture, while, in the case of 1b, the presence of small amounts of water (MeOH/water 9:1 mixture) was beneficial for the formation of 8. The use of a sensitizer (acetone, 10% v/v in MeOH/water 1:9; λirr = 310 nm)35 drastically changed the product distribution. In both cases, the sensitization led to a mixture of phosphorus/chlorine-free derivatives, with 6 being the main product. Interestingly, small amounts of an acetone-incorporating adduct (tertiary alcohol 10) were also detected (Tables 1 and 2). To test the reactivity of 1a in a physiological environment, while maintaining the presence of an organic co-solvent, irradiation experiments in buffered water (pH 7.2)/MeCN 9:1 and buffered water (pH 7.2)/ MeOH 9:1 mixtures were carried out. Irradiation of the alcoholic solution pushed the reaction toward the formation of bibenzyl (12),

whereas, in aqueous acetonitrile, a complex mixture containing (among others) the solvent incorporating compounds 6 and 11 was obtained.36 We then tested the photochemical behavior of 1a−c in aqueous buffered solutions at different pHs. As mentioned, pH 7.2 was adopted to establish the reactivity of chlorobenzylphosphonates at a physiological pH, while pH 5 was tested for 1a with the aim to obtain data on the reactivity of monoprotonated 1′a (the only species present in solution, see Figure 1). Quantum yields of photodecomposition (Φ−1) were measured in an aqueous phosphate buffer (Tables 1−3), and the compounds exhibited only modest reactivity (Φ−1 in the 0.07−0.16 range), with the exception of 1a at pH = 11 (Φ−1 = 0.26). 12164


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The Journal of Organic Chemistry

As apparent from Tables 1−3, a pH and substrate-dependent product distribution resulted. More specifically, when 1a−c were irradiated in phosphate buffer at 254 nm, two main products were formed, viz. hydroxybenzylphosphonic acids 4a−c and benzyl alcohol 6. Under acidic conditions, the main products were phenols 4a−c for all of the chlorophosphonic acid isomers. At pH = 11, compound 6 became the exclusive product in the case of 1a; no significant differences were observed for 1b, and alcohol 6 was obtained in 30% yield at the expense of 4c in the case of 1c. The presence of acetone as the sensitizer (10% v/v) in the buffered solution caused an increase of 1a−c consumption (Tables 1−3) and caused the formation of benzylphosphonic acid 5 (with the exception of 1a), a different acetone-incorporating product (ketone 9), and bibenzyl 12. Furthermore, under sensitized conditions, 1a yielded exclusively products that belong to the phosphorus/chlorine-free family, though with a low mass balance. The same selectivity holds for 1b/1c, where products 5, 6, 9, and 12 were obtained at the expense of product 4. It is interesting to note that under acidic/neutral conditions, α,n-DHT deriving products 6−12 were always accompanied by products 4a−c/ 5. The irradiation under strong basic conditions, however, caused the complete detachment of the chloride and metaphosphate anions in derivatives 1a−c. The latter conditions are obviously incompatible for

Scheme 3. Photoproducts Obtained by the Irradiation of 1a−c

Table 4. Effect of the Presence of Sugars on Product Distributions by Irradiation of 1a and 1b and n-Chlorophenylacetic Acids 13a and 13b in Phosphate Buffer at pH = 7.2a

1 h irradiation. Total consumption of starting aromatic chloride in each case. bMGP = methylglucopyranoside. cEt3NH+ AcO− (0.05 M) buffer, pH = 7. a

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chloroaromatics (Figure 2a inset).39 Elongation of the C−Cl bond furnished different potential energy surfaces (PESs, Figure 2a and

biological applications, and we evaluated if the chelate complexes that 1a and 1b may form with sugars at pH 7.2 (Table 4) could help in the metaphosphate release from the phenyl cation intermediates. We first tested the capability of cyclodextrins (CD) to form inclusion complexes with 1a to verify if a change in the overall reactivity would occur, in analogy to what was previously observed with other chloroaromatics (e.g., 4-chlorophenol).37 The addition of 1 equiv of αCD or γ-CD mainly caused the disappearance of phenol 4a with the concomitant formation of 5, while slightly lowering the amount of 6. Phosphonic acid 5 became, by far, the main product when using β-CD (Table 4). Interestingly, in the presence of ethylene glycol (1 equiv), benzyl alcohol 6 was formed in a high yield (71%), along with a minor amount of 4a. An even more dramatic effect was, however, found when methyl glucopyranoside (MGP)38 or glucose were added, since benzyl alcohol 6 became the almost exclusive photoproduct at the expenses of both 4a and 5. Similar results were obtained when replacing the phosphate buffer with a triethylammonium acetate buffer (pH = 7). A related effect was observed in the experiments with 1b, where the presence of MGP strongly increased the amount of 6. The acetate buffer here caused the disappearance of 4b, with 5 becoming the main product. These results were compared with those obtained by irradiating 4- and 3-chlorophenylacetic acids (13a and 13b). Notably, no change in the product distribution resulted when MGP was present in an equimolar amount (Table 4). 1a was also irradiated for 1 h at three different pHs (2.5, 7.2, and 11) in water in the absence of a phosphate buffer, and the resulting solutions were subjected to ion chromatography analysis (Table S3). The data reported in Table S3 show that the phosphate anion was exclusively released in the reaction, and a nice match with the expected amounts of free phosphate was found. Computational Studies. Computational studies were carried out to rationalize the different behavior of the involved species at different pH values. In particular, we were interested to have better insights on the mechanism of the photochemical cleavage of the aryl−Cl bond (e.g., 1a, path a, Scheme 4) that is supposed to lead to the formation of

Scheme 4. Main Computational Pathways Investigated

Figure 2. (a) Plot of the energy surfaces of the ground state (1a), first singlet (11a) and triplet (31a) excited states of 1a as a function of the C−Cl bond length (see Table S4). In the inset, the structure of the puckered triplet state of 1a is depicted. The ESP charges on the chlorine atom before and after (in parentheses) elongation of the C− Cl bond up to 3.3 Å have been reported. (b) Active orbitals containing the unpaired electrons in the cationic 315a+ species obtained after complete detachment of the chloride anion from the protonated species 1a. (c) Geometry of the singlet aryl cation 115a+, characterized by a marked ring deformation at the dicoordinated carbon atom.

the triplet aryl cation 315a+ (Scheme 4).19−22 Subsequently, the energetic barriers of the C−P bond cleavage from the dechlorinated species were evaluated (path b, Scheme 4) to study the feasibility of the formation of the didehydrotoluene intermediate, following the mechanism we previously reported for chlorophenylacetic acids.19 In order to look for a parallelism, if any, between the photochemical reactivity of 1a−c and that of the aforementioned chlorophenylacetic acids,19 paths a and b of 1a were taken as a model and were investigated (Scheme 4). In order to fully characterize the diradical species that could arise from the photochemical reaction, the complete active space selfconsistent field (CASSCF) approach, a multiconfigurational ab initio method, was deemed mandatory to describe the system. The choice of the active space depended on the structure considered. The protonated species 1a was optimized in its ground state and its first triplet and singlet excited states using a CASSCF(10,10)/6-31G(d) level of theory, and the energy of the resulting structures was evaluated in bulk water (CPCM model). In particular, the active space contained the 6 orbitals belonging to the π structure of the ring, as well as the σ/ σ* pairs of both the C−Cl and C−P bonds. While the morphology of the excited singlet 11a was very similar to the ground state, the triplet state 31a adopted the puckered structure typically found in triplet

Table S4) according to the considered state, in a very similar fashion as what was already found in the case of chlorobenzyltrimethylsilanes.21 Detachment of the chloride anion was confirmed to occur from the lowest triplet state with a barrier of 18 kcal mol−1 affording triplet aryl cation 315a+ (Figure 2b). The heterolytic nature of the cleavage was corroborated by the marked localization of a negative charge on the heteroatom upon stretching (Figure 2a). By contrast, the detachment of chlorine was found to follow a homolytic path from both the S1 and the S0 states, but these were characterized by high-energy barriers; their occurrence could thus be safely excluded. The monoacidic and the fully deprotonated species of phosphonic acid 1a turned out to be more difficult to compute, due to the mandatory inclusion of one of the lone pairs of the P−O− moiety in the active space, in a way similar 12166


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The Journal of Organic Chemistry to the case of chlorophenylacetic acids.19 Accordingly, a larger active space, viz. CASSCF(12,11) comprising a p orbital in the oxygen atom, was needed to describe correctly 1′a and 1′′a. Two intersecting triplet states were found to concur in the detachment of the chloride ion from the aromatic moiety, as previously observed for chlorophenylacetic acids.19 In particular, the elongation of the Ar−Cl bond proceeds at first through a structure that possesses a zwitterionic nature (henceforth dubbed as 31′aZ and 31′′aZ, Figures 3a and 4) that electronically resembles a triplet aryl cation in its early stage of formation.39

Figure 4. Potential energy surfaces (PESs) of (a) 1′a and (b) 1′′a as a function of the C−Cl bond length (see Tables S5 and S6).

electronic configuration (the SOMOs of 315a+ are reported in Figure 2b). However, calculations depict a completely different situation for diradicals 16′a−c and 16′′a−c (Figure 5), where the triplet is the ground state in all cases. The S−T gap is lowered to a few kcal mol−1, again in parallel with the case of chlorophenylacetic acids.19 The SOMOs are always found on the dicoordinated carbon and on the oxygen attached to the phosphonate moiety, as can be seen for the species 316′′a (Figure 3c). Detachment of the phosphonate group was studied for the three species arising upon chloride loss at the CPCM−CASCCF (8,9) level of theory for 15a+ and CPCM−CASCCF (10,10) for 16′a and 16′′a, both in the triplet and the singlet state. The species 15a+ generates α,4-DHT with a barrier of ca. 36 kcal mol−1 (Figure 6) for the triplet and 68 kcal mol−1 in the case of the singlet (Figure S11). The elongation of the C−P bond proceeds energetically uphill in a monotonic fashion. However, the barriers for the detachment of the electrofugal group from diradicals 16′a and 16′′a are characterized by a discontinuity that lowers the activation energy to 14 kcal mol−1 for both spin states (see Figure 6 for the triplets, Figure S11 for the singlets; a more detailed description of the cleavage of the C−P bond and the nature of the discontinuity is presented in the Supporting Information). DFT calculations at the B3LYP/6-31G(d) level of theory were then applied to qualitatively prove the existence of a noncovalent interaction between the deprotonated species 1′′a (the most abundant species at pH = 7.2), taken as a model compound, and methylglucopyranoside (MGP). A marked interaction was indeed found between the negative oxygen atoms of the phosphonate di-anion (that act as an acceptor of the hydrogen bond) and the hydroxyl groups of MGP (Figure 7).

Figure 3. Active orbitals containing the unpaired electrons in the triplet species: (a) 31′′aZ, (b) 31′′aD, and (c) 316′′a. A small stretching of the C−Cl bond (up to ca. 2.0 Å for both 31′aZ and 31′′aZ) from the equilibrium position resulted in the crossing of the zwitterionic surface with a second triplet state defined by a diradical nature (hence called 31′aD and 31′′aD, respectively; Figures 3b and 4), characterized by an antibonding character. The barrier for the aforementioned process is quite low in both cases, viz. 5 kcal mol−1 to reach 31′aD and 1.4 kcal mol−1 to populate 31′′aD taking the equilibrium geometry of 31′aZ and 31′′aZ, respectively, as the reference point. Finally, complete chloride detachment from the monoprotonated and the fully deprotonated species forms the diradical species 16′a and 16′′a (Figure 3c). Isodesmic reactions were computed on the three isomers of 15a− c+, 16′a−c, and 16′′a−c, in order to deepen our knowledge on the relative stability of the spin states of the intermediates generated upon chloride detachment (Figure 5). The calculations were performed by applying an MP2 correction to the CASSCF energies (details can be found in the Supporting Information). Relative energies and structures of cations 15a−c+, in either spin state, resemble those arising from chloroalkylaromatics39 and chlorophenylacetic acids,19 with the singlet state more stable than the corresponding triplet (with a computed singlet−triplet gap around 15 kcal mol−1 for the three isomers). In particular, 115a−c+ are predicted to be closed-shell structures with a π6σ0 electronic configuration and a cumulenic character at the dicoordinated carbon (Figure 2c). However, the ring in the structures of 315a−c+ is closer to the common hexagonal benzene, with a π5σ1 12167


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Figure 6. Barriers for the detachment of the phosphonate group from the differently protonated species 315a+, 316′a, and 316′′a in bulk water. Energies are reported as the difference between the value obtained at the chosen C−P length and the energy of the system at equilibrium, taken as a reference (Table S7).

Figure 7. Complex between 1′′a and methylglucopyranoside (MGP) calculated at the B3LYP/6-31G(d) level of theory. A hydrogen bond interaction can be envisaged between the oxygen atoms of the phosphonate moiety and the hydroxyl groups of MGP. The main distances defining the noncovalent interaction are reported.

Scheme 5. Possible Pathways in the Photoreaction of 1a Under Acidic Conditions

Figure 5. Relative energy of the spin states of isomeric (a) cations 15a−c, (b) diradicals 16′a−c, and (c) diradicals 16′′a−c with respect to the isodesmic reaction reported in the inset.

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DISCUSSION The results obtained in the present work point out the dependence of the photoreactivity of chlorobenzylphosphonic acids 1a−c on their protonation state, viz. if they are present in solution in the fully protonated (1a−c) or deprotonated (1′a− c or 1′′a−c) forms, as summarized in Schemes 5 and 6. At a 12168


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The Journal of Organic Chemistry Scheme 6. Possible Pathways in the Photoreaction of 1a Under Neutral/Basic Conditions

species is well-known and includes the addition of organic solvents, such as MeOH,16,20 acetone,22 and acetonitrile,36 via homolytic C−H cleavage followed by radical recombination (compounds 7, 9, 11, path h′). Dimerization of the DHTs led to 12 (path g′), whereas the O−H cleavage in MeOH or water was responsible of the formation of products 6 and 8 (path f′, Scheme 6). Benzyl methyl ether 8 was predominantly formed in MeOH/water 9:1 in the case of meta isomer 1b and arose from the so-called ionic path of α,n-DHTs.36,44−46 Sensitization has the main advantage to speed up the reaction allowing, at the same time, an irradiation at a longer wavelength. The different product distribution obtained in acetone-containing solutions was safely attributed in part to the effect of the change in polarity of the reaction media and in part to its H-donor ability. In some cases, acetone behaved as a non-innocent bystander since it, in the excited state, may abstract a hydrogen atom from MeOH and the resulting ketyl radical may couple with α,nDHTs to give alcohol 10, as previously observed. 22 Unfortunately, no exclusive generation of the desired α,nDHT diradicals took place at a physiological pH since the chemistry of the phenyl cation intermediate competed with the loss of the metaphosphate. The presence of carbohydrates, however, enabled a switch of the reactivity in chlorobenzylphosphonic acids. Cyclic sugars (cyclodextrins) are known to complex chloroaromatics depending on the size of the cavity, thus modifying the ensuing photochemistry.37 In the present case, despite the rather low amount of CD present (1 equiv), the partial inclusion of compound 1a within differently sized α-CD or γ-CD led to the formation of variable amounts of phosphonic acid 5, becoming the predominant product when β-CD was present (Table 4). Such reduction product arose from hydrogen abstraction by the triplet phenyl cation from the C−H bonds of the surrounding CD. α-CD or γ-CD behaved as a modest hydrogen donor due to the loose inclusion complexes formed with 1a. Hydrogen abstraction was so efficient in β-CD that it hampered any other process, including α,n-DHT formation. However, in the presence of polyalcohols such as glycols and, at a higher extent, monosaccharides (again 1 equiv) such as methylglucopyranoside (MGP) or glucose, a significant shifting toward the formation of the α,n-DHT-deriving product 6 took place at a physiological pH. The effect of MGP on the reaction outcome was safely attributed to the presence of the phosphonate moiety in 1′′a−c since the shift to other negatively charged electrofugal groups (e.g., COO− in chlorophenylacetic acids 13a and 13b) had no

low pH, the substrates were in the 1a−c form and, after excitation and subsequent ISC, generated the corresponding triplet phenyl cations 315a−c+ (path a, Scheme 5 for the case of 1a) via heterolytic loss of the nucleofugal group (chloride anion). These intermediates either reacted with a hydrogen donor (an organic (co)solvent such as methanol or the acetone used as a sensitizer) and were reduced to benzylphosphonic acid 5 (path b) or underwent intersystem crossing to singlet phenyl cations 115a−c+ (path c),37 which are aggressive electrophiles, and promptly reacted with water to yield phenols 4a−c (path d). Hence, the majority of the products maintained the phosphonate group and safely arose from a typical phenyl cation chemistry. The presence of high amounts of water induced a stabilization of cations 315a−c+, thus favoring path c vs path b, as previously observed in related cases.40 This is consistent with the observed product distribution in MeOH/water. However, organic (co)solvents can also act as hydrogen donors and favor the formation of dechlorinated 5. The loss of the metaphosphate moiety from 315a−c+, to form DHTs (path e), is a negligible path due to the high-energy barrier related to the C−P bond cleavage (see Figure 6). A different and more complicated scenario resulted when the pH is ≥5 and the 1′a−c or 1′′a−c forms were exclusively present (see Scheme 6 for the case of 1′a). We can envisage that triplet zwitterions 31′a−cZ and 31′′a−cZ, actually triplet aryl cations in their early stage of formation, were initially formed (path a′). The latter zwitterions may be reduced (in analogy with 315a−c+, path b′) or may form solvolysis products 4a−c (path c′) via ISC to 11′a−cZ and 11′′a−cZ. However, 3 1′a−cZ and 31′′a−cZ easily underwent a surface crossing with very small barriers to the diradical states 31′a−cD and 31′′a−cD (see Figure 4), ultimately leading to diradicals 316′a−c and 3 16′′a−c (path d′). Calculations showed that the latter pathway was exclusive for 1′a−c and 1′′a−c, due to the presence of at least one negatively charged oxygen bearing a lone pair (path d′, Scheme 6). Triplet DHTs were then formed after the facile C−P bond cleavage from 316′a−c and 316′′a−c (path e′) with the concomitant liberation of H3PO4 (in turn arising from the hydration of the metaphosphate anion).41−43 The almost quantitative formation of the phosphate anion was confirmed by the ion chromatography analysis of the photolyzed solutions (Table S3). The presence of at least a negative charge on the starting phosphonate group was thus mandatory for the formation of the desired didehydrotoluenes. The chemistry of the latter 12169


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were carried out using a Thermo Scientific DSQII single quadrupole GC−MS system. A Restek Rtx-5MS (30 m × 0.25 mm × 0.25 μm) capillary column was used for the separation of analytes with helium as a carrier gas at 1 mL min−1. The injection in the GC system was performed in split mode, and the injector temperature was 250 °C. The GC oven temperature was held at 80 °C for 2 min, increased to 220 °C by a temperature ramp of 10 °C min−1, and held for 10 min. The transfer line temperature was 250 °C, and the ion source temperature was 250 °C. Mass spectral analyses were carried out in full scan mode. HPLC analyses under gradient conditions were carried out using a Supelco Discovery C18 HPLC Column (25 cm × 4.6 mm, 5 μm particle size). Solvents used for the elution process were H2O (in the presence of 0.1% HCOOH) and MeCN, and a flow rate of 0.5 mL min−1 was used. The mobile phase composition was kept constant at 90% acidified water for 8 min, followed by a linear change up to 10% water. The UV detector was set to operate at 230 or 240 nm. Synthesis of Benzylphosphonic Acids 1a−c, 4b, and 4c. Acids 1a−c, 4b, and 4c were obtained from the corresponding benzyl chlorides through a two-step synthesis as previously described.31 Step 1, General Procedure for the Synthesis of Benzyldiethylphosphonates.31 A mixture of the chosen benzyl chloride (1 equiv) and triethylphosphite (1.2 equiv) was refluxed under a constant stream of nitrogen for 12−48 h at 120 °C. The unreacted triethylphosphite was then removed from the crude mixture upon distillation under reduced pressure (3 × 10−2 torr) at 90 °C, and the desired product was used for the next step without any further purification. Diethyl 3-Chlorobenzylphosphonate (3b).51 Compound 3b was synthesized from 3-chlorobenzyl chloride (2b, 2.53 mL, 20 mmol) and triethylphosphite (4.12 mL, 24 mmol). The removal of the unreacted phosphite afforded the desired product (4.4 g, 84% yield) as a colorless oil. The spectroscopic data of 3b were in accordance with the literature.51 Diethyl 2-Chlorobenzylphosphonate (3c).52 Compound 3c was synthesized from 2-chlorobenzyl chloride (2c, 2.5 mL, 20 mmol) and triethylphosphite (4.12 mL, 24 mmol). The removal of the unreacted phosphite afforded the desired product (4.8 g, 92% yield) as a colorless oil. The spectroscopic data of 3c were in according with the literature.52 Diethyl 3-Methoxybenzylphosphonate (15b).53 Compound 15b was synthesized from 3-methoxybenzyl chloride (17b, 2.70 mL, 20 mmol) and triethylphosphite (4.12 mL, 24 mmol). The removal of the unreacted phosphite afforded the desired product (4.6 g, 89% yield) as a colorless oil. The spectroscopic data of 15b were in accordance with the literature.53 Diethyl 2-Methoxybenzylphosphonate (15c).53 Compound 15c was synthesized from 2-methoxybenzyl chloride (17c, 2.70 mL, 20 mmol) and triethylphosphite (4.12 mL, 24 mmol). The removal of the unreacted phosphite afforded the desired product (4.3 g, 83% yield) as a colorless oil. The spectroscopic data of 15c were in accordance with the literature.53 Step 2, Synthesis of Benzylphosphonic Acids 1a−c, 4b, and 4c. To a 2 M solution of the chosen diethylphosphonate (1 equiv) and KI (3 equiv) in anhydrous MeCN was added freshly distilled trimethylsilyl chloride (TMSCl, 3 equiv). The obtained mixture was thus stirred for 5 h at 60 °C. In the case of 15b and 15c, 6 equiv of both KI and TMSCl were required. The resulting solid was subsequently filtered off, and the solvent was removed in vacuo. The crude residue was treated with a few drops of HPLC-grade water, and the resulting precipitate was purified via recrystallization from acidic water (HCl 1 M). 4-Chlorobenzylphosphonic Acid (1a).31 Compound 1a was synthesized from commercially available diethyl 4-chlorobenzyl phosphonate (3a, 2 g, 7.6 mmol), KI (1.34 g, 22.8 mmol) and TMSCl (2.90 mL, 22.8 mmol) in MeCN (10 mL). Purification afforded 1a (940 mg, 59% yield) as a white solid, mp 172−173 °C (lit.54 mp 168−171 °C). The spectroscopic data of 1a were in accordance with the literature.31 3-Chlorobenzylphosphonic Acid (1b). Compound 1b was synthesized from diethyl 3-chlorobenzylphosphonate (3b, 1.5 g, 5

effect on the product distribution. Such a trend confirms the presence of a specific non-bonding interaction between the sugar moiety and the phosphonate anions 1′a−c or 1′′a−c, also corroborated by computational analyses. The presence of a phosphate anion in the buffer only had a limited effect on such complexation, as witnessed by the use of an alternative acetate buffer (see Table 4). This interaction between the electrofugal group and the sugar derivative assists the cleavage of the phosphonic moiety from diradicals 316′a/316′′a after the loss of the chloride anion (Scheme 7). Such a result seems Scheme 7. Sugar-Assisted Formation of α,n-DHTs

extremely promising for the potential applications of phosphonic acids as electrofugal groups in the generation of α,n-DHTs under physiological conditions. It should be noted that an optimization of the α,n-DHT formation path is concomitant with the release of 1 equiv of the phosphate anion, which is compatible with the cellular environment and possesses potential biological activity.47−50

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CONCLUSIONS Summing up, the photochemistry of the three isomers of chlorobenzylphosphonic acids may be tuned by changing the pH of the solution and by the presence of additives (e.g., sugars) that drive the generation and the ensuing reactivity of the photogenerated intermediates (phenyl cations or diradicals). A typical case is that of 1a, where a pH-dependent photobehavior is apparent. In fact, at an acidic pH, a predominant cationic reactivity was observed, whereas, under basic conditions, a diradical reactivity was exclusive. It is noteworthy that the introduction of a sugar derivative, such as MGP at a physiological pH, pushed the process toward the selective formation of α,n-DHTs. This work may lay the basis for the preparation of purposely designed biomolecules, conjugate DHT precursors bearing phosphonate groups.

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EXPERIMENTAL SECTION

General. 1H, 13C, and 31P NMR spectra were recorded on a 300, 75, and 122 MHz spectrometer, respectively. The attributions were made on the basis of 1H, 13C, and 31P NMR experiments; chemical shifts are reported in ppm downfield from TMS. GC−MS analyses 12170


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The Journal of Organic Chemistry mmol), KI (2.49 g, 15 mmol) and TMSCl (1.90 mL, 15 mmol) in MeCN (8 mL). Purification afforded 1b (350 mg, 34% yield) as a white solid, mp 178−179 °C. 1H NMR (300 MHz, DMSO-d6): δ 7.54−6.93 (m, 4H), 2.96 (d, J = 21.5 Hz, 2H). 13C NMR (75 MHz, DMSO-d6): δ 137.0 (d, J = 8.6 Hz), 132.5 (d, J = 3.4 Hz), 129.8 (d, J = 2.8 Hz), 129.4 (d, J = 6.2 Hz), 128.5 (d, J = 6.4 Hz), 125.8 (d, J = 3.4 Hz), 34.9 (d, J = 131.2 Hz). 31P NMR (122 MHz, DMSO-d6): δ 20.01 (t, J = 21.0 Hz). IR (KBr, ν /cm−1): 2923 (br), 1596, 1570, 1428, 1410, 1270. MS (ESI): [M + H]+ 207. 2-Chlorobenzylphosphonic Acid (1c).55 Compound 1c was synthesized from diethyl 2-chlorobenzylphosphonate (3c, 2 g, 7.6 mmol), KI (1.34 g, 22.8 mmol) and TMSCl (2.90 mL, 22.8 mmol) in MeCN (10 mL). Purification afforded 1c (575 mg, 37% yield) as a white solid, mp 184−185 °C (lit.55 mp 183 °C). 1H NMR (300 MHz, DMSO-d6): δ 7.42 (t, J = 6.9 Hz, 2H), 7.25 (dq, J = 14.9, 7.3 Hz, 2H), 3.14 (d, J = 21.7 Hz, 2H). 13C NMR (75 MHz, DMSO-d6): δ 133.3 (d, J = 7.9 Hz), 132.3 (d, J = 8.6 Hz), 131.8 (d, J = 5.0 Hz), 129.1 (d, J = 2.8 Hz), 127.8 (d, J = 3.4 Hz), 126.7 (d, J = 3.2 Hz), 32.5 (d, J = 132.4 Hz). 31P NMR (122 MHz, DMSO-d6): δ 20.00 (t, J = 21.2 Hz). IR (KBr ν/cm−1): 2923 (br), 1413, 1265, 1096, 1016. MS (ESI): [M + H]+ 207. 3-Hydroxybenzylphosphonic Acid (4b).56 Compound 4b was synthesized from diethyl 3-methoxybenzyl phosphonate (18b, 2 g, 7.7 mmol), KI (2.68 g, 45.6 mmol), and TMSCl (5.80 mL, 45.6 mmol) in MeCN (15 mL). Purification afforded 4b (101 mg, 8% yield) as a white solid, mp 220−222 °C. 1H NMR (300 MHz, CD3OD): δ 7.11 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 3.1 Hz, 2H), 6.67 (d, J = 8.1 Hz, 1H), 3.05 (d, J = 21.7 Hz, 2H). 13C NMR (75 MHz, CD3OD): δ 158.7, 136.0, 135.8, 130.6, 130.6, 122.5, 122.4, 118.2, 118.1, 114.8, 114.8, 37.0, 35.2. IR (KBr, ν/cm−1): 2935 (br), 1615, 1604, 1515. MS (ESI): [M + H]+ calcd, 189.0317; found, 189.0311. 2-Hydroxybenzylphosphonic Acid (4c).56 Compound 4c was synthesized from diethyl 2-methoxybenzyl phosphonate (18c, 2 g, 7.7 mmol), KI (1.34 g, 22.8 mmol), and TMSCl (2.90 mL, 22.8 mmol) in MeCN (10 mL). Purification afforded 4c (250 mg, 19% yield) as a white solid, mp 135−137 °C. (lit.56 mp 132 °C). 1H NMR (300 MHz, DMSO-d6): δ 7.55 (s, 6H), 7.23−7.13 (m, 1H), 7.03 (tt, J = 7.7, 1.9 Hz, 1H), 6.85−6.64 (m, 2H), 2.97 (d, J = 21.1 Hz, 2H). 13C NMR (75 MHz, DMSO-d6): δ 155.4 (d, J = 6.3 Hz), 131.2 (d, J = 6.1 Hz), 127.2 (d, J = 3.1 Hz), 120.6 (d, J = 8.4 Hz), 119.0 (d, J = 2.6 Hz), 116.0 (d, J = 2.6 Hz), 29.6 (d, J = 134.0 Hz). IR (KBr, ν/cm−1): 2900 (br), 1600, 1520, 1400, 1309, 1183, 1151. MS (ESI): [M + H]+ 189. Photochemical Experiments. Irradiations of 1a−c were performed by using nitrogen-purged solutions in quartz tubes in a multilamp reactor fitted with ten 15 W phosphor-coated Hg lamps (maximum of emission at 310 nm) or with four 15 W low-pressure Hg lamps (maximum of emission at 254 nm). Quantum yields were measured at 254 nm (1 Hg lamp, 15W). Solvents of HPLC purity were employed. The reaction course was followed by both GC and HPLC analyses. Compounds 4a−c and 5 were identified by comparison with either commercially available (4a and 5) or synthesized (4b and 4c) samples and quantified via HPLC analyses. Compounds 6,20 7,20 8,20 9 (MS (m/z) 148 (M+, 88), 133 (19), 105 (83), 91 (89), 43 (100)), 10,22 11 (MS (m/z) 131 (M+, 18), 91 (100), 65 (15)), and 1220 were identified by means of GC−MS analyses and quantified by comparison with commercially available authentic samples. The acidity released was determined by 5 mL of the photolyzed solutions diluted with water (25 mL) and titrated with aqueous 0.1 M NaOH by means of a potentiometer equipped with a pH glass combined electrode module. The release of the phosphate anion was determined via HPLC ion chromatography and quantified by means of a calibration curve obtained with a commercially available phosphate salt.

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1 H and 13C NMR spectra of new compounds and computational studies. HPLC and GC data for the examined compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +39 0382 987198. Fax: +39 0382 987323. ORCID

Stefano Crespi: 0000-0002-0279-4903 Stefano Protti: 0000-0002-5313-5692 Davide Ravelli: 0000-0003-2201-4828 Daniele Merli: 0000-0003-3975-0127 Maurizio Fagnoni: 0000-0003-0247-7585 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Fondazione Cariplo (grant no. 2011-1839). We are grateful to B. Mannucci and F. Corana (Centro Grandi Strumenti−Pavia) for the valuable assistance. This work was funded by the CINECA Supercomputer Center, with computer time granted by ISCRA projects (code HP10CBEIAU).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01963. 12171


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Sugar-Assisted Photogeneration of Didehydrotoluenes from

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