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Final 1.0, 4/13/2004 Excited State Reactions of Carbonyl Compounds 9. 1. Introduction In this chapter we shall focus mainly on ketones and aldehydes. In the ground state, the basic chemistry of the carbonyl chromophore is to a large extent independent of the nature of the groups (aryl or alkyl) attached to the carbonyl carbon. These groups by altering the electronic nature of the lowest excited state can however have an enormous influence on the excited state chemical and physical behavior of the carbonyl chromophore. In general, it is important to gain an understanding of the factors that control the nature of the lowest excited state and also to obtain a model for the electronic configuration of the reactive state. In a photochemical reaction a reactant is transformed into a product but between these two there are many events that need to be understood. The primary questions (Figure 9.1) one should ask during analysis of a photoreaction are (a) What are the products of the photoreaction? (b) What are the electronic characters of the reactive state? (c) What are the spin characters of the reactive state? (d) What intermediates are involved in the reaction? (e) What orbitals are involved and how do they interact during the chemical transformation? (f) What are the various chemical and physical processes and what are their rates with which a reaction of interest competes? hn R P hn *R R hn R 1*R ISC P I 3*R 3I ISC 1I P Figure 9.1 1 Final 1.0, 4/13/2004 9. 2. Reactive State The electrons that are of importance in deciding the reactivity of the carbonyl chromophore are the two lone pairs on the oxygen and the two electrons in the p-bond connecting the carbon and oxygen. Excitation of a lone pair electron to the p* level results in an np* excited state. Similar excitation of a p-electron to the p* level results in a pp* excited state. Each of these singlet excited states (np* and pp*) has a corresponding triplet state. For example, acetone’s lowest singlet excited state is np* in nature and the second excited state in the singlet manifold is of pp* character. In the triplet manifold there will be the corresponding np* and pp* states. Since, in the case of dialkyl ketones, the energy difference between np* and pp* singlets is large, the ordering of the nature of the states is preserved in the triplet manifold as well. Thus, the reactive states, namely the lowest excited singlet and lowest excited triplet states, of dialkyl ketones are of np* character. This ordering is rarely altered by either the medium or by alkyl group substitution. The energy diagrams for acetone and biacetyl are shown in Figure 9.2. It is important to note that the rates of photophysical processes from S1 (intersystem crossing from S1 to T1 as well as radiative transition to S0 ) are not very high suggesting that dialkyl ketones (for which we have taken acetone as an examplar) can react, under favorable conditions, from both S1 and T1. The state energy diagram for benzophenone is shown in Figure 5.16. An important point to note is that the gap between the 1 np* and 1 pp* states for benzophenone is smaller than for acetone. The expected splitting between 1 pp* and the corresponding 3 pp* being much larger than that between the np* states, a closer 1 pp* and 1 np* states result in 3 pp* being lower than 1 np*. Under such conditions, as discussed in Chapter 5 the intersystem crossing rate from S1(np*) to T1(pp*) is much larger (El Sayed’s rule). Hence we would predict that diaryl ketones (aryl alkyl ketones as well) would react only from T1 but not from S1. If a reaction is to take place from S1 it should be able to compete with the very fast intersystem crossing process (>101 0 sec-1). Such could be expected for intramolecular but not for intermolecular reactions. 2 Final 1.0, 4/13/2004 O Figure 9. 2 Figure 5.15 and 5.10 (reproduced) 3 Final 1.0, 4/13/2004 The magnitude of the gap between 1 np* and 1 pp* states can also have an impact on the ordering of the states in the triplet manifold. As seen in Figure 5.10 a decrease in the 1 np* and 1 pp* gap results in 3 pp* being lower than 3 np* state. Thus depending on the nature of the aryl group (e.g., phenyl, naphthyl, or anthryl group), the electronic configuration of the lowest excited singlet as well as triplet states can change and this will influence the rate of intersystem crossing. For example, while for acetophenone and benzophenone the lowest triplet has np* character that for pyrenealdehyde, 2-acetonaphthone and fluorenone the lowest triplet is pp* in character. The subtle dependence on the nature of the lowest excited state for a number of acetophenones, benzophenones and valerophenones on the substituent is listed in Table 9. 1. From the table it is clear that the triplet lifetime is very much dependent on the substituent on the aryl ring. For example, the triplet lifetime of valerophenone (VP) in 2-methylpentane at 77°K is 0.0064 sec while that for 4-methoxy VP is 0.45 sec. This large difference is due to the difference in nature of the emitting state in these two cases. While in VP it is np* that in 4-methoxy VP it is pp*. A point to note is that in all cases the emitting states may not be such ‘pure’ states. For example, 4-methyl VP and 4-fluoro VP have lifetimes of 0.13 and 0.039 sec, in between that of VP and 4-methoxy VP. Such intermediate values indicate that the emitting states are not ‘pure’ np* and pp* states but a mixture of the two (for a discussion on state mixing see sections 5.8-5.10). Another point to note from Table 9. 1 is that the ketones may show two emissions with different lifetimes. These come from two close lying T1 and T2 states having different extents of np* and pp* character. In general, electron-donating substituents such as CH3 and OCH3 stabilize the pp* state, and electron withdrawing groups such as CF3 and CN stabilize the np* state. State configuration mixing is a common phenomenon with most chromophores (Chapter 5). The extent of mixing depends on the energy gap between the two states and availability of a vibration that would mix the two electronic configurations. Therefore, it is important to recognize that no excited state can be represented by a single configuration, especially so when there is another excited state within 5 kcal/mole. 9.3. Electronic Configuration of Reactive States 4 Final 1.0, 4/13/2004 In the ground electronic configuration, the electrons present in the p-orbital of a carbonyl chromophore are polarized in such a way that the carbonyl carbon is positively polarized. Most reactions of the carbonyl chromophore in the ground state can be understood on the basis of this simple model. The non-bonding lone pair present on the oxygen is nucleophilic, and many electrophilic reactions with the carbonyl chromophore evolve from this face (n-face). Just like the ground state, the carbonyl chromophore possessing an np* electronic configuration is also a bipolar species, but the dipole is reduced relative to that of the ground state. For example, the dipole moment of benzophenone in the ground state is 2.9 D while that in the np* triplet state is 2.1 D. The double bond character of the carbonyl chromophore is reduced in the np* state compared to that in the ground state. This is also indicated by the C=O stretching frequency in the case of 4-trifluoromethylacetophenone and benzophenone both of which have np* as the lowest triplets. For 4-trifluoromethylacetophenone the C=O stretching in the ground state is 1696 cm-1 while that in the np* state is 1326 cm-1. For benzophenone the C=O stretching frequency in the S0 and T1 states are 1665 and 1222 cm-1. In the np* excited state a chemical reaction can occur either along the n-or p-plane. The characteristics of the orbital involved being different, different reactivities are expected on these two planes. The np* state is both electrophilic and radical-like in the plane containing the n-orbital (Figure 6.13; Chapter 6). The p-plane, which contains 3 electrons, is electron rich and nucleophilic. Although the overall dipole moment is still towards oxygen, in the p* orbital the carbonyl carbon is electron rich compared to oxygen. (Remember that a nonbonding electron from oxygen has been removed and placed between the two atoms to be shared). This simple picture of the np* state holds true for both dialkyl, aryl alkyl and diaryl carbonyl compounds. In the latter two systems the p* orbital is delocalized into the aryl ring while in the dialkyl ketones this is localized on the C=O chromophore. This difference in the character of the p* orbital does not alter the general reactivity of the carbonyl chromophore along the n-orbital. The frontier orbital diagram for the np* state along with the orbital levels of a few generic molecules is is shown in Figure 9.3. Based on this picture, the singly occupied n-orbital which may be considered to be in need of an electron is expected to interact with a filled C–C s bond, a C–H s bond, a C=C p-bond, or a pair of 5 Final 1.0, 4/13/2004 non-bonded electrons. Since the second p-orbital which is required to complete product formation is in a plane perpendicular to the n-orbital, the interaction between n-orbital and filled s, p or n-orbital alone is not sufficient to form a stable product. Therefore the interactions shown in Figure 9.3 are expected to result in an intermediate such as diradical or radical ion pair. Figure 9.3 lists also n-orbital initiated reactions of carbonyl compounds. (Electron poor olefin) Oxetane p*C=C (Electron rich olefin) Oxetane pC=C p* s*CC b-Cleavage nN (lone pair) Electron Transfer n sCH a-Cleavage sCC Hydrogen abstraction p Figure 9. 3 The singly occupied p* orbital is higher in energy and is more willing to donate or share its electron with a center carrying a lower lying empty orbital (LUMO) (Figure 9.3). For example, the p* orbital of the carbonyl would be expected to interact with the p* orbital of electron poor alkenes and s* orbital of a weak C—C bond. Since in the p* orbital the carbon center is more electron rich than the oxygen end of the carbonyl chromophore, a nucleophilic attack will be initiated by the carbon center. Expected reactions from this type of interaction are listed in Figure 9.3. 6 Final 1.0, 4/13/2004 In the pp* state the lone pair (n-orbital) on the oxygen remains intact, and there are electronic changes only on the p-face. Although on the basis of first principles one might expect the pp* excited carbonyl to behave similar to an alkene, the fact that the electron distribution in p and p* orbitals is unequal between carbon and oxygen of the C=O bond would make it behave slightly differently. Since neither 1 pp* nor 3 pp* are the lowest excited states in alkyl ketones and aldehydes we will not consider these further. On the other hand, depending on the nature of the aryl group and the substituent on the aryl ring, the pp* triplet could become the lowest state in aryl and diaryl ketones. In these systems both p and p* orbitals are delocalized into the aryl ring. Because of this, the pp* state of aryl and diaryl ketones are likely to be less reactive than the np* triplet. The frontier orbital interaction diagram for pp* excited state is shown in Figure 9.4. Based on the interactions shown electron transfer, hydrogen abstraction, [2+2] addition, and b-cleavge are expected. The dipole moment of pp* triplets of several aryl ketones have been estimated to be higher than that in the ground state. For example, the dipole moment of 2,5-dimethoxybenzaldehyde is 3.0 and 4.5 in S0 and T1 (pp*) states. This suggests that in the pp* state the electron density is shifted from the aryl ring to the carbonyl chromophore. Although the electron density is shifted from the ring to the chromophore, in the p* state still the carbon (of C=O) is more electron rich than the oxygen. As indicated by the IR frequency of the C=O stretching, the double bond character in the T1 (pp*) state is reduced but not to the same degree as in T1 (np*) state. The C=O stretching frequencies for 4-methoxy acetophenone in S0 and T1 (pp*) states are 1676 and 1462 cm-1 respectively. 9.4. A Close Analogue of the Reactive np* Carbonyl Chromophore The closest chemical analogue of an np* excited carbonyl chromophore is an alkoxy radical. The two are compared in Figure 9.5. Like the oxygen atom of an np* excited carbonyl compound, oxygen of the alkoxy radical contains a reactive half filled n-orbital. If one ignores the p-face of the np* excited carbonyl group, the close similarity between alkoxy radicals and np* excited carbonyl compounds is obvious. Assuming for a moment that this is true, we can predict the reactivity of np* excited carbonyl compounds on the basis of the behavior of alkoxy radicals. Alkoxy radicals (a) abstract hydrogen from hydrocarbons, and (b) 7 Final 1.0, 4/13/2004 undergo cleavage of the s-bond connected to the alkoxy carbon (b-cleavage) and (c) react with alkenes. The np* excited carbonyl chromophore also undergoes all these reactions. Hydrogen abstraction Addition to C=C bond a-Cleavage Figure 9.5 9. 5. Photoreduction: Addition to a C—H bond Reduction in the ground state is one of the most useful reactions of carbonyl chromophore. A number of reagents have been developed to selectively reduce carbonyl chromophores present as a part of various functional groups (ester vs. ketone etc.). However, one can‘t selectively reduce in the ground state, for example, acetophenone in presence of 4-methoxy acetophenone or acetone in presence of acetophenone. But these processes can be carried out photochemically. Photochemical reduction of carbonyl compounds is a useful complimentary method to the numerous thermal methods. In addition to its synthetic utility, since this is one of the ubiquitous reactions excited ketones and aldehydes undergo in almost any organic solvent, one needs to understand the mechanisms of photochemical hydrogen abstraction by carbonyl compounds. The irradiation of ketones and aldehydes in the presence of hydrogen-atom-donating substrates (alcohols, hydrocarbons, amines etc.) commonly results in the photochemical process of hydrogen abstraction, followed by product formation via secondary thermal reactions (Scheme 9.1). The primary bond-forming step in this transformation is the addition of a hydrogen atom to the C=O chromophore to form a new O—H bond. Formation of a new O—H bond can occur by way of two mechanisms: (a) direct abstraction of a hydrogen atom (Scheme 9.1), or (b) an electron transfer followed by a proton transfer (Scheme 9.2). The reduction occurs from both np* and pp* states. The characteristics of these two processes are slightly different, and will also be discussed in this section. 8 Final 1.0, 4/13/2004 OH Ph hn O + 2 Ph2CHOH Ph Ph Ph Ph C Ph HO OH Ph Ph OH Ph CH3 + C hn + O Ph PhCH2 Ph Ph Ph OH Ph Ph Ph OH Ph OH + PhCH2CH2Ph + Ph H OH Ph2C = O + hn CH3OH + HOH2C Ph C CH2OH Ph OH H O + C Ph Ph Ph OH Ph OH C O OH Ph + H Ph Ph hn CH3 Ph C PhC H OH OH OH Ph + CH3 Ph CH2OH OH Ph + CH3 C CH3 H O Ph Ph C Ph OH OH O Ph Ph Ph Ph C Ph + CH3 C CH3 OH Scheme 9.1 9 Final 1.0, 4/13/2004 *3 O Ph C Ph Ph + (CH3)2NPh C Ph O N Ph Ph proton transfer Ph C CH3 OH + CH2 N CH3 Ph CH3 OH OH Ph CH Ph C Ph Ph Scheme 9.2 9. 6. Photoreduction of carbonyl in the np* state via hydrogen abstraction Benzophenone is photoreduced by a number of hydrogen atom donors such as isopropanol, benzhydrol, ethers and toluene (Scheme 9.1). Both chemical and physical evidence support the fact that the reactive state is the triplet np* state (see Chapter 8). The key primary intermediate in all these reactions is a benzophenone ketyl radical. Direct spectroscopic evidence for the benzophenone ketyl radical is available from time resolved ESR, transient absorption, and transient emission studies. OH OH coupling O OH OH hn 2 OH OH + disproportionation H O hydrogen transfer OH + H Scheme 9.3 10 Final 1.0, 4/13/2004 In principle, when two radicals meet, three processes can occur: a reverse hydrogen transfer to yield the starting reactants, a radical coupling reaction to yield a coupling product, and a disproportionation reaction to yield oxidation-reduction products (Scheme 9.3). Which pathway is preferred depends on the radical pair. For example, during the photoreduction of benzophenone inspite of the np* triplet being the reactive state and the benzophenone ketyl radical the primary intermediate, the ultimate product isolated varies depending on the nature of the hydrogen donor and the conditions used for irradiation. When benzophenone is irradiated in toluene, one isolates three products, benzpinacol, 1,2-diphenylethane and diphenyl benzyl carbinol (Scheme 9.1). Formation of these three products is easily understood on the basis of the intermediacy of benzophenone ketyl radical and benzyl radical. For example, when methanol is used as the hydrogen source, benzpinacol, mixed pinacol and a product dervied from a para coupling reaction are obtained (Scheme 9.1). Based on what we know about the photophysics of dialkyl, aryl alkyl and diaryl ketones/aldehydes (see Section 9.2), we can predict that aryl-alkyl and diaryl ketones and aryl aldehydes will react only from their triplet states, whereas hydrogen abstraction from the S1 and T1 states of dialkyl ketones is likely. This is what has been found experimentally. For example, in the case of acetone the S1 and T1 states are both reduced by iso-propanol and tributyl tin hydride. The rate of hydrogen abstraction in the S1 state is slightly higher than in T1 . In spite of the higher rate of hydrogen abstraction in the S1 state the quantum yield of reduction product formation is lower in S1 state than in T1 state. The rates of hydrogen abstraction by acetone in S1 and T1 states from iso-propanol are 9.1x106 and 1x106 M-1s-1 and from tributyl tin hydride are 1x109 M-1s-1 and 5.4x108 M1 -1 s respectively. The lower efficiency (<25%) of product formation from S1 in spite of higher rate of hydrogen abstraction could be due to fast back hydrogen transfer between the singlet geminate radical pair (Scheme 9.3). The photoreduction of acetone by iso-propanol results in products from both coupling and disproportionation. The occurrence of disproportionation is not apparent in the analysis of the products of photoreduction, since the enol is unstable under the reaction conditions (Scheme 9.3). The formation of enols in intermolecular hydrogen abstraction reactions was first discovered by the observation of 1 H-NMR signals ascribable to enols in CIDNP experiments. Confirmation that disproportionation of the radical pair can occur 11 Final 1.0, 4/13/2004 via abstraction of a hydrogen atom from the carbon rather than the oxygen of the acetone ketyl radical intermediate has been obtained by product analyses in which d6 -acetone was irradiated in isopropanol to give deuterated isopropanol. The CIDNP experiments established that the enol products are stable for seconds at room temperature. In fact, irradiation at -70° C yields a stable acetone enol that has been characterzied by NMR. This technique of generating enols has been used to determine the equilibrium constants for keto-enol tautomerism for a number of ketones and aldehydes. From the above presentation it is clear that ketones abstract hydrogens from hydrogen donors to yield radical intermediates. Hydrogen abstraction is also one of the primary reactions of the alkoxy radical. Note that the relative rates of hydrogen atom abstraction by triplet benzophenone and t-butoxy radical are in the similar range (Scheme 9.4). Ph OH hn O Ph2CHOH Ph Ph C Ph HO Ph Ph Ph OH Ph Rate of hydrogen abstraction by triplet benzophenone: 5x106 M-1s-1 Solvent Reaction Rate constant (M-1 s-1) ButO• + PhCH3 ButOH + PhCH 2• Benzene/ t- 2.3 x 105 butyl peroxide ButO• + PhCH2 CH3 ButOH + PhCH(•)CH3 Benzene/ t- 1.05 x 106 butyl peroxide ButO• + CH 3CHOHCH3 ButOH + CH3 C(•)OHCH3 Benzene/ t- 1.8 x 106 butyl peroxide t Bu O• + Benzene/ t- t Bu OH + 5.4 x 107 butyl peroxide Scheme 9.4 12 Final 1.0, 4/13/2004 Table 9.2 summarizes some experimental data for the quenching (kq ) of np* triplets of three ketones with varying triplet energies by hydrogen atom donors of different bond strengths. The range of values spans several orders of magnitude. For substrates possessing strong C—H bonds (e.g., acetone, acetonitrile), hydrogen abstraction is extremely inefficient (kq <103 ). For a given donor, the ketone with the higher triplet energy has a higher kq . This is evident when one compares the kq values for the quenching of acetone and biacetyl triplets by iso-propanol. The difference in triplet energy of ~30 kcal/mole reduces the kq values by two orders of magnitude. Thus np* hydrogen abstraction is subject to the simple rules of thermodynamics, i.e. (a) more stable the intermediate radical pairs faster the reaction and (b) more energetic the reactants faster the hydrogen abstraction. A qualitative diagram shown in Figure 9.6 aptly describes the situation. When the energies of the radical pair are higher than the triplet energy of the ketone the hydrogen abstraction would be endothermic and less likely to occur. When the energies of the radical pair is lower than the triplet energy of the ketone the hydrogen abstraction would be exothermic and the reduction is likley to occur. The rate of hydrogen abstraction is related to the exothermicity of the reaction. Figure 9.6 13 Final 1.0, 4/13/2004 Table 9.1 (From MMP, p. 374) 14 Final 1.0, 4/13/2004 9. 7. Photoreduction of the carbonyl pp* state via hydrogen abstraction Reluctant photoreduction of aryl alkyl and diaryl ketones/aldehydes having lowest pp* triplet states is known. A comparsion of the rates of hydrogen abstraction by several substituted acetophenones with varying np* and pp* character is provided in Scheme 9.5. Systems that have low-lying np* triplets certainly react faster (by three orders of magnitude) than the ones with pp* character. When the pp* and np* states are farther apart (>10 kcal/mole) and the lowest excited state is pp*, the reduction is presumed to occur from the ‘pure’ pp* state. Under such conditions, the rate of reduction is lower than that from np* state. Two relevant examples in Scheme 9.5 are benzophenone and para-phenyl benzophenone. Systems with pp* triplet that react slowly are the polynuclear aromatic ketones such as naphthyl phenyl ketones. The observed rate represents the inherent hydrogen abstraction ability of a carbonyl in the ‘pure’ pp* state (~103 M-1s-1). kr M-1s-1 O *3 OH 2x106 OH O *3 OH 1x103 OH O *3 OH 1.6x106 OH O *3 OH 1.6x105 OH H3C O H3C *3 OH 3.2x104 OH H3C H3C CH3 CH3 Scheme 9.5 15 Final 1.0, 4/13/2004 Low hydrogen abstraction rate constants do not necessarily mean low quantum yield of photoreduction. Benzophenone and 4-phenyl benzophenone abstract hydrogen from iso-propanol at a rate of 106 and 103 M-1S1 respectively. This is consistent with the lowest excited state being np* in the former and pp* in the latter. In spite of the low rate of hydrogen abstraction a fairly high quantum yield (0.3) of reduction is obtained for 4phenyl benzophenone (p,p* )3 in iso-propanol as the solvent. The high quantum yield arises because, at very high concentrations of hydrogen donor (as the solvent), all the triplets react via hydrogen abstraction: i.e. kr[RH] >> Skd. One can also improve the efficiency of the photoreduction of ketones with low-lying 3 pp* states by using powerful hydrogen donors. For example, naphthyl ketones are photoreduced efficiently by tin hydrides. The Sn—H bond is quite weak, and therefore tin hydrides serve as substrates for photoreduction of even pp* triplets. In the case of 2-acetonaphthone, kr is ~106 M-1 sec-1, i.e., of the order for benzophenone triplets with iso-propanol as a substrate. Why does a pp* excited carbonyl compound have a lower reactivity, and how does a carbonyl group with a low-lying pp* state abstract hydrogen? To answer these questions we need to take a closer look at the nature of the two states (see also Section 9.3 in this chapter). The pp* state is not intrinsically unreactive towards hydrogen donors. It should be noted that a pure pp* states of C=C as well as C=S are capable of abstracting a hydrogen atom from a hydrogen donor (see Section 9.x). In simple terms, hydrogen abstraction may be viewed as a reaction that is initiated by the interaction of a singly occupied orbital of the carbonyl and the C—H s orbital (Figures 9.7 and 9.8). Better interaction leads to a faster rate. The preferred interactions for np* and pp* states are shown Figures 9.7 and 9.8. The np* state being a localized state, the orbital coefficent on the ‘n’ orbital is 1. Therefore, a good overlap between the ‘n’ orbital of C=O and the C—H s orbital is expected. The pp* state certainly cannot beat this situation as the electrons in the p and p* orbitals are delocalized over the carbonyl and the aromatic rings. In other words, since the single electron in the p* orbital is diffused, a rapid attack by C=O on the C—H is unlikely. Of the two centers in C=O, oxygen abstracts the hydrogen as it yields a more stable product (R2 C°–OH) than the one (R2 CH–O°) obtained (R2 CH–O°) via carbon abstracting the hydrogen. This conclusion could also be drawn by analyzing the orbital 16 Final 1.0, 4/13/2004 interaction between p, p* and sC—H orbitals (Figure 9.8). The main interaction that leads to hydrogen abstraction is the one between the partially occupied p of C=O and sC—H orbitals. In the p orbital of the carbonyl, the orbital co-efficient being much larger on oxygen the interaction is expected to occur at this center which would lead to R2 C°–OH. In-plane approach Perpendicular approach X H H s* LUMO X s* LUMO No Bonding p* Large energy gap n E1 E1 p s HOMO H s HOMO C O H C First Excited State (np*) Figure 9.7 17 Final 1.0, 4/13/2004 In-plane approach X X H H O O O H H X X s* LUMO E2 C C O O p* n p C E1 O s HOMO H O C First Excited State (pp*) Figure 9.8 9. 8. Consequences of close-lying np* and pp* triplets When the pp* and np* states are closer (<5 kcal/mole) and the lowest excited state is pp*, the rate of hydrogen abstraction will be higher than that expected for a pp* state but is likely to be lower than that for a pure np* state. This can be understood on the basis of two models: (a) state mixing and (b) state equilibrium (Scheme 9.6; see also sections 4.23). The ‘state mixing’ model assumes that when two states are close-by the two states cannot be ‘pure’ states and each is contaminated by the other. Thus the reactivity of the pp* is 18 Final 1.0, 4/13/2004 borrowed from that of np* character. In the ‘state equilibrium’ model, the pp* reactivity comes from low concentrations of the np* triplet in equilibrium with the lower pp* state (Scheme 9.6). Equations in Scheme 9.6 describes the rate constants for hydrogen abstraction, with the np* state providing most or all of the reactivity when DE between the np* and pp* states is less than 5 kcal/mole. The rate of hydrogen abstraction from isopropanol by 4-trifluoromethylacetophenone (np* triplet) is 8.8x106 M-1sec-1 while that for 4methylacetophenone (pp* triplet) is 6.7x104 M-1sec-1. The reactivity of the two ketones differ by two orders of magnitude clearly illustrating that the pp* (4-methylacetopheone) is less reactive than np* triplet (ptrifluoromethylacetophenone). The fact that acetophenone is in between these two values (2.1x106 M-1sec-1) suggests that the reactive triplet in this case is mixed with pp* character. A point to note is that in spite of having nearly same triplet energy all acetophenones may not abstract hydrogen from the same donor with the same rate. The observed rate is a reflection of the contributions of np* and pp* characters to the reactive state. np *3 + pp *3 Products n p* 3 pp *3 + np *3 p p* 3 Reaction from np* state Activated reaction Rate depends on the gap H Products The two states are not pure Reactivity depends on extent of mixing and np* character n,p k obs = cn,p k H + cp,p k p, p H cn,p = (1 - cp,p) = e-DE/RT 1 + e-DE/RT Scheme 9.6 9. 9. Photoreduction of carbonyl (np* state) via electron and charge transfer Irradiation of benzophenone in tert-butanol leads to no product. On the other hand, irradiation of benzophenone in tert-butyl amine leads to benzpinacol. Benzophenone triplet is not quenched by tert-butanol 19 Final 1.0, 4/13/2004 but it is quenched by tert-butyl amine at ~108 M-1s-1 (benzene solvent). Benzophenone is reduced to benzpinacol by isopropanol with a limiting quantum yield of 2. On the other hand, it is reduced by sec-butyl amine with a limiting quantum yield of 1.2. This reduction in quantum yield occurs in spite of the higher rate of quenching of benzophenone triplet by sec-butyl amine (~108 M-1s-1); compared with ~106 M-1s-1 by isopropanol). The rates of quenching of the excited carbonyls by amines are listed in Table 9.2. Clearly the rates are much higher than by alcohols and the rates show a relationship with the ionization potential than with C–H bond energies. In spite of differences, certain features of the reduction by amines and alcohols are the same. The spin configuration of the reactive state of the carbonyl compound is the same, triplet. The intermediate that has been characterized during reduction by amines is benzophenone ketyl radical, the same one that was identified during the reduction by alcohols. Let us focus on the first step, the interaction between the benzophenone triplet and the reducing agents, amine and alcohol. The first step during the reduction by isopropanol has been identified as the hydrogen atom abstraction. If this is the mechanism by which reduction by amine occurs, one would expect the rate of quenching by amine to be not more than 106 M-1s-1. In fact the rate is higher by two orders of magnitude. The rate of hydrogen abstraction surprisingly is independent of the bond energy of the C—H bond being abstracted. On the other hand, there is a linear correlation between the ionization potential of the amine and the rate of quenching. Such a relationship , suggests that the primary interaction between a carbonyl triplet and an amine has charge transfer character (exciplex) (Scheme 9.7). kE Ar2CO* + R2NCH3 d d [Ar 2CO R 2NCH3]* kr d d [Ar 2CO R 2NCH3]* Ar2COH + R2NCH2 Scheme 9.7 Quantum yields of ketyl radical formation from ketone triplets in which amines are hydrogen donors have been estimated to be near unity. Benzophenone ketyl radical is formed from both tert-butyl amine and 20 Final 1.0, 4/13/2004 triethylamine, indicating that the NH as well as the a CH hydrogens are abstracted readily within the CT complex. In spite of the high quantum yield of benzophenone ketyl radical formation, the overall quantum yield of reduction is low. This is believed to be due to a disproportionation reaction (Scheme 9.8), which is absent when isopropanol is used as the hydrogen source. Ar2C=O*(T 1) + RCH2NR'2 k ir [Ar 2C-O- RCH 2NR'2 ] kh Back electron transfer Ar2C=O + RCH2NR'2 Ar2COH + Proton transfer RCHNR' 2 Disproportionation/ back hydrogen transfer OH Ar C CHNR2 Ar R + Ph HO Ph Ph OH Ph Scheme 9.8 21 Final 1.0, 4/13/2004 The reduction by amines can be visualized as taking place by orbital interaction between the half filled n-orbital of the carbonyl oxygen and the doubly occupied n-orbital of the amine nitrogen (Scheme 9.9). Such an interaction is expected to lead to a flow of an electron from the amine to the carbonyl oxygen. By this process the oxygen gains partial negative charge and becomes the active site for the next step, namely proton transfer. When there is a full electron transfer radical ions are formed and if they escape the cage could be detected by spectroscopic methods such as ESR. The main difference between reduction by an alcohol and an amine is that, in the former process, both an electron and a proton (i.e., hydrogen atom) move simultaneously towards the carbonyl oxygen, whereas in the latter, the proton follows the electron. C O p* p* n n C n p p O NH2 O O H np* pp* O NH2 H Scheme 9.9 9. 10. Photoreduction of carbonyl (pp* state) via electron and charge transfer 22 Final 1.0, 4/13/2004 Fluorenone, para-phenylbenzophenone, 2-acetonaphthone and 4-aminobenzophenone systems with pp* as lowest triplets, which are not reduced efficiently by isopropanol are reduced by sec-butyl amine to the corresponding pinacols. A linear dependence of the quenching rate on the ionization potential of the amine indicates that the quenching mechanism involves an electron flow from the amine to the excited ketone/aldehyde. The quenching may be visualized as occurring through the interaction of the singly occupied p-orbital of the carbonyl group and the lone pair n-orbital of the amine nitrogen (Scheme 9.9). Such an overlap is expected to result in electron transfer from amine to carbonyl to yield R2 C°–O- . Thus independent of the nature of the reactive state (np* or pp*) the resulting intermediate as well as the final products are the same. 9. 11. Competition between hydrogen abstraction and charge transfer Any quenchers that have low oxidation potentials can interact with the excited carbonyl by a charge transfer process. Such a process in principle can lead to photoreduction of the carbonyl chromophore. Example of this type would be the photoreduction of xanthone (np*3 ) and azaxanthone (pp* 3 ) by electron rich alkylbenzenes (Scheme 9.10). The triplets of these two ketones might be quenched by alkylbenzenes such as toluene or para-xylene by either hydrogen or a charge transfer quenching process. The occurrence of photoreduction by charge transfer rather than hydrogen atom abstraction is evidenced by the following observations: • The rate constants for photoreduction by charge-transfer are higher than those expected for radicallike hydrogen atom abstraction, based on an alkoxy radical model (Scheme 9.10). • The quantum yields are solvent-polarity dependent. • pp* states are more efficiently photoreduced by a hydrogen donor capable of reactivity via a charge-transfer mechanism than by hydrogen donors capable only of hydrogen atom transfer. • In favorable cases, direct spectroscopic evidence for radical cations produced by complete electron transfer, can be obtained. 23 Final 1.0, 4/13/2004 xanthone quencher Get (eV) kq (M-1 s-1) 1-axaxanthone ketyl radical Get (eV) kq (M-1 s-1) ketyl radical TOL 1.00 5.8 x 106 0.53 0.66 1.6 x 108 0.38 m-XYL 0.74 4.6 x 107 0.49 0.40 1.1 x 109 0.36 MES 0.71 2.2 x 108 0.45 0.37 3.1x 109 0.46 DUR 0. 44 1.1 x 109 1.0 0.10 1.1 x 1010 0.70 Scheme 9.10 Let us suppose that photoreduction occurs and we wish to determine whether a hydrogen atom abstraction or an electron transfer mechanism is operating. An example of such a case occurs in the photoreduction of acetophenones by alkyl substituted arenes (Scheme 9.11). The products evidently arise from radical coupling, and an electron transfer or a hydrogen abstraction mechanism may be written to rationalize product formation. Of these possibilities, only the hydrogen abstraction process should display a kinetic deuterium isotope effect. Thus, if the reaction rate constant is not sensitive to replacement of C-H by CD, the rate-determining step probably involves electron transfer rather than hydrogen abstraction. Furthermore, we expect that if an electron transfer mechanism operates, the sensitivity of the rate constants to ionization potential will be much greater than expected for a hydrogen abstraction process. 24 Final 1.0, 4/13/2004 O C Ph CH3 T1 (n, p*) Charge transfer + O + CH C Ph CH CH3 OH Hydrogen abstraction Ph C CH3 + C Scheme 9.11 Table 9.3 presents some data on the photoreduction of acetophenone and trifluoromethyl phenyl ketone by toluene and p-xylene. The data is interpreted as follows: Hydrogen abstraction occurs when acetophenone is the reactive species and electron transfer occurs when trifluoromethyl phenyl ketone is the reactive species. This conclusion is consistent with (a) the presence of a large deuterium isotope effect observed in the photoreduction of acetophenone by toluene and the absence of an isotope effect in the photoreduction of trifluoromethyl ketone, and (b) the much greater rate enhancement for the trifluoro ketone as one changes from toluene to p-xylene. The greater inefficiency of photoreduction in the case of the trifluoromethyl phenyl ketone (compare the F of reduction of acetophenone (0.13) and trifluoromethylacetophenone (0.053) by toluene) is interpreted to result from a rapid back electron transfer (to generate ground states) in competition with proton transfer (to generate a radical pair). In general, reduction by hydrogen abstraction occurs when the electron transfer process is endothermic (Rehm-Weller equation) and proceeds via an electron transfer (or charge transfer) pathway when it is exothermic (Scheme 9.12). Whether the reduction will occur at all will depend upon the energetics of the radical products with respect to the triplet energy of the carbonyl system (Figure 9.6) 25 Final 1.0, 4/13/2004 Table 9.3 (from MMP p. 385) 26 Final 1.0, 4/13/2004 O + RH O *3 + RH O *3 + RNH2 OH + R O + RNH2 OH + R O + RNH2 O + RH Scheme 9.12 Charge transfer interaction between excited ketones and even benzene solvent is likely. For example, benzophenone and xanthone triplets are quenched by benzene with rate constants of 1.3x104 M-1s-1 and 5x105 M-1s-1. These quenchings are believed to involve either an interaction between the electrophilic n-orbital and porbitals of benzene or nucleophilic p face of carbonyl and p* orbitals of benzene (Scheme 9.13). O* Scheme 9.13 27 Final 1.0, 4/13/2004 9.12. Intramolecular Photoreduction Intramolecular hydrogen abstraction is no different from the intermolecular process discussed above. Of the various known intramolecular hydrogen abstraction process g- hydrogen (1,5) abstraction is by far the most common process and this is discussed in the next section. When appropriate geometry can be attained during the excited state lifetime abstraction from positions other than g- is also known. Examples of 1,6; 1,7; 1,8; and 1,9 hydrogen abstractions are provided in Scheme 9.14. When there are both g as well as other (b, d, e, etc.) hydrogens available, in general g-hydrogen abstraction is preferred. This is attributed to the ease of formation of a six membered chair-like transition state compared to any other cyclic transition state. All variations of the intermolecular hydrogen abstraction mechanisms are known also in the case of intramolecular hydrogen abstraction: (a) A ketone with pp* excited triplet reacts slower than the one with np* state (Scheme 9.15, eq. 1). (b) The presence of an electron donor on the chain favors charge transfer initiated hydrogen abstraction process (Scheme 9.15, eqs. 2 and 3)). 28 Final 1.0, 4/13/2004 RCH2 O R O O OH hn Ph Ph RO RO HO CH 3 Ph O CH 2 CH C Ph hn Ph hn O OH Ph O Me O O Ph Me O hn O CH 3 Ph HO Ph O O H Ph hn Ph H Ph OH Ph OH Ph + O O Scheme 9.14 29 Final 1.0, 4/13/2004 hn (1) pp* Ph CHPh CHPh Ph O Ph OH Ph OH H O HO hu Ph NMe 2 Od - NMe 2 H Ph d+ NMe 2 HO H Ph OH NMe 2 NMe 2 Ph Ph CO2Me O CO2Me CO2Me N hn HO Z N Ph (2) + + N Ph Z (3) HO Ph Z Ph Ph Ph Z = tosyl or benzoyl Scheme 9.15 9.13. g-Hydrogen abstraction: Norrish Type II reaction and Yang Cyclization Irradiation of 2-pentanone possessing g-hydrogen atoms yields acetone and ethylene (R = CH3 in Scheme 9.16). Products have been rationalized to have risen via a cleavage of the b C—C bond. Since this reaction was originally discovered by Norrish and there was already a Norrish type I reaction (a-cleavge), the new reaction was called the Norrish type II reaction. Yang first isolated cyclobutanols by irradiation of 30 Final 1.0, 4/13/2004 dialkylketones possessing g- hydrogen atoms (Scheme 9.16). Cyclobutanol formation prompted by ghydrogen abstraction is generally called the Yang cyclization. Yang was also the first to work out the correlation between g-hydrogen abstraction, b-cleavage and cyclization. The connection was made through a 1,4-diradical intermediate (Scheme 15). In this section we discuss the mechanism of g-hydrogen abstraction, the reactive state(s) involved, and the identification, characterization and behavior of the 1,4-diradical intermediate. HO OH R hn C R OH R OH O + R R Scheme 9.16 O H O hn OH II HO OH HO + A B Scheme 9.17 Evidence in favor of a diradical intermediate came from irradiation of 6-heptene-2-one. In addition to the expected cyclobutanol photoproduct A, a cyclohexenol derivative B was also isolated (Scheme 9.17). 31 Final 1.0, 4/13/2004 Should the reaction proceed via a concerted process, only cyclobutanol should be formed. The fact that a cyclohexenol accompanies cyclobutanol formation indicates that a 1,4-diradical may be involved (Scheme 9.17). S1(n, p*) T1 (n, p*) H C C CH2 Ph H CH2CH3 O CH3 CH2 CH3 O C C CH2 Ph CH2CH3 CH2 CH3 O C CH2CH3 C Ph CH3 H CH2 CH2 optically pure O hn H C Ph CH2 C PhCOCH 3 CH3 CH2CH3 CH2 + racemic CH2 C CH2CH3 OH CH3 Ph CH2CH3 Scheme 9.18 Another aspect of this reaction became evident when optically pure (+)-4-methyl-1-phenylhexanone was irradiated (Scheme 9.18). The recovered starting ketone following brief irradiation showed loss of optical activity. This can happen only if g-hydrogen abstraction occurs reversibly. Thus, the three common reactions of the 1,4-diradical intermediate are cyclization, cleavage and hydrogen reversal. 32 Final 1.0, 4/13/2004 The 1,4-diradical has been chemically interrogated by several means. The earliest observation involves the solvent dependent behavior of aryl alkyl ketones. For example, the quantum yield of product formation from valerophenone in benzene is 0.4, while in tert-butanol it is 1.0. Further, when an optically active ketone is irradiated in tert-butanol, racemization of the starting material via back hydrogen transfer could be completely suppressed. These two effects have been rationalized on the basis of hydrogen bonding of the tert-butanol to the intermediate 1,4-diradical (Scheme 9.19). The hydrogen bonding is believed to alter the preferred conformation of the 1,4-diradical intermediate and influence the decay process of the 1,4-diradical. Of the three modes of decay, cyclization, cleavage and hydrogen reversal, only reverse hydrogen transfer results in the breakage of the hydrogen bond. Thus the enhanced quantum yield and reduced racemization in hydrogen bonding solvents are the direct result of interception of the 1,4-diradical intermediate by the solvent. Ph O R Ph Solvent H Ph O Solvent R1 R H R1 Racemization O R O H R1 R PhCCH 3 + CH2=C R1 Scheme 9.19 As discussed in Chapter 8, the 1,4-diradical intermediate from aryl alkyl ketones has also been intercepted by reagents such as thiols, methyl methacrylate, di-tert-butyl seleneketone, and HBr (Scheme 8.x). In these cases, the more reactive alkyl radical terminus forms a covalent bond with the trapping agent. Direct spectroscopic detection of the 1,4-diradical has been possible, and the lifetimes of a number of systems have been measured to be in the range of 10–200 ns (Chapter 8). 33 Final 1.0, 4/13/2004 Based on our understanding of the spectroscopy of carbonyl systems (see section 9. 2), we anticipate that dialkyl ketones will undergo g-hydrogen abstraction from both their excited singlet and triplet states, and that aryl alkyl ketones should react through their excited triplets only. This has been found to be true. For example, the g-hydrogen abstraction reaction of 2-hexanone (a dialkyl ketone) cannot be completely quenched by the triplet quencher 1,3-pentadiene. On the other hand, the g-hydrogen abstraction reaction of valeropheone (an aryl alkyl ketone) can be completely quenched. Lack of complete quenching suggests that a part of the reaction come from the excited singlet state. On the basis of the kinetics and thermodynamics of the intermolecular hydrogen abstraction process (section 9.6) the rate of g-hydrogen abstraction would be expected to depend on the bond strength of the C—H bond. The kr values for several ketones shown in Table 9.4 are consistent with this expectation. Perusal of Table 9.4 also indicates that systems with low-lying pp* triplets abstract g-hydrogen at a slower rate than those with lowest np* triplets. This is consistent with what we have learned earlier for intermolecular hydrogen abstraction. An elegant illustration of this can be found in the photochemistry of 1-benzoyl-4anisylbutane (Scheme 9.20). Although potentially both ends can react, the major products (>90%) come from the more reactive benzoyl end of the molecule. OMe O* O 2 x 10 OMe 7 + O O 107 108 OMe O O 1 x 10 OMe 5 + O O* Scheme 9.20 34 Final 1.0, 4/13/2004 Table 9.4 (from MMP p. 388) 35 Final 1.0, 4/13/2004 A linear relationship with a slope (r value) of –1.85 observed between the s-values of the d-substituents in valerophenones and kr suggests that intramolecular hydrogen abstraction is initiated by an electrophilic attack of the half vacant n-orbital on oxygen. This requires that the C—H bond be aligned with the oxygen n-orbital, a coplanar approach. It is important to note that the structure of the excited ketone is tetrahedral and not planar as in the ground state. Therefore the co-planarity postulate should be considered only as an approximate guide. An important difference between inter- and intramolecular hydrogen abstraction concerns the relative geometry between the carbonyl group and the C—H bond. While an unconstrained hydrogen atom donor can explore many geometries of approach within the lifetime of the excited state species before it finds an ideal one, the hydrogen donor that is constrained by a methylene chain will not be able to do so. C—H bond is situated favorably, the g-hydrogen abstraction process may fail. Therefore, unless the For example, irradiation of trans-4-tert-butyl-2,6-di-n-propyl cyclohexanone, yields the axial isomer A, which is relatively stable to further irradiation (Scheme 9.21). This result requires that the equatorial n-propyl side chain be more readily involved in a g-hydrogen abstraction reaction than the axial side chain. Indeed, the equatorial, but not the axial side chain, is capable of achieving the required geometry for hydrogen abstraction without producing severe molecular distortion. Another elegant example of this phenomenon is provided by ketones shown in Scheme 9.22. The only product observed upon irradiation of ketone A is the bicyclic alcohol formed via the Yang cyclization. In contrast, irradiation of the isomeric ketone B gave only benzaldehyde and ketone C, products of a Norrish type I reaction as the primary photoproducts. Only in the former ketone can the carbonyl n-orbital reach a g-hydrogen. O O (equatorial) hn (axial) (axial) Scheme 9.21 A 36 Final 1.0, 4/13/2004 O Ph Ph hn OH A B Ph hn O Ph PhCHO + O C D Scheme 9.22 Restriction of conformational freedom in the starting ketone is also a source of rate enhancement. The mobility of the participating molecules (carbonyl compound and hydrogen donor) is severely restricted at the transition state during the intermolecular hydrogen abstraction process. This restriction will cost in terms of entropy of activation. When the carbonyl group and the hydrogen donor are linked, DS‡ is less than when they are not linked. This is reflected in the different values of kr for intermolecular abstraction of hydrogen by acetophenone from cyclohexane and intramolecular g-hydrogen abstraction by valerophenone. The difference in kr is more than two orders of magnitude! According to this model, the more one freezes the bond rotations in the starting ketone, the higher the rate of hydrogen abstraction. This is illustrated with examples in Scheme 9.23 (the abstracted hydrogen in all three examples are secondary and the variations in DH# are likely to be small). Remember that it is not enough to freeze the positions of the hydrogens but they should be properly aligned. O O O Ph kH 1.3 x 108 6 x 10 8 Ph 7 x 10 9 Scheme 9.23 37 Final 1.0, 4/13/2004 9.14. 1,4 Diradicals as intermediates in g-hydrogen abstraction When initially formed, the 1,4-diradical generated via g-hydrogen abstraction, would (ideally) have its two p-orbitals perpendicular to each other and would be present in a folded conformation (Scheme 9.24). The only reaction the diradical generated in folded conformation can undergo is the reverse hydrogen transfer. By rotating about its terminal or central C—C bonds the 1,4-diradical can adopt cisoid or transoid conformations, (Scheme 9.24). The 1,4-diradical that exists in the conformations shown in Scheme 9.24, can in principle undergo three reactions: cyclization, fragmentation and reverse hydrogen transfer. The geometric requirements for each of these reactions are slightly different. The fragmentation process can only occur when the two porbitals of the 1,4-diradical are parallel to the central C—C s-bond that is being broken Thus fragmentation can occur from both cisoid and transoid conformations. Both cyclization and reverse hydrogen transfer require that the two ends of the diradical be close to each other, i.e., it requires a cisoid conformation. However, for cyclization to occur, the two p-orbitals should face each other, whereas for reverse hydrogen transfer, the p-orbital at the alkyl end should face the O—H s-bond (i.e., the two p orbitals should be perpendicular to each other. R O R HO HO R OH H R OH R HO R HO + R Scheme 9.24 38 Final 1.0, 4/13/2004 Depending on the nature of the reactive state the generated 1,4-diradical can be either in the singlet (1 DR) or triplet state (3 DR). Since the lifetime of 1 DR is much shorter than 3 DR the final products obtained from these two diradicals are expected to be different. The 1 DR generally does not live long enough to undergo bond rotations. The photobehavior of optically pure 5-methyl-2-heptanone illustrates this point. Quantum yields of racemization (of the reactant ketone) upon excitation of (S)-(+)-5-methyl-2-heptanone in presence and absence of the triplet quencher 1,3-pentadiene (2.5 M) are provided in Scheme 9.25. The quantum yields in presence of 1,3-pentadiene correspond to the reaction of 1 DR from the excited singlet state of (S)-(+)-5-methyl-2-heptanone. Under this condition, the F of racemization is low (0.002). In the absence of the triplet quencher 1,3-pentadiene, the reaction from both S1 and T1 takes place. As seen in Scheme 9.25 under such conditions the F of racemization of the starting ketone is higher (0.08). The photobehavior of (S)(+)-5-methyl-2-heptanone indicates that the 1 DR is too short lived to yield racemized starting ketone. OH OH hu O CH3 H C CH2 C O CH2CH3 CH3 C CH2CH3 H CH3 OH CH2 OH + CH3 C + CH2 CH2 Solvent f racemization Hexane 0.08 + 0.02 t-Butyl alcohol 0.04 + 0.02 Hexane + 2.5M cis-1,3-pentadiene 0.002 + 0.019a Scheme 9.25 The 1,4-diradical that is formed from the triplet excited states of dialkyl and aryl alkyl ketones is a triplet species (3 DR). Since the final isolated products have all electron spins paired (closed shell products) 39 Final 1.0, 4/13/2004 intersystem crossing (ISC) from 3 DR to 1 DR must precede product formation. In the absence of any external perturbation the lifetimes of triplet diradicals (3 DR) are in the range of 10 to 200 ns and this assures that triplet diradicals attain conformational equilibrium (Scheme 9.26) before they intersystem cross to the singlet state (1 DR). If the ISC rates are the same for all conformers, then the product distribution will be a direct reflection of the equilibrium distribution of the conformers. In some cases, it is likely that each conformer may have different intrinsic rates of ISC, and if this is the case, the product distribution is not a reflection of the conformer distribution and it would represent the rate of ISC. 3 HO R HO R OH R kisc kisc R kisc HO R HO R OH HO R kisc HO R Slow 1 Fast O R H OH R HO + R Scheme 9.26 The ISC rate from 3 DR to 1 DR can be enhanced by paramagnetic quenchers such as oxygen, di-tertbutyl nitroxide and Cu (II) derivatives. Such physical quenchers will shorten the lifetime of a 3 DR and thereby prevent it from establishing an equilibrium between various conformers. The product distribution obtained under such conditions will be different from the one obtained under conditions under which 3 DR establishes an equilibrium with various conformers. For example, in the case of g-methylvalerophenone, the presence of ditert-butyl nitroxide enhances fragmentation yields by >200%. Recall that the product distribution is a reflection 40 Final 1.0, 4/13/2004 of the conformer that crossed from the triplet to singlet spin configuration. Since the product distributions are different in the presence and absence of the paramagnetic quencher, the conformer that intersystem crosses more effectively in its presence and in its absence must be different. Two factors determine the product distribution from the triplet diradical: (a) the rate of ISC from 3 DR to 1 DR and (b) the specific conformer population of 3 DR at the equilibrium. In the absence of a complete understanding of the factors that control ISC rates in 1,4-diradicals, our ability to control the product distribution seems limited. In spite of this handicap, certain trends emerge. Of the conformers shown in Scheme 9.25 the transoid is most likely the lowest energy one. This conformation is ideally suited for the cleavage process; the transition state for the cleavage process will be lowered when there is an overlap between the terminal p-orbitals and the central s-bond undergoing cleavage. This geometry allows the maximum development of the double bond character of both the enol and the alkene as the central bond breaks. Thus with most systems that react from triplet state we would expect higher percentage of cleavage compared to cyclization. Further, thermodynamics favors clevage over cyclization. These conclusions are generally true. Normally with most systems less than 25% of the product corresponds to cyclization. Under special circumstances when the alignment required for elimination is not possible fragmentation will have higher activation energy, and by default cyclization and reverse hydrogen transfer become preferred; much higher yield of cyclization product is obatined. Several examples of this type are known (Scheme 9.27) in cyclic ketones. Ph HO O Ph hn OH HO Ph Ph H H + hn O Ph HO Ph HO Ph No transoid diradical and the two p-orbitals can't become parallel to the central s-bond. No fragmentation, only cyclization. Scheme 9.27 41 Final 1.0, 4/13/2004 9.15. Conformational effects in Norrish Type II reaction and Yang Cyclization 1-Methylcyclohexylphenyl ketone (Scheme 9.28) can exist in two conformations. In one the reactive benzoyl group is axial and in the other equatorial. The geometry of the molecule is such that only when the benzoyl group is axial can it undergoes the g-hydrogen abstraction. The conformer that has the benzoyl group in the equatorial position can undergo only a-cleavage. Thus upon excitation the two interconverting conformers are expected to undergo different reactions- the g-hydrogen abstraction and a-cleavage. Which products are formed depends on two factors: (a) the rate of interconversion between the two conformers in the excited state and (b) the rates of the two reactions (g-hydrogen abstraction and a-cleavage). The rate of interconversion between the two conformers and the rates of the two reactions are provided in Scheme 9.28. Since the conformers in their excited states react faster than they interconvert, it follows that the product quantum yields should depend upon the conformer populations (in the ground state as well as excited state) and the efficiency of product formation from each conformer, but not on the relative rate constants of the ghydrogen abstraction and a-cleavage reactions. Product yields obtained are consistent with this analysis. This analysis predicts that 1-methylcyclohexylphenyl ketone should have two triplets with distinct lifetimes, one due to the axial and the other to the equatorial conformer. In fact quenching of product formation with the triplet quencher naphthalene reveals this nicely (Figure 9.9). Figure 9.9 42 Final 1.0, 4/13/2004 Ph C=O (axial) 5 -1 10 s (equatorial) O H3 C C Ph hn hn Ph Ph C H3 C C=O* OH k H = 1.7 x 108 s-1 H H3 C H H CH3 O* 105 s-1 H H C Ph k a cleavage = 2.5 x 107 s-1 CH3 PhCO + CH3 H3 C Ph PhCHO OH + H3 C Scheme 9.28 9. 16. Intramolecular Hydrogen Transfer by a Tunneling Mechanism An important difference between inter- and inramolecular hydrogen abstraction is that the intramolecular hydrogen abstraction in special cases may proceed by a hydrogen tunneling mechanism that is unlikely during intermolecular hydrogen abstraction process. Surprisingly, anthrone and tetralone systems undergo intramolecular hydrogen abstraction even at temperatures as low as 20 K. The energy of activation for hydrogen abstraction both during inter- and intramolecular process has been determined to be in the range of 2-3 kcal/mole. Such a barrier would be insurmountable at 20 K. In spite of this, intramolecular hydrogen abstraction of 1,4-dimethyl anthrone (Scheme 9.29) occurs and no phosphorescence from this ketone is detectable at this temperature. The primary mechanism of hydrogen abstraction at very low temperatures (<30 K) has been identified to be a tunneling process. 43 Final 1.0, 4/13/2004 1 O H C H H 3 O H C H H H H S CH3 T CH3 O C hn O 1,4-MAT CH3 CH3 OH Photoenol CH2 CH3 CH3 Scheme 9.29 The name tunneling implies that the reactants may ‘tunnel’ through the classical potential to reach the products without possessing the thermal energy necessary to go over the barrier (Figure 9.10). Quantum mechanical tunneling originates from the fact that the location of the tunneling particle cannot be accurately represented by a classical potential. The wave function describing the location of the tunneling particle does not vanish at the turning points but it permeates through the barrier with a probability that is inversely proportional to its mass and to the height and width of the barrier (Figure 9.11). Tunneling is possible for lighter nuclei in lower vibrational states if there is a finite portion of the vibrational wave function beyond the classical limit which overlaps with a vibrational wave function in the product well (Figure 9.11). Since the permeability of the wave function decreases with increasing particle size, tunneling is most common in reactions where a proton, hydride, or hydrogen atom transfer is part of the mechanism. It should be kept in mind that even with light atoms the probability of tunneling is very small. Although tunneling may occur at all temperatures, at high temperatures the activated reaction dominates the total rate. As the temperature decreases, reaction over the barrier is slowed down enough for tunneling to contribute significantly to the total rate. Tunneling rates of the lighter isotope (e.g., H) are greater than those of the heavier isotope (e.g., D) and the 44 Final 1.0, 4/13/2004 corresponding tunneling correction is larger. At the lowest temperatures, the thermally activated process may be completely arrested such that only tunneling contributes to the total rate. Figure 9.10 Figure 9.11 Since the tunneling will become dominant only at very low temperatures, and unless the hydrogen to be abstracted is properly oriented, diffusional and conformational restrictions will prevent the hydrogen transfer from taking place both by conventional and tunneling mechanisms. At 20K the hydrogen transfer by a tunneling mechanism will occur only if there is a strong structural similarity between the reactant and the product. A remarkable influence of tunneling is obvious when phosphorescence yields and lifetimes of 2,3dimethylanthrone, 1,4-dimethylanthrone-d8 , and 1,4-dimethylanthrone are compared. In non-polar glasses at 77K, 2,3-dimethylanthrone decays with a lifetime of 3 msec and a quantum yield of emission near unity (Figure 9.12). In the isomer 1,4-dimethylanthrone the ortho methyl group is ideally positioned for reaction and it reacts so fast that it dominates the triplet decay. No phosphorescence is seen from this system at 77K and therefore no lifetime could be measured. When the hydrogens in the ortho-methyl group are substituted with deuterium, an expected isotope effect slows down the reaction enough for emission to compete. The yield of emission is much lower than that of the model compound, 2,3-dimethylanthrone. The fact that reaction can 45 Final 1.0, 4/13/2004 be observed at temperatures as low as 15-20K suggests that reaction occurs by quantum mechanical tunneling. This has been confirmed by Arrhenius analysis of reaction rate data obtained from the triplet decay rates. Figure 9.12 The observed products due to intramolecular hydrogen abstraction, short triplet lifetimes and low phosphorescence intensities of the reactant ketone, as well as the large isotope effects are more likley to be due to tunneling below 30K than due to a conventional hydrogen abstraction mechanism. Thus one should keep in mind that at very low temperatures, especially in rigid systems hydrogen abstraction by tunneling is a possibility. 46 Final 1.0, 4/13/2004 9. 17. The Norrish Type I Reaction (a-cleavage process) A number of carbonyl compounds (cyclic and acyclic ketones and arylalkyl ketones) upon excitation give products resulting from an a-cleavge process. This reaction, originally reported by Ciamician and Silber and developed by Norrish, is called the Norrish Type I reaction, and has become a useful synthetic tool in making strained compounds, novel reactive intermediates and natural products. The fact that np* excited carbonyl compounds undergo a-cleavage is expected on the basis of their similarity to alkoxy radicals (Scheme 9.30). Many features of the a-cleavage process occurring from an excited np* state can be predicted on the basis of the known behavior of alkoxy radicals. In the b-cleavage reaction of alkoxy radicals (note b-cleavage of an alkoxy radical corresponds to a-cleavage of a carbonyl; b with respect to oxygen and a with respect to carbonyl carbon) it has been established that the substituent that fragments is the one corresponding to the generation of the more stable radical. This in turn corresponds to cleavage of the weakest bond b to the radical center. On this basis, we can postulate that, for an np* state of a given multiplicity, the a-cleavage that produces the more stable radical pair will occur faster. For example, in the case of phenyl tert-butyl ketone, the tert-butyl radical being more stable than phenyl radical a-cleavage would occur to produce the former (Scheme 9.31). Acetone is not expected to undergo NorrishType I reaction. k ~ 102 sec-1 O CH3 CH3 R2 C CH3 O R1 R1 O C O + R3 O CH3 CH3 CH3 O hn No Cleavage CH3 CH3 CH3 CH3 R2 R3 R1 R1 C R3 O k ~ 109 sec-1 O C O + R3 CH3 C(CH3)3 O CH3 CH3 CH2 C(CH3)3 np* O Scheme 9.30 CH3 k ~ 109 sec-1 C(CH3)3 O C(CH3)3 CH3 47 Final 1.0, 4/13/2004 O O hn PhCC(CH3)3 PhC O + C(CH3)3 PhCH HC(CH3)3 + H2C + C(CH3)2 Scheme 9.31 ka (np*3) 3.3 x 107sec-1 4.7 x 108sec-1 Ph H 1.8 x 109sec-1 O O Ph O O O H 1.6 x 106 sec-1 O Ph Ph H3C H 2.1 x 107 sec-1 Ph Ph H3C CH3 1.2 x 108 sec-1 Scheme 9.32 We may use the alkoxy radical model as a rough guide for reactivity relationships. For molecules of similar structure, the more stable the radical pair produced by a-cleavage, the faster will be the absolute rate constant for reaction. An elegant illustration of the dependence of the rate of cleavage on radical stability is provided by substituted cyclopentanones and cyclohexanones (Scheme 9.32 and Table 9.5). In cyclic systems, the reactivity pattern of ring opening of alkoxy radicals follows that expected for the relief of ring strain (Scheme 9.33). Similar results are found photochemically. For example, the rate of a-cleavage of cyclobutanone in Sl (np*) is at least 10 times faster than the rate of a-cleavage of cyclopentanone in Sl (np*) (Table 9.5). 48 Final 1.0, 4/13/2004 R O O R O R < < Alkoxy radicals Rate of a-cleavage Increasing ring strain O* O* < O* < n, p* states Rate of a-cleavage Increasing ring strain Scheme 9.33 If the radical stability matters, one would expect the excitation energy of the ketone that is undergoing the cleavage would also have an influence on the rate of cleavage. In fact this is the case. For the same electronic configuration and spin multiplicity, dialkyl ketones (RCOR), which have higher excitation energies, undergo a-cleavage to R°CO and °R radicals faster than the analogous aryl alkyl ketones (ArCOR) (Scheme 9.34). O O hn k ~ 107sec-1 Ph O H3C hn O H3C C(CH3)3 k < 109 sec-1 ET = 73 kcal/mol ET = 80 kcal/mol Scheme 9.34 The dependence of the rate of cleavage on radical stability, on relief of ring strain and the excited state energy suggests that there is a barrier for cleavage in the excited state. Consistent with the above expectation the activation energies (~2-7 kcal/mole) have been measured for the a-cleavage of ketones in the excited state. 49 Final 1.0, 4/13/2004 Although there is no doubt (see below) that the final product of an a-cleavage reaction in most systems is a diradical, the nature of the transition state during the cleavage is not fully resolved. Indications that the transition state has some ionic character are available in the literature (see discussion on deoxybenzoins, benzoin ethers and dibenzylketones). 9. 18. Diradical Intermediate Thus far we have assumed that a-cleavage yields a radical pair or a diradical. The experimental evidence for homolytic a-cleavage of ketones is substantial. In addition to the consistency of product structures and structure-reactivity relationships with homolytic cleavage, direct spectroscopic identification has been reported for both the acyl and the alkyl radical. For example, irradiation of methyl tert-butyl ketone in the cavity of an ESR spectrometer results in direct observation of the ESR signal of the CH3 °CO and (CH3 )3 C° radicals. In addition, CIDNP studies provide further support that acyl and alkyl radicals are produced. Acylalkyl diradicals have been intercepted by n-butylmercaptan, nitric oxide and butadiene (Scheme 9.35). Direct detection of the acylalkyl diradicals from numerous cyclic systems has also been possible, and the lifetimes have been estimated to be in the range 10-100 ns. O O O + NO NO hn O O hn O O -78o C Scheme 9.35 9. 19. Nature of the Reactive State In general, the a-cleavage reaction occurs from the lowest np* excited state. Ketones/aldehydes with lowest pp* excited states either do not undergo a-cleavage or do so with low rate constants. For example, 50 Final 1.0, 4/13/2004 phenyl tert-butyl ketone (Tl = np *; ET~73 kcal/mole) undergoes relatively rapid and efficient a-cleavage (ka~107 sec-1; Fa~0.16 in benzene), but 4-methoxy-phenyl tert-butyl ketone (T1 = pp*; ET= 71 kcal/mole) is stable toward cleavage (rate estimated to be less than 7x105 sec-1; Fa~0.0 in benzene) (Scheme 9.36). O O hn k ~ 107sec-1 Ph O hn Ph O C C(CH3)3 k < 105 sec-1 H3CO Scheme 9.36 A non-intuitive aspect of a-cleavage is the fact that Tl (np*) reacts much faster than the corresponding singlet (S1 ). For example, the rate constant for a-cleavage of Sl (np*) of tetramethylcyclopentanone is at least 102 times slower than the rate constant for a-cleavage of the same compound from T1 (n, p*) (Table 9.5). In the case of di-tert-butyl ketone the rates of a-cleavage from S1 and T1 have been estimated to be ~ 6x107 and 8x109 sec-1 respectively. This is surprising considering the fact that S1 (np*) is more energetic than Tl (np*). The explanation could lie in differences in the activation energies or the Arhenius A factors or both. The A factor for both Sl (np*) and Tl (np*) have been measured, and it is smaller for the Sl (108 sec-1) than that for the triplet state derived reaction (101 3 sec-1) (see next section for the origin of differences in the A factor). While alkanones cleave from both S1 (np*) and T1 (np*) states, phenyl alkyl ketones cleave only from T1 (np*). This behavior is consistent with the rapid rate of intersystem crossing from S1 to T1 for phenyl alkyl ketones (101 1 sec-1; Figure 9.2). 51 Final 1.0, 4/13/2004 Table 9.5 52 Final 1.0, 4/13/2004 9. 20. A Model We need a simple model that will answer the following questions: (a) Why is a-cleavage more favorable from np* rather than pp* excited states? (b) Why does T1 (np*) react faster than S1 (np*)? (c) Why is there a barrier for a-cleavage in the excited state? An orbital overlap model presented in Scheme 9.37 provides an answer for the different reactivities of np* and pp* excited states. In the np* state the carbonyl oxygen has a single electron in the n-orbital, which lies in the plane of the a-bond. A p-type parallel interaction between the singly occupied n-orbital and the doubly occupied s orbital of the a-C—C bond is expected to weaken the a-bond and result in cleavage. Such an overlap results in a new p-bond and a pair of radicals. In the pp* state the electrons are present in orbitals that are perpendicular to the a-bond, and no overlap between p and s orbitals is possible. Therefore, the a-cleavge is unlikely to occur from pp* excited state. This qualitative model does not explain the difference in behavior between the singlet and the triplet np* states. C—C s* p* R R C R C O n C—C s p R O a-C—C Note p*— s* interaction is not favored, they are perpendicular to each other. Scheme 9.37 An insight into the mechanism can be obtained by inspection of the Salem diagram for the a-cleavage process presented in Chapter 6. Basic conclusions drawn from the Salem diagram are the following: (a) At the first level, the correlation diagram predicts that cleavage from both the np* singlet and triplet is disfavored. Both correlate with a higher energy diradical species. (b) At the level where coupling between surfaces of the same spin occurs, cleavage from the np* triplet state becomes allowed. In Figure x of Chapter 6 note that the 53 Final 1.0, 4/13/2004 triplet np* and pp* surfaces cross at a point slightly off from the vertical excited state. Due to avoided crossing between the triplet np* and the triplet pp* surfaces, cleavage from the triplet np* state becomes possible. (c) The cleavage will have a barrier and its height is controlled by the point at which the triplet np* and the triplet pp* surfaces cross. According to the Hammond’s postulate this point will depend on the energy gap between the triplet state and the product acyl and alkyl radical pair. The transition state would be stabilized if the alkyl radical is more stable resulting in a lower activation energy. (d) The only manner in which the np* excited singlet molecule can reach the diradical species is via the pp* triplet surface, that is by crossing from the singlet np* to the triplet pp* surface. Such a process is spin forbidden and is expected to have a low probability. In other words the reaction will have a low A factor. These predictions are consistent with the experimental results presented in the previous section. 9. 21. Reactions of the acyl-alkyl radical pair The final isolated product resulting from a- cleavage of a ketone depends on what type of reactions the primary acyl and alkyl radical pair undergoes. The most common reactions of radical pairs produced from acleavage of dialkyl and alkyl aryl ketones are radical recombination, disproportionation, and decarbonylation (Scheme 9.38). In the last case a new pair of radicals is formed, which may itself undergo radical recombination and/or disproportionation. Depending on the structure of a cyclic ketone two additional reactions can occur: ring expansion to a carbene and rearrangment to a different diradical. 54 Final 1.0, 4/13/2004 O recombination (CH2)n -CO decarbonylation O CH2 + (CH2)n (CH2)n CH(CH2)n-1CH 3 O disproportionation (CH2)n H CH2 (CH2)n disproportionation CO (CH2)n ring expansion OR CH3 ROH O O (CH2)n CH3 OR ROH (CH2)n n(H2C) O Scheme 9.38 Recombination: Recombination is a process in which the excited molecule fragments and recombines in an energy wastage process. This process will be evident in the form of low quantum yield of a-cleavage products and racemization and epimerization of the a-carbon (if an optically pure reactant ketone is involved). Note that the primary radical pair formed from a triplet ketone would have triplet spin and would not recombine within a ‘geminate cage’ unless it crosses to a singlet radical pair. Since the lifetime of a radical pair in solution is too short lived for any intersystem crossing mechanism to operate, the recombination reaction during a triplet reaction must occur from random free radicals and not from geminate triplet radical pairs. Support for the recombination pathway during a-cleavage is found in the observation that, under irradiation, the optically active ketone shown in Scheme 9.39 undergoes both disproportionation and racemization. Racemization that occurs with very low efficiency can be completely suppressed by the addition of radical scavengers such as dodecanethiol and stable nitroxide radical. Since the racemization is eliminated 55 Final 1.0, 4/13/2004 by very small amounts of the quenchers suggests that the recombination occurs between random free radicals and not between geminate primary radical pair. This is consistent with the expectation that intersystem crossing of the triplet radical pair to the singlet state requires much longer time (>10-6 sec) than the lifetime of a solvent cage (<10-9 sec) in solution. O H Ph CH3 hn OH Ph Ph CH3 Ph O CH2 Ph Ph disproportionation PhCHO + PhCH H CH2 recombination with racemization O O hn O O hn O O Scheme 9.39 Disproportionation: Excitation of cyclopentanone and cyclohexanone results in ketene and enal products, via disproportionation of the acylalkyl diradical. Along with disproportionation, recombination and decarbonylation also occur. Idealized transition state geometries for the formation of ketene and enal products from the acyl alkyl diradical are shown in Scheme 9.40. Although both ketene and enal formation involve hydrogen abstraction at the diradical stage the sites involved are different for the formation of these two products. 56 Final 1.0, 4/13/2004 O O hn C C=O O Scheme 9.40 Decarbonylation: The third typical reaction of acyl alkyl radical pairs is decarbonylation of the acyl fragment. This reaction generally does not compete with recombination and disproportionation unless the radical produced by decarbonylation is exceptionally stable (i.e., an allyl, benzyl or tert-butyl radical). For example, irradiation of methyl tert-butyl ketone results mainly in formation of acetaldehyde and isobutylene (disproportionation products), whereas irradiation of di-tert-butyl ketone results mainly in formation of decarbonylation products (Scheme 9.41). O O H + hn O + H O O hn + H + CO + Scheme 9.41 57 Final 1.0, 4/13/2004 Rearrangement: If the acyl or alkyl fragments produced by a-cleavage are capable of rearrangement (e.g., of the cyclopropyl carbinyl ~ homoallyl type), this process may compete with other reactions of the diradical. One such example which involves two sequences of a-cleavage, ring opening, and cyclization is provided in Scheme 9.42. O O O hn a-cleavage ring opening cyclization O O O hn ring opening and cyclization a-cleavage Scheme 9.42 Ring expansion to an oxacarbene: Ring expansion was first observed during the photolysis of bicyclic ketones (Scheme 9.43). In this case the oxacarbene was trapped by various alcohols as well as cyclohexene. Ring expansion occurs only when disproportionation and decarbonylation are disfavored or slow. As a result, ring expansion occurs only with selected systems. O OR ROH O hn O CHO O hn + O R'OH O + OR' Scheme 9.43 58 Final 1.0, 4/13/2004 9. 22. Photochemistry of Cyclobutanones The photochemistry of cyclobutanone and its derivatives is dominated by the primary photochemical process of a-cleavage. Cyclobutanones undergo efficient a-cleavage from Sl (np*) to produce a singlet 1,4acyl-alkyl diradical, 1 D. From Scheme 9.44 it is clear that the fate of 1 D is very different from that of the 1,n diradicals produced by photolysis of cyclopentanones and cyclohexanones. The latter compounds undergo acleavage predominantly via a Tl (np*) Æ 3 D process, and yield mainly disproportionation products (Scheme 9.40). The following reactions generally result from the 1,4-acyl-alkyl diradical: (a) decarbonylation, (b) cycloelimination, and (c) oxacarbene formation (Scheme 9.44). Decarbonylation of 1 D produces 1,3-diradicals which generally cyclize. The oxacarbene intermediate derived from 1 D has been trapped by alcohols. + CO Decarbonylation O O O hn S1(n, p*) 1D Cycloelimination CH2=C=O CH2=CH2 Ring expansion O ROH O H OR Scheme 9.44 Another important difference between cyclobutanone photochemistry and that of larger cycloalkanones is the observation of stereospecificity during the cleavage of the former. For example, the ethyl alkoxy cyclobutanone A undergoes stereospecific decarbonylation to yield B, cycloelimination to yield C , and oxacarbene formation to yield D (Scheme 9.45). Note in all cases the cis stereochemistry between the alkoxy and the alkyl groups is maintained. 59 Final 1.0, 4/13/2004 O S1(n, p*) RO 1D hn -CO O hn CH3OH RO O CH2=C=O + + RO RO A OCH3 RO B C D Scheme 9.45 9.23. Chelotropic Decarbonylation Reaction Not all a-cleavage process involves a radical pair or diradical intermediates. Concerted loss of carbon monoxide from excited singlet state leading to stable products is known. Such reactions follow WoodwardHoffman rules. A few such examples are provided in Scheme 9.46. O hn hn O O O O hn C6 H6 hn O Scheme 9.46 9. 24. Photochemistry of Dibenzylketones 60 Final 1.0, 4/13/2004 Dibenzylketone upon excitation undergoes decarbonylation to yield diphenylethane as the only product. This reaction is very efficient (F=0.8). When 1-(4-methoxyphenyl)-3-phenyl-2-propanone is irradiated three products shown in Scheme 9.47 are obtained in the precise ratio of 1:2:1. The ratio remained the same in various solvents whose viscosity changed between 0.56 (benzene) and 41.1cps (cyclohexanol). This suggests that there is no geminate cage recombination in isotropic solvent media. Generation of aryl acetyl radical has been established by trapping it with the nitroxide, a radical trap 2,2,6,6-tetramethylpiperidine1-oxyl. This observation is consistent with the suggestion that the decarbonylation proceeds by a two step process (Scheme 9.47). Decarbonylation of the aryl acetyl radical is consistent with the behavior of di-tertbutyl ketone presented in Scheme 9.41. OCH3 hu H3CO O H3CO H3CO 1 : 2: 1 AA + AB + BB H3CO O H3CO O N O O N N H3CO O Scheme 9.47 Photofragmentation of dibenzylketone upon direct excitation has been established to occur from T1 (np*) states. Observation of a linear Hammett relationship between relative rates of a-cleavage and s+ values of the substituent suggests that the transition state for a-cleavage from the triplet state of dibenzyl ketones has certain amount of ionic character (Figure 9.13). In this context it is interesting to note that while 1,3-diphenyl-2-propanone cleaves with a F of 0.7, 1,3-bis (4-cyanophenyl)-2-propanone does not cleave at all. 61 Final 1.0, 4/13/2004 The unexpected influence of substituent on the a-cleavage is consistent with the results of deoxybenzoins and benzoin ethers discussed below. pOMe p-Me Figure 9.13 pF p-Cl m-Cl PhCH2COCH2Ar hn d PhCH2CO d CH2Ar PhCH2CO + CH2Ar * O d X d 9. 25. Photochemistry of Deoxybenzoins and Related Systems The key primary reaction deoxybenzoins and benzoin ethers undergo is the Norrish type I a-cleavage. The radicals formed via this primary process are utilized to initiate polymerization. 62 Final 1.0, 4/13/2004 hu O X O O X O X X X = p-CH3 k ~ 109sec-1 7 X = m-CF3 k ~ 10 sec-1 hu O O X O O X X X = OCH3 X = CN k ~ 1010sec-1 k ~ 107sec-1 Scheme 9.48 O hu O X X Figure 9.14 PhCOCH2Ar hn d PhCO d CH2Ar PhCO + CH2Ar * O d X d 63 Final 1.0, 4/13/2004 The rates of a-cleavage in deoxybenzoin derivatives, expectedly, increase upon substitution of a-hydrogens by methyl groups (Scheme 9.49). The rates of a-cleavage for a number of aryl substituted deoxybenzoins in benzene show a linear relationship (with s+ of the substituent) with a r value of –1.1. This observation plus the fact that the p-methoxy enhances and p-cyano decreases the rate of a-cleavage are consistent with the model that the transition state for a-cleavage has the structure shown in Figure 9.14. This proposal is also supported by three orders of difference in the rate between a-cyano (2.2 x 107 sec-1) and a-methoxy (>101 0 sec-1) substituted deoxybenzoins. Since no evidence for ionic intermediate is available, one need to conclude that the heterolytically inititated cleavage process leads to a radical pair via an internal electron transfer process. Further experiments are needed to fully understand this process. O Ph X R R' O hu Ph R X R' X = Ph; R = R'= H ka = 0.16 x 107 sec-1 X = Ph; R = H; R'= CH3 ka = 2.1 x 107 sec-1 X = Ph; R = R'= CH3 ka = 12 x 107 sec-1 X = R = H; R'= CH3 ka = 1.1 x 107 sec-1 Scheme 9.49 9. 26. Reluctant a-Cleavage Reactions We learnt that a-cleavage is either slow or non-existant in systems whose triplet energy is lower than the energies of the product radical pair. Such systems when excited to upper excited states do undergo acleavage. Two experimental strategies have been used to achieve a-cleavage in such reluctant systems. TWO LASER (TWO COLOR) FLASH PHOTOLYSIS: In the two laser (two color) technique, two lasers of different wavelengths, firing sequentially, are employed to produce the upper states of molecules. The first laser produces the lowest excited state of the molecule and the second laser selectively excites these molecules 64 Final 1.0, 4/13/2004 into an upper level. By this approach a variable delay can be introduced between the two photons to allow the lower excited state concentration to build up. By using a tunable laser the wavelength of the second photon can be adjusted to correspond to the absorption maximum of the lower excited state. Since excited singlets (S1) are too short lived in comparison with the laser pulse duration to allow for efficient upper singlet production, the two laser set up is better suited for populating upper triplets than upper singlets. An illustration of the above technique is found in the cleavage reaction of benzil (Scheme 9.50). Benzil does not cleave when populated to the T1 (pp*) state by either direct excitation or triplet sensitization. However, generation of a higher triplet through excitation of T1 results in a-cleavage. O 2 photons O 2 O O 2 photons 2 Scheme 9.50 LASER JET EXPERIMENTS: The two laser (two color) technique described above provides excellent spectroscopic information on the transients produced during the formation of products from upper excited states. However, isolation of the products of a photoreaction by this approach could be tedious. For product isolation ‘laser jet’ apparatus is often used. In this laser jet technique, a high velocity microjet of a solution of material to be irradiated is injected into the focal region of an argon ion laser beam. The typical microjet flow rates can be controlled and the sample recycled as many times as necessary to bring the reaction to completion. Consequently, isolation of significant quantities of products is possible. Usually a high intensity CW argon ion laser is used to excite molecules. In this method sufficient concentrations of molecules in their S1 or T1 states are trapped within a ‘microbubble’ so that they can absorb a second photon. Reactions generally occur 65 Final 1.0, 4/13/2004 from the upper excited states. Structural and electronic details of the state from which the reactions occur are often lacking. The ketone A shown in Scheme 9.51 is stable to low intensity light (Rayonet Reactor). However when irradiated with an Argon ion laser under laser jet conditions it yields the product shown in Scheme 9.51 believed to be derived via Tn. Ph Ph O Ph nhn Ph O C Ph hn -CO Ph Ph Ph Ph + A Scheme 9.51 66 Final 1.0, 4/13/2004 9.27. b-Cleavage The np* excited states (singlet and triplet) of conjugated cyclopropyl ketones commonly undergo homolytic cleavage of a b-bond (Scheme 9.52). A model that can be used to rationalize this reaction shown in Scheme 9.53 involves overlap of the singly occupied p* orbital (C=O) with the s* orbital of the b-bond. Since the cleavage is initiated by the interaction between p* and s* orbitals the reaction could occur from either np* or pp* states. O O O -H hn H Scheme 9.52 s* p* C n s b C—C p* O n C=O p s* p* H H n C=O p pp* np* s b C—C Scheme 9.53 If two bonds are potentially available for cleavage, the bond capable of best overlap (based on energy matching and geometry) with the p* orbital will be cleaved preferentially. For example, the photochemical interconversion of cis and trans-5,6-diphenylbicyclo[3.1.0]hexanones shown in Scheme 9.54 can be accounted for by b-cleavage of any of the three bonds, marked a, b or c. Cleavage of ‘c’ is unlikely as it is neither a nor b bond. However both ‘a’ and ‘b’ are b-bonds and both are likely to cleave. In the case of an optically pure trans isomer cleavage of either one of them would yield the same product (cis isomer) but their stereochemical implications would be different (Scheme 9.54). As shown in the scheme products are 67 Final 1.0, 4/13/2004 enantiomers. It has been shown that only one of the two enantiomers, A alone is obtained upon photolysis of the optically pure ketone. Preferential cleavage of ‘a’ can be rationalized on the basis that it is the one with which the p* orbital overlaps best (Scheme 9.54). O H O O Ph Ph H Ph Ph H Ph Cleavage of bond 'a' O O hn b a Only Ph Ph Ph Ph Cleavage of bond 'b' O O H O Ph Ph H Ph H Ph Ph Cleavage of bond 'b' Scheme 9.54 If the p* orbital indeed assists in cleaving the b-bond of cyclopropanes, cleavage of epoxides should occur even more easily, since the s* orbital of the epoxide C—O bond is expected to be lower in energy than the corresponding cyclopropyl orbital. The photoisomerization of benzalacetophenone epoxide to dibenzoylmethane has been known since 1918 (Scheme 9.55). A fission of the Ca—O bond of the epoxide ring, followed by a 1,2-H shift, explains the 1,3-diketone formation. 68 Final 1.0, 4/13/2004 H C 6H 5 C H Cb Ca O H hn C 6H 5 C 6H 5 H C Ca Cb O O hn hn O C 6H 5 O O O O Scheme 9.55 9.28. b-Cleavage resulting in loss of a-substituents A number of a-substituted carbonyl compounds suffer the loss of the a-substituent upon excitation. The a-substituents that have been established to cleave are acetoxy, sulphonyloxy, phosphate esters, halogens, N,N-dimethylamino, sulphonium, alkyl sulfide, alkyl sulfoxide and sulfone groups (Scheme 9.56). The b- cleavage of phenacyl alkyl sulfides is extremely rapid, kb~108 s-1 and the rate is independent of the nature of the lowest excited state (np* or pp*). For example, the rates of cleavage for para-cyano phenacyl phenyl sulfide, para-methoxy phenacyl phenyl sulfide and phenacyl tert-butyl sulfide are nearly the same (~108 s-1). Depending on the leaving group the cleavage could be either homolytic or heterolytic. One could visualize the b-cleavage of the above substituents as being facilitated by the overlap of p* orbital of the carbonyl and the s* orbital of the C—X groups (similar to the one in Scheme 9.53). O Ph O hn CH2X Ph X O Solvent CH2 Ph CH3 X = Cl; S(CH3)2 BF4; OCOCH3; OPO(OR)2; SPh; Scheme 9.55 69 Final 1.0, 4/13/2004 9.29. Benzoin Esters and Related Systems Although based on the behavior of deoxybenzoins and benzoin ethers, a-acetoxybenzoins (see section 9.25) would be expected to undergo a-cleavage, they preferentially undergo b-cleavage. The b-cleavage is a general reaction with benzoins having a-substituents that can be easily lost as an anion. Following the release of the a-sbustituent deoxybenzoin cyclizes to 2-phenylbenzofuran (Scheme 9.56). The extent of 2phenylbenzofuran formation is dependent on the a-substituent. For example, while chloro substituent gives only 1% of 2-phenylbenzofuran, dimethylamino hydrochloride substituent yields the furan in 54%. Being a triplet reaction (np* or pp*), the cation that results following anion loss must remain in the triplet state, i.e., the reaction must be adiabatic in character (Scheme 9.57). Although the mechanism of these reactions has not been investigated, a triplet a-keto cation has been spectroscopically characterized and chemically trapped with trifluroethanol during the photolysis of benzoin diethyl phosphate in water (Schemes 9.58 and 9.59). In the absence of the trapping agents the excited a-keto cation probably cyclizes to yield the benzofuran. This mechanism for the b-cleavage operates only in water and very polar hydroxylic solvents. The overall When X can be lost as an anion b-cleavage occurs. X hn O O X = Cl Better the anion as the leaving group faster the bcleavage. 1% X = OCOCH3 15% X = N(CH3)2. HCl 54% Scheme 9.56 R R Ph Scheme 9.57 O Ph Ph O Ph pp* pp* 70 Final 1.0, 4/13/2004 O O + O H2O / CF3CH2OH P (OEt)2 OH O O OEt CH2CF 3 hn P O OEt O O CH3CN + OEt P HO OEt Scheme 9.58 O Ph O 3 O hn Ph O ISC 3 A O = P - OEt -PO(OEt)2OH CF3CH2OH O H Ph Ph OCH2CF3 H Ph Ph Ph OEt O Ph Scheme 9.59 . 9. 30. Addition to olefins Photoaddition of olefins to carbonyl compounds was discovered at the turn of the 20th century. This addition generally yields a product known as an oxetane, and the reaction is termed the Paterno-Buchi reaction to recognize the two chemists who played key roles in its development (Scheme 9.60). These additions are triggered by the excitation of the carbonyl chromophore to an excited state. The olefin reacts from its ground state. All three types of ketones - dialkyl, aryl alkyl and diaryl- as well as aldehydes undergo this reaction. Addition occurs to electron-rich and electron-poor olefins, acetylenes and allenes. 71 Final 1.0, 4/13/2004 O O hn + Ph Ph H Ph O Ph H H H O O H Ph Ph + C hn H Ph Ph Ph O Ph hn O hn + O hn H H H O O Ph H + O Ph O H Scheme 9.60 9. 31. Addition to electron-rich alkenes: Reactive state Irradiation of acetone in presence of either cis-1-methoxybutene or trans-1-methoxybutene gives four isomeric oxetanes (Scheme 9.61). An indication that acetone adds to enol ethers from two different excited states is provided by the observation that the ratio of the isomers is dependent on the concentration of the olefin used. For example at low concentrations of cis -1-methoxybutene (extrapolated to zero) the ratio of oxetane A and B is 1.06 and at high concentrations it is 2.5. The difference in selectivity between high and low concentrations is an indication that two reactive states with different lifetimes are involved in the addition (Chapter 8). Lower concentrations trap the state with longer lifetime (T1), while higher concentrations are required to trap the state with shorter lifetime (S1). While dialkyl ketones add to alkenes from both S1 and T1, expectedly, aryl substituted ketones and aldehydes react only from T1. 72 Final 1.0, 4/13/2004 CH3O (CH3)2CO H + C C H C2 H5 hn CH3 O CH3 C2 H5 OCH3 H H A O + CH3 H CH3 CH3 CH3 O + CH3 H OCH3 H5 C2 H B CH3 H H CH3O O + CH3O C2 H5 C C2 H5 H D hn H (CH3)2CO + H C CH3O C C2 H5 Scheme 9.61 9. 32. Addition to electron-rich alkenes: Diradical intermediates The addition of triplet excited ketones (dialkyl ketones as well as aryl substituted ketones and aldehydes) to electron rich olefins such as enol ethers and alkyl substituted olefins involves an intermediate as indicated by several factors. First, the addition is not stereospecific, meaning there is a step in which the stereochemistry of the incoming alkene is lost. Second, the recovered olefin is geometrically isomerized, suggesting that there is an intermediate formed that reverts to starting material with loss of olefin stereochemistry. Since the triplet energy of enol ethers and alkyl substituted olefins is well above that of acetone, a triplet-triplet energy transfer mechanism cannot be responsible for the geometric isomerization of the olefins. Third, with certain olefins, side products are observed. For example, in the case of acetone and tetramethylethylene, biradical disproportionation products are formed in addition to oxetane (Scheme 9.62). Yet another observation that supports the involvement of an intermediate is the isolation of a rearranged product 73 Final 1.0, 4/13/2004 during the addition of benzophenone to vinyl cyclopropane (Scheme 9.63). Diradical intermediate accounts for the observed rearrangement. O O O + coupling 20% n, p* disproportionation O + O 8% 8% Scheme 9.62 O O Ph2C O + CH2 hn C Ph Ph Ph Ph H 65% Ph O Ph Ph O Ph 15% Scheme 9.63 The above results are understandable in terms of a mechanism in which reaction between Tl and an electron-rich olefin leads to a triplet diradical (3D). Similar diradical mechanism is likely during the addition of excited singlet dialkyl ketones to electron rich olefins. In this case a singlet diradical (1D) would result. Of the two diradicals, 3 D is expected to have a longer lifetime and thus would be expected to suffer greater stereochemical loss compared to 1 D. As a result, oxetane formation is expected to be more stereoselective from Sl than from T1 . The reaction is unlikley to be stereospecific from both S1 and T1 states since the olefin 74 Final 1.0, 4/13/2004 addition to the n-orbital yields a 1,4-diradical in which the resulting two p-orbitals are perpendicular to one another (similar to the one obtained during g-hydrogen abstraction) and must undergo bond rotation prior to ring closure. As indicated above, the ratio of the two oxetanes is dependent on the enol ether concentration and at higher concentration when the S1 state will be captured by the olefin the addition is more stereoselective. A confirmation for the involvement of a diradical during the addition of ketones (triplet) to electron rich olefins comes from flash photolysis studies. A direct detection of the 1,4-diradical has been made during the addition of benzophenone and xanthone triplets to 1,4-dioxene and benzophenone to tetramethylethylene. The involvement of diradical as an intermediate also accounts for the exo-endo selectivity observed during the addition of various aldehydes to the electron rich olefin 2,3-dihydrofuran (Scheme 9.64). The reaction occurs mainly from the triplet state and the main product (>98%) is the one predicted based on radical stability. This product can exist in two arrangements, exo and endo (Scheme 9.64), of which the former less sterically hindered product is thermodynamically more stable. As illustrated in Scheme 9.64, the endo/exo ratio depends on the steric properties of the aldehyde. Bulkier aldehydes give higher endo selectivity. How can a diradical intermediate account for this counter-intuitive results? R H O hn + RCHO O O R + benzene O H Endo R= H endo : exo O H Exo R= endo : exo methyl 45 : 55 phenyl 88 :12 ethyl 58 : 42 o-tolyl 93 : 7 isobutyl 67 : 33 mesityl > 98 : 2 Scheme 9.64 75 Final 1.0, 4/13/2004 R 1 endo H O k ISC A A X 3 O H H X k ISC B H 3 A R 1 B exo B Scheme 9.65 A closer look at the triplet diradical that is formed after the initial addition of furan to triplet benzaldehyde (Scheme 9.65) provides an answer. The two conformations of the triplet diradical are shown in Scheme 9.65; closure of (B) will yield the thermodynamically more stable exo isomer, while A produces the endo isomer. Note that the two p-orbitals of the diradical are perpendicular to each other (as a result of addition of n-orbital to the p-bond of the olefin) and this geometry as per Salem rules (Chapter 6) is ideal for intersystem crossing. The precursor diradical B that yields the thermodynamically more stable exo isomer is sterically more hindered and is expected to be present in a lesser amount in the equilibrium. Since 1 D will close to the oxetane as soon as it is formed, the final product distribution is a reflection of the distribution of the conformers in the 3 D state rather than the stability of the final product. 9. 33. Addition to electron-rich alkenes: Involvement of exciplex Indirect evidences in favor of triplet exciplex during the addition of diaryl ketones to electron-rich alkenes have been provided: (a) During the addition of benzophenone triplet to cis or trans-2-butene no 2 Hisotope effect was observed. This suggested that the primary photoreaction is not bond formation to give the 1,4-diradical intermediate. (b) The rate of phosphorescence quenching of 4-carboxymethyl-benzophenone triplet by alkenes showed a linear relationship with the ionization potential of the latter. For example, while 1hexene quenched the triplet at a rate of 7.1x106 M-1s-1, 2,3-dimethyl-2-butene quenched it at a rate of 1.6x109 M-1s-1. The rates of quenching of acetone S1 and T1 by electron rich alkenes correlate linearly with the 76 Final 1.0, 4/13/2004 ionization potential of the alkene, providing additional information that during the acetone–alkene interaction, the alkene acts as an electron donor and the excited acetone as an acceptor. In highly activated ketones such as quinones an ion pair intermediate has been detected detected by time resolved CIDNP and time resolved transient spectroscopy. Thus addition of excited ketones and aldehydes to olefins may result in an exciplex, an ion pair and/or diradicals. 9. 34. Addition to electron-rich olefins: Regioselectivity The addition of electron rich olefins to excited np* carbonyls consists of the following steps (Scheme 9.66): (a) The first step is the nucleophilic attack of the filled p-orbital of the electron rich olefin on the excited carbonyl oxygen (n-orbital) to form an exciplex. (b) The attack results either in full or partial electron transfer to generate a radical ion pair. (c) The ion pair or exciplex combines to form a C—O bond resulting in a diradical intermediate. (d) The diradical, if triplet, lives long and undergoes other reactions before crossing to the singlet state. (e) Finally the singlet diradical closes to yield the oxetane. O R R O R R O R O R Exciplex + R R O O R R R + R O R R Scheme 9.66 The above addition can be understood on the basis of the orbital interaction diagram provided in Scheme 9.67. This correlation requires that the filled HOMO of the alkene (p) must interact with the partially occupied n orbital of acetone. Such an interaction requires that the alkene approach the excited acetone along 77 Final 1.0, 4/13/2004 the n-orbital (Scheme 9.67). This geometry of approach is called the ‘perpendicular’ approach. This has been supported by the variation in the fluorescence quenching rate between several norbornyl ketones (Scheme 9.68). When the approach to the n-orbital is restricted by the bulky methyl groups, the rate of quenching is decreased. Perpendicular approach Parallel approach C C O O n p* p p* C C C C C C C C D p* LUMO LUMO C C LUMO p* p* A p HOMO n D HOMO C C HOMO p C=C A D C=C A electron-deficient alkene A - electron acceptor C = O* np* electron-rich alkene D - electron donor Scheme 9.67 78 Final 1.0, 4/13/2004 Fluorescence Quenching of 2-Norbornanone Singlets by trans-DCE and cis-DEE k qr x 10 -9 [M -1 sec -1] p-orbital attack n-orbital attack NC EtO CN 5.1 O OEt O "faces" "edges" 1.2 OR O CN O O FAST 1.0 SLOW 1.5 O O 0.48 O OR O CN < 0.03 SLOW FAST Schematic of the use of substituent effects on the rate of quenching of norcamphor and its derivatives by electron-rich (enol ethers) and electron-deficient (cyanoethylenes) to demonstrate "edge" (n-p interaction) and "face" interactions of the n,p* state and ethylenes. Scheme 9.68 Regiochemistry of addition is expected to depend upon whether the interaction between the n-orbital of the carbonyl and the p-orbital of the alkene leads to a diradical or a radical ion pair. Two examples of addition of electron rich alkenes to acetone provided in Schemes 9.69 and 9.70 highlight this point. Both additions involve diradical intermediates. However, while the addition of acetone to 2-methylpropene is regioselective and it can be predicted on the basis of radical stability that to enol ethers is not regioselective. In the latter case, although isomer A usually predominates, the selectivity is less than what might be expected on the basis of diradical stability. Obviously, diradical stability is not of paramount importance in this case. It is quite likely that the regiochemistry of oxetanes is decided prior to formation of diradical intermediate. Possibly in this electron rich olefin electron transfer precedes the bond formation. Under such conditions the bond formation will be dictated by the orbital coefficients of the interacting orbitals of the radical ion pair. The addition may be considered as a nucleophilic attack by the filled n-orbital of carbonyl oxygen on the singly occupied p-orbital 79 Final 1.0, 4/13/2004 of the olefin radical cation. The orbital coefficients of the olefin radical cation provided in Scheme 9.71 nicely accounts for the absence of regioselectivity in this case. Thus it is clear that in order to accurately predict the regioselectivity during oxetane formation one needs to know whether electron transfer or carbon oxygen sbond formation is the primary step. It is important to recognize that there are a number of examples where excellent regioselectivity has been achieved ( Scheme 9.72). CH3 O hu Ph2CO + (CH3)2C=CH2 CH3 O Ph CH3 + Ph Ph CH 3 Ph less stable more stable CH3 O Ph CH3 O CH3 + Ph Ph CH3 Ph 90% 10% Scheme 9.69 O hu + n, p* OR O O OR E O + OR OR D OR O + O OR 60% 40% Scheme 9.70 80 Final 1.0, 4/13/2004 Comparison of Charge Distribution at the Ethylenic Carbons for the Ground State and Radical Cation of a 1,1-Dialkoxyethylene (CH3)2C (CH3)2C O* + CH2 biradicals, etc. + C(OR) 2 31 O [CH2 14 C(OR)2] 34 32 Scheme 9.71 O Ph hn + Ph SiMe 3 O + Ph SiMe 3 Ph SiMe 3 O Ph Ph 24 : 1 CH3 O + Ph Ph hn CH3 OTMS O Ph + OTMS O OTMS Ph Ph CH3 Ph 94 : 6 Ph SMe H O Ph + hn H SMe O Ph H SMe + O H Ph Ph H Ph H 100 : 0 Scheme 9.72 81 Final 1.0, 4/13/2004 9. 35. Addition to electron-deficient alkenes Results from photocycloaddition of ketones to electron-poor alkenes such as cyanoethylenes (Scheme 9.73) contrast sharply with those for photocycloaddition of ketones to electron-rich ethylenes: (a) Only Sl (np*) forms oxetanes with cyanoethylenes. (b) Quenching of S1 (np*) does not cause cis-trans-isomerization of the alkene as a side reaction. (c) Quenching of Tl (np*) sensitizes cis-trans-isomerization of the cyanoethylene but does not lead to oxetane. (d) Oxetane formation from S1 (np*) is stereospecific. (e) Oxetane formation from S1 (np*) is regiospecific, but the product structure does not conform to that expected from the most stable diradical rule based on attack on the carbonyl oxygen. CN O (CH3)2C O + CN S1(n, p*) CN stereospecific CH3 CH3 CN CH3 O CN (CH3)2C O + CH3 S1(n, p*) CH3 CN regiospecific CH3 CN (CH3)2C O T1 (n, p*) (CH3)2C T1 (n, p*) O + (CH3)2C + CN + O CN CN cis-transisomerization CN (CH3)2C O CH3 + CN CN dimerization Scheme 9.73 Rates of quenching of S1 (np*) of acetone by several electron deficient alkenes generally increases as the electron affinity increases. The relationship between rate of quenching and the electron affinity of the alkene suggests that the excited acetone acts as the electron donor and the alkene as the acceptor. Note that the roles of the excited carbonyl and the alkene are reversed compared to the situation with electron rich alkenes. For an 82 Final 1.0, 4/13/2004 excited carbonyl to act as an electron donor the alkene has to approach the ketone along the p-face. This approach is called the ‘parallel’ approach. This geometric preference is supported by the variation in quenching observed when the p-face of the ketone is blocked (Scheme 9.68). The rate of quenching is reduced by substituents that block access to the p-face of the carbonyl group. The orbital interaction between the np* ketone and electron poor alkenes is shown in Scheme 9.67. In this case the interaction occurs between the p* (LUMO) of the carbonyl and the p* (LUMO) of the alkene. A number of indirect lines of evidence indicate that exciplexes may act as intermediates during oxetane formation between acetone and electron-poor alkenes: The fact that np* states (S1) may be completely quenched by ethylenes but generally lead to products with much less than 100% efficiency is consistent with the presence of a deactivation channel (an intermediate that can lead to the reactants without bond formation) to the ground state along the pathway to the product. For example the quantum yield of oxetane formation between 1 acetone* and 1,2-dicyanoethylene is only 0.1 although the excited singlet is quenched almost at diffusion controlled rate (5x109 M-1s-1). The fact that the rate constants for quenching are much higher than those predicted from simple radical addition is inconsistent with the direct primary formation of diradical intermediates in the quenching step. A linear relationship between the quenching rate constant and the electron affinity of the alkene suggests a charge transfer interaction between the alkene and the excited ketone. The above data suggest that a charge transfer complex (exciplex) or a D± (radical ion pair) may precede the product formation. Let us consider the regiochemistry of addition of acetone to a-methyl acrylonitrile. Four different diradicals are possible in the addition of acetone np* singlet to a-methyl acrylonitrile (Scheme 9.74). If diradical stability controls the regiochemistry, isomer B would be predicted to be formed. But the isolated isomer is A. Obviously the regiochemistry is decided prior to diradical formation and the stability of diradical has no role to play in this step. Salem diagram discussed in Chapter 6 correctly predict the regichemistry of addition. 83 Final 1.0, 4/13/2004 O CN E (CH3)2C S1(n, p*) O + CH3 CN O O CN O CN O CN A CN B D C O not formed CN F Scheme 9.74 Salem diagrams for the formation of the two diradicals, precursors to oxetanes E and F (Scheme 9.74) are shown in Figure 9.15. Correlation diagram is drawn for two approaches, perpendicular and parallel approaches (Scheme 9.67). The parallel approach applies to electron deficient olefins and perpendicular approach to electron rich olefins. While addition to carbon is allowed that to oxygen is forbidden from excited np* state. During the addition to oxygen the energy increases from both np* singet and triplet. On the other hand addition to carbon smoothly leads the diradical A. Therefore independent of the stability of the two diradicals A and C, A alone is favored to be formed which explains the formation of the unexpected oxetane based on the behavior electron rich alkenes. Reaction that is favored from S1 is expected to be inefficient due to the presence of a ‘hole’ (avoided crossing) in the excited state surface. This prediction is consistent with the experimental obervation. In spite of all the S1 being quenched by 1,2-dicyanoethylene, only 10% of it yield the oxetane. 84 Final 1.0, 4/13/2004 Figure 9.15 9. 36. Diastereoselective and enantioselective addition of alkenes Paterno-Buchi reaction of benzaldehyde under normal conditions would proceed equally from the two prochiral faces of the carbonyl chromophore. If one wishes to control the addition, the olefin should be able to to distinguish the two faces. Two approaches have been used to achive this goal. In one a chiral auxiliary is covalently linked to the alkene and in the other a template is used to block one face of the carbonyl chromophore. Addition of phenyl glyoxalate to various alkenes serves as an example of how a chiral auxiliary may influence an oxetane formation. The menthyl derived chiral auxiliaries were localized in the keto ester part and thus relatively far from the reaction site. In all cases, independent of the structure of cycloalkene and the ester substituent, exclusively the endo phenyl distereomers were formed (Scheme 9.75). Importantly the remote chiral auxiliary steered the addition mostly towards a single diasteromer (d.e. in the case of 8-phenyl menthyl substituted: 96%). Ability for the alkene to distinguish the two faces arises from the steric blocking of one face by the chiral group (Scheme 9.76). 85 Final 1.0, 4/13/2004 O O Ph COOR* O O hn + O O Ph Ph + O O CO2 R* R*O2 C R* (-)-8-Ph-Menthyl (-)-Menthyl O de > 96% 57% Scheme 9.75 One face of carbonyl blocked by the menthyl group Ph O O O Ph OCH3 Ph O O Scheme 9.76 In the second approach, the alkene is steered to approach the carbonyl preferentially from one face by the use of external forces. The example shown in Scheme 9.77 illustrates this concept. The alkene, dihydropyridone when pre-associated to the carbonyl with the help of hydrogen bonding to the chiral amide the addition selectively occurs from one face. A diastereomeric ratio of 95:5 is achieved in toluene while that in acetonitrile is 50:50. Importance of pre-organizing the dihydropyridone prior to exciting the carbonyl is evident from the fact that when the chiral amide is modified (R=CH3 ) so that it can not form hydrogen bond with the dihydropyridone the diastereomeric ratio is 50:50. 86 Final 1.0, 4/13/2004 O O O hn H O O N + H O NR O O O O N H NR O O N H O NR O O O R=H acetonitrile benzene toluene 50/50 83/17 95/5 R = CH3 benzene 50/50 H O N H H N O O O Scheme 9.77 9. 37. Intramolecular photocycloaddition Similar to intermolecular addition of excited carbonyl to alkene, intramolecular oxetane formation is also known. The mechanism for intramolecular addition is exactly the same as the ones for intermolecular addition. Enones where the ‘ene’ and ‘one’ parts are separated by more than two carbons readily undergo intramolecular oxetane formation without any complications due to side reactions (Scheme 9.78, eqs. 1-3). Even systems where the alkene and the carbonyl chromophores are separated by 15 atoms (including the aryl ring) undergo intramolecular oxetane formation. One such example involves the addition of alkene to benzophenone both connected by a methylene chain (Scheme 9.78, eq. 4). 87 Final 1.0, 4/13/2004 O O O hn + (1) 2:5 O O hn O (2) O O O (3) hn (CH2)9 O O hn C O O (CH2)9 C O (4) O Ph Scheme 9.78 9.38. Synthetic applications of photoreactions of carbonyl compounds Several reactions we have learnt in this chapter have been utilized during synthesis of complex organic molecules. Without going into the details the reaction involved and the molecule being synthesised are highlighted with selected examples below. Intramolecular d-hydrogen abstraction has been used repeatedly with significant success (yiled>65%) during the synthesis of dodecahedrane (Scheme 9.79). Synthesis of pharmaceutically important estrone has been achived through the use of Norrish-Yang reaction (Scheme 9.80). In this case the photoenol formed via 88 Final 1.0, 4/13/2004 g-hydrogen abstraction is intramolecularly trapped to build a steroidal skeleton. Overall yield of the photochemical step is 45%. O HO H CH OPh 2 CH2OH (1) hn (2) Li, NH3 R (3) H+ R OH O hn dodecahedrane Scheme 9.79 O O hn OH O H H MeO MeO [61 %] O O H H H OH H MeO H O HO ( + )-estrone H OH H MeO Scheme 9.80 89 Final 1.0, 4/13/2004 The first total synthesis of (±) asteltoxin, inhibitor of oxidative phosphorylation, makes use of the Paterno-Buchi reaction between 3,4-dimethylfuran and b-nezyloxypropanol (Scheme 9.81). Syntheses of several pheromones and insect sex attractants have utilized the Paterno-Buchi reaction. One such examples is provided in Scheme 9.82. Intramolecular Paterno-Buchi reaction of 2-allylcycloheptanone serves as a simple route to azulene (Scheme 9.83). Me Me Me H OBn + O O O OBn Me hn O H (63%) Bn = CH2Ph OH OH OH O O O O asteltoxin OMe Scheme 9.81 H O O + + H H H H O O H OH Fruit Fly Attractant Scheme 9.82 90 Final 1.0, 4/13/2004 O O hn H D OH + Scheme 9.83 The oxacarbene generated via Norrish type I cleavage has been utilized during the synthesis of prostaglandins and analogues (Scheme 9.84), the natural product muscarine (Scheme 9.85), and thromboxane analogues (Scheme 9.86). OH O OH O hn R' Wittig H2O R R OH HO R Prostaglandin F2a OH R' = R= COOH OH Scheme 9.84 Me OSiMe2tBu O hn Me CH2Cl2 H O OMe 4 steps Me O + NMe3 -78o t BuMe2SiO HO Muscarine Scheme 9.85 91 Final 1.0, 4/13/2004 O H H (CH2)6CO2Me 11 steps R HO CH3 HO 1 R1 O OR2 Me hn, MeOH (CH2)6CO2Me MeO O R1 thromboxane analogue Scheme 9.86 9.39. Norrish type I reaction utilized in photoimaging Photoimaging is a technique used for capture and replication of image information which utilize photons. This technique is employed in photography, office copying, printing business, in the manufacture of printed circuit boards and printing plates and in the generation of holographic images. Figure 9.16 diagrams the imaging steps and illsutrates the process application for the preparation of two representative kinds of images. All photoimaging processes can be reduced to three elementary steps: image capture, image rendition and image readout. The fundamental photochemistry of the imaging system resides in the image capture step. A final photoimage will result only if the light-struck regions of the light sensitive medium can be differentiated from the unexposed regions. One process used in the imaging technique is photopolymerization. Photopolymerization is the generic process of converting small molecules into larger ones triggered by light. The imaging is created with the help of a mask that controls the area that is exposed to light. Once the light exposed and light unexposed areas are differentiated through monomer-polymer compositions a permanent image can be created through furtheer processing. Two ingredients play an important role in the imaging process i.e. monomer and light sensitive initiator. The photoinitaor generates free radicals that initiates polymerization in the light exposed area. 92 Final 1.0, 4/13/2004 Figure 9.16 Many photoinitiators used in imaging industry are molecules that we have come across (Scheme 9.87) in this chapter. These molecules undergo a-cleavage upon exposure to light. The primary radicals produced by a-cleavage or the secondary radicals formed from the primary radicals initiate polymerization of the monomer coated onto a support. Initiator is a key component that creates a permanent image although superior processing and other manipulations lead to a saleable product. O OCH3 C C hn O OCH3 C + C O H3CO OCH3 OCH3 CH3 O O O + H O H OCH3 CH3 O O O C2H5 CH3 C2H5 O CH2 O O CH3 HO CH3 H5C2 N HO N CH3 H3C O Photoinitiators Scheme 9.87 93 Final 1.0, 4/13/2004 9.40. Phototriggers and photoprotecting groups: b-Cleavage reaction exploited The physiological investigation of neuronal circuits and behavior of living brain slices frequently demand a fast and focal administration of bioactive substances. Traditionally, this has been accomplished with pressure injections or ionophoresis. During the last few years, photolysis of ‘caged’ compounds has become an increasingly viable alternative to these traditional methods. Caged compounds are comprised of bioactive molecules that are covalently bound to a photoabsorbing group that results in a photolabile, inactive ‘caged’ molecule. Upon UV illumination, the photolabile caged compound is cleaved into a free biologically active molecule and the free caging group. This process is termed triggering. Ideally a phototrigger (photoactive compound + biactive compound) should be biologically inert and chemically stable prior to photolysis. Once irradiated, it should react rapidly with a high quantum efficiency and the photocleavage product should also be biologically inert. One of the main reactions used in this context is b-cleavge of benzoin esters (Section 9.29). In the examples provided in Scheme 9.88 benzoin esters are used as photoactive compounds to release biological molecules such as adenosine monophosphate, neurotramsitters such as GABA and glutamate and oligopeptides. The first step is to link the biological molecule of interest with benzoin (as an ester). Once this is done the caged molecule can be photolyzed in the medium of interest to release the molecule. Release of oligopeptides by this process can be utilized to investigate the process of protein folding. 94 Final 1.0, 4/13/2004 NH2 N O O O P O O O N N N N hn O O P OH2 O OH N O OH NH2 N N + O Ph cAMP Desyl "caged" cAMP NH3+ O O hn O + O NH3 O_ + O GABA Ph Ac-Val-Gly-Glu-Arg-Gly-OH + Ac-Val-Gly-Glu-Arg-Gly-O Ph hn Ph O O O O CO-Gly-Arg-Nle-Lys-Glu-NH CO-Gly-Arg-Nle-Lys-Glu-NH2 Scheme 9.88 95 Final 1.0, 4/13/2004 9. 41. A comparison of carbonyl photochemistry with that of thiocarbonyls: Reactions from S2 pp* state While discussing the reactivity of carbonyl compounds our attention focussed essentially on the reactivity of np* excited state. Only in aryl alkyl and diaryl ketones we were concerned to a small degree about the reactivity of pp* state. Even in these cases we were not sure whether the reactivity is due to ‘pure’ pp* state or due to mixing with close lying np* state. Thus it is unclear whether a ‘pure’ pp* state of a carbonyl would undergo hydrogen abstraction, addition to alkenes etc. When one analyzes the excited state reactivity of thiocarbonyl chromophore, a close analogue of carbonyl, it is clear that even pure pp* state can display many of the reactions of np* state. In this section we briefly highlight the reactions of thiocarbonyls from S2 (pp*) state to dispel the notion that pp* state can’t exhibit reactivity similar to a np* state. Reactions from the lowest excited np* triplet of thiocarbonyls are similar to that of carbonyls and will not be discussed. The difference in energy between S1 and S2 in thiones is 20–40 kcal/mole making the two states ‘pure’. Thioketones, in general, are colored compounds with electronic absorption in the region 200-700 nm (Figure 9.17). The absorption at the longest wavelength for each of the thiones, is attributed to the spinforbidden S0 Æ T1 (np*; e~1–5) transition. The stronger band in the visible region (with small differences in band maxima between aromatic, aliphatic and arylalkyl thiones) corresponds to the S0 Æ S1 (np*; e~100) transition. The strongest absorption band of the aliphatic thiones in the 230-250 nm region has been attributed to a pÆp* transition. The absorption of substituted thiobenzophenones between 300-375 nm is ascribed to the pÆp* transition. The thiocarbonyl chromophore possesses several interesting chemical and spectroscopic properties. Many of the characteristic features of these systems arise from the large energy separating the S1(np*) and S2(pp*) states when compared to the same in carbonyls. One of the more unusual features is the observation of fluorescence from the second excited singlet state (Figure 9.18). Thiones displaying anomalous fluorescence in solution include several diaryl, aryl alkyl, dialkyl and a,b-unsaturated thiones. In addition to the anomalous emission from S2 , thiones also react from S2 (pp* state). In this section we are concerned with the reactivity of S2 . 96 Final 1.0, 4/13/2004 Figure 9.17 Figure 9.18 9. 42. Intramolecular hydrogen abstraction Similar to their carbonyl counterparts thiocarbonyl compounds, have been established to undergo hydrogen abstraction process. In carbonyl compounds, hydrogen abstraction generally occurs from the np* state and the partially filled electrophilic n-orbital initiates this process. In contrast, thiocarbonyls abstract hydrogen from both the lower np* state and the upper pp* state, and the abstracted hydrogen adds to either the C or S atom of the thiocarbonyl chromophore. Aryl alkyl thiones containing saturated hydrocarbon alkyl chains upon excitation to the S2(pp*) state, yield cyclopentane thiols via a d-hydrogen abstraction from the alkyl chain (Scheme 9.89). does not occur upon irradiation to the S1(np*) band. This reaction Successful quenching of the reaction by singlet quenchers and unsuccessful triplet sensitization are taken to support S2(pp*) as the reactive state. 97 Final 1.0, 4/13/2004 R S R R HS . hu pp* HS . !! R = CH3 , Ph R = CH3 , Ph Scheme 9.89 Aryl alkyl thiones in which the d-carbon is replaced by an ethereal oxygen atom, photochemical hydrogen abstraction occurs from carbons adjacent (e and/or g) to the oxygen atom (Scheme 9.90) as a result of activation of the neighboring hydrogens by the heteroatom. e-Hydrogen abstraction leads to six membered ring thiols, while g-hydrogen abstraction leads to cyclization (cyclobutanethiols) and cleavage (alkene) products. Whereas the g-hydrogen abstraction can be initiated by light of short and long wavelength, ehydrogen abstraction is wavelength specific and occurs only upon excitation to the S2 state. O hu SH + pp* S O O O + HS O hu np* + O HS Scheme 9.90 Bridged bicyclic thiones (e. g., bicycloheptanethiones and bicyclooctanethiones) on irradiation yield binsertion products. This reaction, which occurs only upon excitation to the S2 (pp*) state, is illustrated in Scheme 9.91 using bicyclic thiones - thiofenchone and 2,2-dipropyl thiofenchone, as examples. In both these thiones, hydrogen abstraction leading to tricyclic thiols takes place from the carbon b to the thiocarbonyl group. Availability of b, g, and d-hydrogens in the alkyl side chain of 2,2-dipropyl thiofenchone does not 98 Final 1.0, 4/13/2004 change the course of reaction. The participation of b-endo-hydrogen during cyclization has been confirmed by deuterium labeling studies. No analogous reaction is known among structurally similar bicyclic ketones (recall that fenchone, camphor etc. upon excitation undergo a-cleavage reaction). hu pp* S SH hu + pp* S SH SH Scheme 9.91 Monocyclic thiones such as 2,2,5,5-tetraalkyl thiocyclopentanones and 2,2,6,6-tetraalkyl thiocyclohexanones also react from the S2(pp*) state similar to bicyclic thiones, but the mode of hydrogen abstraction is dependent on the alkyl side chain (Scheme 9.92). When the alkyl groups are methyl groups, the products of hydrogen abstraction are cyclopropyl thiols (b-insertion). However, irradiation of thiones with a longer alkyl chain leads to g-insertion as major and b-insertion as minor products; d-insertion pathway is virtually absent. These reactions which can not be sensitized are believed to originate from S2. S HS hu pp* S HS hu pp* HS + (11%) (61%) Scheme 9.92 The pp* singlet of thiocarbonyls is established to abstract hydrogens at rate ~108 s–1, a rate higher than that reported for pp* states of carbonyls and alkenes. For an efficient hydrogen abstraction to occur the 99 Final 1.0, 4/13/2004 C—H bond must lie above or below the p-plane of the thiocarbonyl chromophore or else radiationless decay or reaction with a solvent molecule occur. The conformation in which the molecule finds itself upon excitation is clearly of major importance. With a short lifetime of the reactive state from which the thione undergoes hydrogen abstraction, the relevant hydrogen atom necessarily has to be in the space pertinent to the reaction at the time of excitation. This is presumably why the endo hydrogen successfully competes with b, g, d hydrogens for abstraction in bicyclic thiones. In the case of arylakylthiones, the volume of space within which the hydrogen has to be present is more easily satisfied by the d hydrogen than by the g-hydrogen. The location of the hydrogen atoms that are abstracted by the pp* excited thiocarbonyl chromophore are thus different from the corresponding carbonyl compounds. 9.43. Intermolecular hydrogen abstraction Photochemical behavior of adamantanethione brings out clearly the reactivity of pp* state towards hydrogen abstraction. Irradiation of adamantanethione in the np* band in cyclohexane gives only the 1,3dithietane dimer and no reduction products are observed. In contrast to the np* state, the pp* state of adamantanethione is a fairly indiscriminate abstracter of hydrogen atoms. In cyclohexane, solvent insertion products, sulfide and thiol (Scheme 9.93) along with the 1,3-dithietane dimer are formed. This reduction has been shown to involve hydrogen abstraction and radical pairs. The most striking result reported in this connection is the lack of discrimination among the different types of C—H bonds. Thus primary, secondary and tertiary hydrogens are abstracted equally efficiently by adamantanethione in its S2 state. For example, when 2,4-dimethylbutane is used as the donor, both the primary and tertiary hydrogens are abstracted at almost the same rate. The indiscriminate hydrogen abstraction process is indicative of low activation energy, an early transition state and a highly exothermic reaction. In agreement with this, the kinetic isotope effect for the abstraction process was determined to be close to unity. The kinetic isotope effect (kH/kD) for triplet benzophenone hydrogen abstraction is 2.8 while that for adamantanethione in its S2 state is ~1.1. The rates of quenching of the S2 state of thiones by hydrocarbons have been estimated to be near diffusion limited. Thus 100 Final 1.0, 4/13/2004 thiones in their S2 (pp*) states are clearly much more reactive towards C—H bonds than carbonyls in their np* states or alkenes in their pp* states. SH S hu / pp* S + S S + Scheme 9.93 An interesting point to note in Scheme 9.93 is that in the pp* state both carbon as well as sulfur of thiocarbonyl chromophore abstracts hydrogen from cyclohexane. This is consistent with the Salem diagrams for approach of C—H along the p-plane towards the C=S chromophore. We can make use of the Salem diagram presented for the addition of carbonyl to alkene along the p-plane (Figure 9.15) to understand the hydrogen abstarction process. As per this correlation diagram addition to carbon as well as sulfur would be favored in the pp* state although in the np* state addition only to carbon is allowed. 9. 44. Addition to alkenes Both diarylthiones as well as dialkylthiones add to alkenes upon excitation to S1 and S2 . Triplet np* is the reactive state upon long wavelength excitation and excited singlet pp* upon short wavelength excitation. Thte characteristics of addition from T1 are similar to that of carbonyls and will not be discussed. Photochemistry of adamantanethione as a representative of the photoaddition of thiocarbonyls (S2 , pp*) to alkenes is presented. Upon excitation to S2, adamantanethione add to both electron rich and poor alkenes to yield thietanes. These additions are stereospecific and regioselective (Scheme 9.94). The characteristics of additions are different from the one occurring from np* triplet state which is nonstereospecific and regiospecific. Based on sensitization and quenching studies and the nature of products formed the reactive state has been identified to be the S2 state. Based on quenching data the lifetime of the reactive state was estimated to be 10-10 sec. 101 Final 1.0, 4/13/2004 S X S X S X + (X = CN ; OEt ) hn S pp* CN NC CN CN Scheme 9.94 From the examples presented above it is clear that pp* excited state of thiocarbonyls are as reactive as np* excited carbonyls. Based on the behavior of thiocarbonyls it should not be a surprise if pp* excited carbonyls undergo hydrogen abstraction and addition to alkenes. 9.45. Other related chromophores In this chapter we have discussed the basic primary chemical processes of excited carbonyl chromophores: hydrogen abstraction, electron transfer, a and b-clevages and addition to unstaturated systems. Although the discussion was restricted to ketones and aldehydes, such reactions are expected from carbonyls present as a part of other chromophores listed in Scheme 9.95. This is illustrated with one example, ester (Scheme 9.96). O O H3C H H H H3C O CH3 R O H CH3 O O R O O CH3 O N H CH3 O O O R R O R O O R R N H N H R Scheme 9.95 102 Final 1.0, 4/13/2004 O OH hu O O H CH3OH Reduction via Hydrogen Abstraction OH O hu O O H Ar2NCH3 Reduction via electron transfer O O O O Norrish type II O hu O R OH hu a-Cleavage O R OH O RH + CO2 + CH4 hu O O b-Cleavage Scheme 9.96 9.46. Overview The most common reactive state of the carbonyl chromophore is the np* state. The np* state can be visualized to be electrophilic along the n-orbital and nucleophilic along the p-face. Upon excitation the carbonyl chromophore gives rise to several primary reactions depending on the nature of the lowest excited state (np* or pp*). a-Cleavage and b-cleavage often result in fragmentation of the carbonyl system. The acleavage process is known as the Norrish type I reaction. In the np* excited state the carbonyl chromophore is capable of abstracting a hydrogen atom or an electron. 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