Photochemistry_of_Organic

Scheme 6.60

In addition, UVA radiation can also cause DNA damage in an indirect process that apparently involves singlet oxygen production733 (Section 6.7.1), due to some yet unidentified endogenous photosensitizers present in the cells.

Special Topic 6.8: Photochemotherapy – treatment of psoriasis

Psoriasis (hyperproliferation of skin cells), one of the least understood skin illnesses of humans, can be treated by a variety of methods of questionable reliability. Aside from conventional topical treatment or medications taken internally, phototherapy (nonburning exposure to sunlight; see also Special Topic 6.2) and photochemotherapy, the

oral or topical administration of psoralen (136; Scheme 6.61) or related compounds and subsequent exposure of the skin to UVA radiation (315–380 nm),736,737 can be

successful in healing patients. Several different mechanisms by which photochemotherapy normalizes psoriatic skin have been proposed but their relative importance is not known. The intrinsic photoreactivity of psoralen derivatives is determined by the electronic structure of their lowest singlet and triplet p,p excited states. They may be responsible for the production of reactive singlet oxygen (Section 6.7.1), intercalate with the pyrimidine bases of DNA or react with proteins, lipid membranes, enzymes and other biologically important molecules. Such processes then slow down the abnormally rapid production of psoriatic skin cells. [2 þ 2] Photocycloadditions are the most common psoralen photoaddition reactions, such as the formation of two different dimers with thymine of DNA. Unfortunately, long-term photochemotherapy

treatment was found to be associated with the development of some types of skin cancers (Special Topic 6.22).

Scheme 6.61

The photo-Bergman reaction (cycloaromatization),738 a photochemically initiated intramolecular reaction of enediynes, consisting of two alkyne moieties connected via an unsaturated bond, is an interesting reaction producing 1,4-dehydrobenzene systems with biradical character.739 For example, irradiation of 1,2-di(pent-1-ynyl)benzene (137) at >313 nm in the presence of propan-2-ol as a hydrogen donor ([H]) gives 2,3- dipropylnaphthalene (138) in 25% chemical yield (at 50% conversion; Scheme 6.62).740 The proposed radical mechanism of this transformation was based on triplet sensitization studies and laser flash photolysis experiments. The cycloaddition – formation of the bond between the radicals in 1,4-dehydrobenzene – cannot be completed because of extreme steric demands. A transition metal-catalysed cycloaromatization is also shown in Scheme 6.289.

Scheme 6.62

6.1.6 a,b-Unsaturated Ketones (enones): Photocycloaddition

and Photorearrangement

O O

hν

+

However, the lowest energy triplet state of cyclic enones is a 3p,p state, not a 3n,p state,761 and it is now believed that the regioselectivity in adduct formation rather reflects differences in the efficiencies of cyclization to products and the efficiencies of

regeneration of the starting material via fragmentation of the singlet 1,4-biradicals (Scheme 6.63).741,743,762 For example, [2 þ 2] photocycloaddition of cyclopentanone

to ethyl vinyl ether in benzene gives two products, head-to-tail (HT; 139) and head-to- head (HH; 140) adducts, in a 3:1 concentration ratio (Scheme 6.65),762 which is well in accord with the above-mentioned preoriented exciplex model.759 As expected, no products derived from the 1,4-biradicals containing a poorly stabilized primary radical centre (141 and 142) are obtained. However, radical trapping experiments revealed that the HT and HH 1,4-biradicals are produced in an equimolar ratio. It was concluded that the cyclization of the HT biradical must be more efficient than fragmentation (Fc > Ff), in contrast to that of the HH biradical, which possibly relates to different populations of extended versus closed conformations of the biradicals.

This mechanistic explanation of regioselectivity could be applied to many other systems.741,743

Scheme 6.65

Case Study 6.12: Organic synthesis – construction of the AB-ring core of paclitaxel

A new method for the construction of the AB-ring core of paclitaxel (Taxol), an anticancer drug, was developed utilizing the cyclopentanone (143)–allene (144) photocycloaddition reaction to give the bicyclic product 145, which was subsequently transformed to a bicyclic diketone 146 in several steps (Scheme 6.66) in 42% overall chemical yield.763

The photocycloadditions of alkenes with the enol form of 1,3-diketones or 1,2-diketones, referred to as the de Mayo reaction,760,767 also gives cyclobutane derivatives.742,749 It is assumed that the mechanism of this reaction involves a triplet

excited dione, possibly an exciplex, and 1,4-biradical intermediates (see also Scheme 6.63).749 Intramolecular regioselective photocycloaddition of the enol acetate 153, as an example of the enolate derived from a 1,3-diketone, leads to the tricyclic adduct 154 in quantitative yield, which undergoes annulation to form a large (eightmembered) ring (see also Special Topic 6.14) of bicycloundecanedione (155) in the presence of a base (Scheme 6.68).768 In another example, an enolized 1,3-diketone group undergoes intramolecular [2 þ 2] photocycloaddition to an enamine moiety of the isoquinolone 156 to form 157 via an unstable adduct 158 in 35% overall chemical yield (Scheme 6.69).769

Scheme 6.69

Cyclic enones, such as substituted cyclohex-2-enones or cyclohexa-2,5-diones, also undergo sigmatropic photorearrangement to form bicyclo[3.1.0]hexanones (lumiketones)

or bicyclo[3.1.0]hex-3-en-2-ones, respectively, for which both concerted and stepwise (biradical) reaction mechanisms have been proposed.640,641,770 For example, a [1,2]-shift

concurrently with the ring contraction (termed the type A reaction) is observed upon

irradiation of the methylphenyl derivative 159 in polar solvents, whereas phenyl migration (termed the type B reaction) predominates in nonpolar solvents (Scheme 6.70).771,772 The

reactions are believed to proceed via both the p,p and n,p triplet ketone states. In the presence of alkenes, cyclic enones may readily undergo a competitive photocycloaddition reaction (Section 6.1.5).

O

Scheme 6.70

Photorearrangements in the crystalline state773 usually afford products with very high selectivity (Special Topic 6.5). Whereas irradiation of 4,4,5-triarylcyclohex-2-enone (160) in benzene solution affords a 1:1 ratio of phenyl to p-cyanophenyl migration to form 161 and 162, the former product is produced exclusively in the solid state (Scheme 6.71).755

NC

O

Scheme 6.71

Photochemistry of cross-conjugated cyclohexa-2,5-diones has historically served to explain the mechanism of some primary photochemical processes774 and later it has been successfully utilized in organic synthesis.775–777 In general, bicyclo[3.1.0]hex-3-en-2- ones 163 are formed from cyclohexa-2,5-diones 164 via the triplet n,p excited states of biradical character and the ground-state zwitterion intermediate.775 This photoprocess can be designated a sigmatropic [1,4]-shift (Scheme 6.72), the equivalent of the type A rearrangement of cyclohex-2-enones (Scheme 6.70).

Santonin (165), a well-studied photochemically active compound, undergoes a number of photorearrangements. The [1,4]-shift product lumisantonin (166) is obtained in 64%

chemical yield in dioxane, whereas a subsequent rearrangement product, photosantonic acid (167), is formed in protic media (Scheme 6.73).778,779

and 1Ba (in order of increasing energy for benzene and naphthalene). Because the lowest excited singlet state mostly determines the photophysical and photochemical properties (Kasha s rule, Section 2.1.8), it is essential to note that the HOMO–LUMO transition (1La) does not correspond to the lowest excited singlet state (1Lb) in benzene and naphthalene and many of their derivatives. The absorption spectra of the linear acenes (benzene, naphthalene, anthracene, etc.) are shown in Figure 4.16. The 1La bands of larger systems (tetracene, pentacene, etc.) lie in the visible region, giving rise to the characteristic colour of these compounds. The lowest triplet state is of 1La character in all benzenoid hydrocarbons.

The fluorescence rate constants of aromatic compounds predicted by Equation 2.11 differ by about two orders of magnitude depending on the nature of the lowest singlet state; the smaller representatives with S1 ¼ 1Lb have kf 2 106 s 1 and the larger ones with S1 ¼ 1La have kf 3 108 s 1. Rate constants of IC and ISC are small in the parent hydrocarbons. Using the rules-of-thumb given by Equations 2.22 and 2.23, one predicts log(kIC/s 1) log(kISC/s 1) 6. Therefore, benzenoid aromatic compounds exhibit substantial fluorescence, with quantum yields approaching unity in compounds with S1 ¼ 1La, and appreciable triplet yields. The quantum yields of fluorescence and ISC add up to less than unity in the larger members, because the rate constant of nonradiative decay, kIC, increases as the energy gap E(S1) E(S0) decreases. Due to the long lifetimes of S1 in the smaller benzenoid compounds,1t 102 ns, ISC may be accelerated by diffusional encounters with oxygen.

Rates of ISC are increased upon substitution with heavy atoms (Br, I) or with functional groups that have low-lying n,p states (carbonyls, nitro groups, diazines). The absorption spectra of some nitrogen-containing benzene derivatives are shown later in Figure 6.8.

The first absorption band of nonalternant hydrocarbons and the band shifts induced by substitution are generally well described by HMO theory (Section 4.7). Absorption to S1 corresponds to the HOMO–LUMO transition. Nonradiative decay often dominates the photophysical properties of nonalternant hydrocarbons and also alternant hydrocarbons with a 4n-membered ring (biphenylene), so that they generally have short singlet lifetimes and low triplet yields and are less prone to undergo photoreactions upon direct irradiation.

Table 6.4 shows the principal photoreactions of aromatic compounds that we discuss in this chapter. Upon irradiation, aromatic compounds, such as benzenes, naphthalenes and some of their heterocyclic analogues, undergo remarkable rearrangements that lead to some non-aromatic highly strained products, such as benzvalene and Dewar benzene (entry 1), which can be isolated under specific conditions. Quantum and chemical reaction yields are usually low; however, photochemistry may still represent the most convenient way for their preparation. While bulky ring substituents usually enhance the stability of those products, aromatic hydrocarbons substituted with less sterically demanding substituents exhibit ring isomerization (phototransposition) (entry 2).

Excited aromatic compounds are also capable of undergoing bimolecular reactions, which are not observed in the ground state. Stepwise regioselective photocycloadditions to alkenes, for example [2 þ 2] photocycloaddition (entry 3), involving short-lived intermediates, provide access to various bicyclic and tricyclic unsaturated hydrocarbons. When an aromatic moiety bears a leaving group, its substitution by nucleophiles (entry 4) is readily available upon excitation. Variations in the nature of the electronically excited state, directing and activating the effects of the ring substituents, and also experimental