The Mechanism of the Paterno-Buchi Reaction and its Application in the Organic Synthesis Review
The Paternò–Büchi reaction, named after two chemists who established its basic utility and form, is a photochemical reaction that forms four-membered oxetane rings from a carbonyl and an alkene. Much
work has been done with the reaction since Dr. Thorsten Bach of the University of Marburg published a review article in 1998 on its mechanism and synthetic utility.
The Paternò–Büchi reaction has been used recently in attempt to synthesize many natural organic products. In these experiments, the chemists are chiefly concerned with the regio- and diastereoselectivity of the products. This paper will address these selectivity concerns and report on the specific products that have been worked with since Dr. Bach’s 1998 review paper, such as (+)-Preussin and (?)-Oxetin. The following review seeks to be a source of information detailing the recent discoveries in the mechanism and application of the Paternò–Büchi reaction, intended specifically for organic chemists involved in synthesis.
I. Introduction…………………………………………………………… 3
II. Mechanistic Knowledge and Recent Discoveries
A. General Mechanism………………………….………………… 5
B. Mechanistic Issues in Synthesis
1. Regioselectivity…………………………………………… 7
2. Stereoselectivity………………………………………….. 8
III. Specific Synthetic Applications
A. Ring Opening Reactions…………………….………………… 11
B. Formation of Natural Oxetane Products…………………….. 13
IV. Summary……………………………………………………………… 13
V. Literature Cited……………………………………………………….. 15
VI. Tables…………………………………………………………………. 18
VII. Figure Captions………………………………………………………. 20
VIII. Figures………………………………………………………………… 21
IX. Schemes………………………………………………………………. 23
Photochemistry is the study of chemical reactions that are affected by or proceed upon application of light energy. Photochemical processes are useful tools in the laboratory because they excite ground-state electrons and form radicals.1 These radicals can be used to add to other molecules to form products that would be impossible or at least more difficult to form using other synthetic methods.
The Paternò–Büchi reaction is a synthetic method used in photochemistry that forms oxetane rings through excitation of the electrons on a carbonyl molecule. When the electron on the carbonyl is excited, it forms a radical and adds to an alkene, forming a 1,4-diradical. The diradical then closes and forms the oxetane ring when the two excited 1,4 electrons combine (see Scheme 1). An oxetane is a four-membered cyclic molecule (or part of a molecule) composed of three carbon atoms and an oxygen atom (see Figure 1).
The configuration of the product oxetane and the diradical explanation of the mechanism were established by Dr. Paternò and Dr. Büchi. The Paternò–Büchi reaction was named for these two chemists. Their work was published separately; Dr. Paternò published his article in Italy in 1909, and Dr. Büchi’s article was in print by 1954.2 Since 1954, chemists have produced several additional reviews of the reaction. These reviews have only recently begun to appear in the literature; most have been published within in the past 20 years.1
In 1998, Dr. Thorsten Bach of the University of Marburg wrote one of the most comprehensive review articles concerning the Paternò–Büchi reaction. The review explained the mechanism of the process based on the information available from previous experimentation. Dr. Bach’s paper then continued to detail the specific products that can be synthesized using the Paternò–Büchi reaction. Much of his work addressed the concerns in regio- and stereoselective yield that arise during photochemical synthesis.1
Understanding the factors affecting regio- and stereoselective yields and other aspects of the Paternò–Büchi reaction mechanism would greatly aid chemists in their effort to synthesize natural compounds and other organic products. Many of these products have oxetane rings in their structure, and several others are alcohols that can be synthesized using the Paternò–Büchi process followed by a ring-opening reaction. In either case, an understanding of the mechanism of the Paternò–Büchi reaction will aid chemists in obtaining yields with high selectivity.1,3
The selectivity of the yield in a synthetic process is especially important during manufacture of biological compounds, where the regio- or stereochemical structure of a drug can mean the difference between recovery and fatality. Regio- and stereochemical control can be achieved using the Paternò–Büchi reaction, which provides more efficient and sometimes essential methods of synthesizing many important biological products. The ?-amino acid oxetin, which acts as an antibiotic and herbicide, and the antifungal agent (+)-Preussin are two examples of natural compounds that can be made using the Paternò–Büchi reaction.4,5
Experiments concerning the synthesis of natural compounds have been recently growing in number. Since the printing of Dr. Bach’s paper in 1998, there have been several such experiments involving the Paternò–Büchi reaction, and publications reporting the regio- and stereoselective issues and mechanics of the process have appeared in numerous journals. Regardless of the specific interest in the Paternò–Büchi reaction or photochemistry in general, chemists who are involved in organic synthesis would benefit from the latest knowledge of an efficient synthetic method.5 This review paper, intended then for organic chemists involved in general synthesis, will seek to compile the experimental results of only those publications in print since Dr. Bach’s review article.
Mechanistic Knowledge and Recent Discoveries
The Paternò–Büchi reaction involves promoting electrons into excited states with light and allowing them to form cyclic bonds. The reaction is a type of [2 + 2] photocycloaddition, or 2? + 2?, which indicates that two electrons in ? bonds are reacting with two other ? electrons to form two different bonds. The two ? bonds in the Paternò–Büchi reaction come from a molecule containing an alkene component and a molecule with a carbonyl component. The new bonds formed through this process are ? bonds. Because these ? bonds complete a ring, the reaction is called a cycloaddition. Adding the “photo-” prefix to the word “cycloaddition” indicates that the reaction is initiated by light energy.1
When enough light energy is applied to the carbonyl group, an electron in either the nonbonding orbital or the ? bond enters into an excited state wherein the electron is promoted to an anti-bonding ?? orbital (see Scheme 1).6 The promoted electron initially retains its spin, and because electrons in the same orbital have opposite spins, the excited electron and the electron with which it was coupled before excitation still have opposite spins. This electron configuration is known as an excited singlet state, which is abbreviated and represented in Scheme 1 as S1. However, the S1 does not last long (approximately 1–2 ns), and the spin of the promoted electron quickly changes. This situation, in which the promoted electron changes its spin, is called intersystem crossing, or ISC.1 In this case, the excited electron goes through ISC from the S1 to the triplet state, abbreviated T1.6
The initial addition to the alkene 1 can happen either in the T1 or S1. If the carbonyl remains in the singlet state long enough to add to the alkene, it will add to form a transition state resembling a 1,4-diradical 3 with a negligibly short lifetime. The brevity of the lifetime of this diradical results from the fact that the S1 carbonyl has its radical electrons in opposite spins. When a radical electron adds to a full orbital (in this case the full ? molecular orbital on the alkene 1), it will only couple with the electron with opposite spin. The remaining displaced uncoupled electron is thus the same spin as the radical electron that initially added. Hence, the two radical electrons of the diradical formed immediately upon the singlet addition to the alkene 1 will be of opposite spin. Electrons must be of opposite spin to form a molecular bond, and thus the radical electrons in this diradical from the S1 will quickly bond, closing the molecule to form the oxetane ring 4 (see Scheme 1).6
However, oxetane ring closure takes longer if the T1 carbonyl adds to the alkene 1. Because the radical electrons in the triplet state carbonyl are of similar spin, the resulting 1,4-diradical 2 will also contain two radical electrons of the same spin. As these radical electrons cannot form a bond due to their identical spin, a relatively longer time must pass before one of the electrons changes spin and the bond forms (see Scheme 1).2
Mechanistic Issues in Synthesis
Because an alkene component, by definition, is composed of two carbon atoms held together by a double bond, there exists two points on the alkene where the excited electron on the carbonyl group may add. In the examples in the figures given previously, the alkene used, 2,3-dimethyl-2-butene, is completely achiral. The two alkene carbons are identical and thus it makes no functional difference to which carbon atom the oxygen adds. However, not all alkene molecules have identical carbons. In fact, most alkenes are chiral and the carbon atoms are not identical. Furthermore, many molecules have two or more carbon-carbon double bonds. The regioselectivity, or the preference of one atom to bond to another, is a major concern in synthesis.7
The regioselectivity concern generally arises when the carbonyl adds to the alkene in the triplet state. If the molecule is going to have a measurable 1,4-diradical configuration, as it does when the T1 carbonyl adds, the excited electron on the oxygen atom will tend to add to the side of the alkene that forms the most stable diradical. Bach1 and Adam7 have done extensive studies on the regioselectivity of the Paternò–Büchi reaction. Adam and Stegmann placed various substrates on a chiral alkene and reacted it with benzophenone. Table 1 displays the scheme of the reaction and his results. As can be observed in each reaction, the methyl groups on the original alkene stabilized the diradical so that the majority of the time the oxygen originally added into the carbon with the R1 and X group. However, in general, as the R1 and X substrates increased in size, decreasing the stability differences between the 1,4-diradicals leading to the 3 and 3’ products, the regioselectivity also dropped sharply (refer to Table 1). This experiment provides excellent evidence that regioselectivity is determined by the most stable 1,4-diradical.7
The stability of the 1,4-diradical is not the sole determinant of regioselectivity, however. The phenomenon of hydrogen bonding also has proven to influence regioselectivity. The oxygen atom on the carbonyl may be attracted to a specific hydrogen atom on one side of the alkene. This attraction will then cause a hydrogen bond to form. The carbonyl oxygen will then prefer to add to the carbon atom closest to the bond-forming hydrogen atom. Even though entry 1 in Table 1 has a larger X substrate (OH) attached to the alkene carbon than does entry 2 (H), it gives a much higher regioselectivity. This observation can be explained by the fact that the carbonyl oxygen tends to form a hydrogen bond with the hydrogen atom of the hydroxy group. Hydrogen bond effects are seen again in Table 2. Note that entry 5 is the only entry without a hydroxy group and hence has the lowest regioselectivity (refer to Table 2). The reaction of substrates 4e-4h can be seen in Figure 2. The carbonyl oxygen coordinates with the hydroxy group in each case to form a hydrogen bond (see Figure 2).7
In the reaction of acetone with 2,3-dimethyl-2-butene (Figure 1), the reactant molecules were achiral and no new stereocenters were formed. However, in most Paternò–Büchi reactions, there are two potentially new stereocenters formed. There could be, of course, feasibly only one stereocenter, or even three, but throughout most of the literature regarding Paternò–Büchi reactions, the chemists are centrally concerned with diastereoselectivity.1 Diastereoselective studies involve the preference of a reaction to produce new molecules with two stereocenters. The selective formation of these stereocenters remains a major aim in synthesis. Therefore, the stereochemical information in this review will tend to focus on the recent discoveries in the diastereoselectivity of the Paternò–Büchi process.
Just as in regiochemistry, the state (T1 or S1) of the excited carbonyl affects the diastereoselectivity of the reaction. Griesbeck and associates2 have researched the dependence of the diastereoselectivity on the electron spin direction. This research specifically concerned the addition of aliphatic aldehydes to 2,3 dihydrofuran and 2,3 dihydropyran. The aldehyde was used as the carbonyl group; it was irradiated to excite the electrons initially into the singlet state.
Because the aldehyde only has a lifetime of 1–2 nanoseconds in its excited singlet state, trapping reagents had to be used to intercept the carbonyl group in the S1. The products of an excited state singlet carbonyl could then be studied. Griesbeck found that increased concentration of trapping reagent gave increasingly lower diastereoselectivity as more of the aldehyde was trapped in its singlet state. This lower selectivity can be explained plainly in terms of the transition state of the reaction. As the transition state between the reactant singlet carbonyl and the product oxetane has a negligible lifetime, there is no need to be concerned about intermediate stability, geometrical restrictions, or steric interactions. Thus, there is no need for the singlet to be selective in its direction of addition.2
However, addition selectivity plays an important role in the T1. When the carbonyl in the triplet state adds to the alkene, it forms a 1,4 diradical that has a relatively measurable lifetime. This diradical must undergo intersystem crossing in order to close into the oxetane, which requires rigorous geometrical restrictions. Thus, the geometric configuration and stability of this diradical affects the diastereochemical makeup of the product oxetane. In this particular experiment, Griesbeck et al. found that the reaction through the triplet pathway yielded diastereoselectivities of up to 90:10.2
Because the geometric restrictions of the intermediate diradical in the triplet pathway is a major factor in determining the stereoselectivity of the Paternò–Büchi reaction, steric interactions must be considered. Adam and Stegmann7 studied the diastereoselectivity of the addition of aromatic aldehydes to allylic alcohols. Increasing the size of the R group on the alcohol gave increasingly higher diastereoselectivities (refer to Table 2). This observation indicates that the R group is a steric hindrance to the formation of the erythro-product (see Figure 2). Additional studies by Abe et al.8 conclude similarly that increased size of substrate groups will increase the stereoselectivity of the Paternò–Büchi reaction.
Hydrogen bonding can also affect the stereoselectivity of the Paternò–Büchi reaction just as this bonding phenomenon has been shown to affect regioselectivity. In another experiment, Griesbeck and Bondock9 tested the Paternò–Büchi reaction of prenol and prenyl acetate. Although there was not a major difference in stereoselectivity attained by replacing the hydroxy group with an acetate group, the hydrogen bonding delayed the intersystem crossing. Hydrogen bonding actually proved to activate the electron further on the carbonyl, causing an increase in the time the carbonyl could remain in its singlet-excited state. This increased lifetime allowed more singlet carbonyls to add to the alkene. Because singlet carbonyls generally add to alkenes irrespective of geometry or orientation, an actual decrease in stereoselectivity was observed due to hydrogen-bonding effects.
On the other hand, Bach et al.10 found that in their study, hydrogen bonding increased diastereoselectivity. In this experiment, a very complex molecule was used as the alkene, 3,4-dihydro-1H-pyridin-2-one. Because the carbonyl, a chiral aromatic aldehyde, formed a hydrogen bond with the amide hydrogen on the alkene, it formed a stable exciplex with the alkene. This stabilization allowed the carbonyl to add specifically in a constant geometrical conformation, yielding high diastereoselectivity.
Because the geometrical conformation of a molecule is often altered by increased heat, temperature can also play a major role in stereoselectivity. Adam and associates11 studied the Paternò–Büchi addition of benzophenone to both cis- and trans-cyclooctene at a temperature range of –95 °C to 110 °C. Except for the two extremes, temperature intervals of 20 °C were used. It was found that increasing the temperature increased the likelihood of the conformation change of the cyclooctene. If the cyclooctene changed conformation, the oxetane product was also changed. Lower temperatures favored the highest diastereoselectivity in each case.
Specific Synthetic Applications
Ring Opening Reactions
Once an oxetane ring is formed, it can be then opened conventionally with an agent such as LiAlH4 or sodium metal, creating an alcohol. The Paternò–Büchi reaction thus becomes an intermediate reaction rather than a terminal one. The advantage of using the Paternò–Büchi reaction as an intermediate in synthesis concerns stereoselective purity. The ring is opened in a way that the reaction takes place at a non-stereogenic center, and the stereoselectivity is thus preserved.12
Ring opening reactions are key in synthesizing many natural products. For example, prostaglandin analogues and ephedrine are products used often in medicine, and these can be synthesized utilizing the Paternò–Büchi reaction and then opening the oxetane ring. Insect pheromones and asteltoxin, a potent inhibitor of ATP synthesis, can also be formed using this ring-opening process as an intermediate.1 Bach and his group specifically completed the total synthesis of (+)-Preussin.13
(+)-Preussin is a useful antifungal agent. However, only the (+)-enantiomer is active. Therefore, it is absolutely imperative that the stereoselectivity is pure. This purity can be preserved through the Paternò–Büchi reaction. The final product can be formed beginning with the commercially available (S)-pyroglutaminol. The total synthesis of (+) Preussin is given in Scheme 2.
(+)-Preussin is certainly useful, but it is in no way the limit of the ring-opening process. As mentioned above, ring-opening reactions can be used to create diastereomerically pure alcohols. The final structure of the alcohol is based on the structure of the oxetane ring molecule. Bach and Eilers12 worked on the synthesis of diols. In this experiment, an oxetane was prepared with a protecting group. The protecting group, a trimethylsilyl ether, and the oxygen atom of the oxetane ring were attached to adjacent carbons. After removing the protecting group, LiAlH4 was applied to the oxetane, opening the ring. A trans-1,2-diol was then obtained at 69-99% yield.
Still, diols are not the only alcohols that can be obtained from oxetane rings. Adding N-Acyl enamines to aldehydes in the presence of light energy causes the Paternò–Büchi reaction. Subsequent ring opening using LiAlH4 or LiSBn then can form a cis 1,2 amino alcohol. Bach and Schröder15 studied this particular synthesis and were able to obtain these products in 65-86% yields.
Formation of Natural Oxetane Products
Although the ring opening process is extremely useful in synthesis, it is not always necessary to continue after the Paternò–Büchi reaction has taken place. Some useful natural compounds contain oxetane components and thus use the Paternò–Büchi process as a terminal step. Oxetanocin, an anti-cancer drug, was synthesized using this reaction. Additionally, the ?-amino acid (?)-oxetin was produced by adding an N-acyl enamine to an aldehyde. (?)-Oxetin has proven to act usefully as an antibiotic and herbicide.4
Understanding the basics of the Paternò–Büchi reaction is straightforward, but the scope of its application and its impact on photochemistry is extensive. Although the majority of chemists do not deal with photochemical processes, knowledge of at least the existence of the Paternò–Büchi reaction can facilitate the solution to many synthetic problems. The simultaneous formation of both a carbon-oxygen bond and a carbon carbon bond is extremely useful in connecting molecules together. Furthermore, the universal concern of regio- and stereochemical yields are usually solved using the Paternò–Büchi reaction, which generally adds both regioselectively and stereoselectively.
One can generally predict the regio- and stereoselectivity by an analysis of the chemical structure of the two reactants. There are several factors influencing the selectivity, which include diradical stability, steric interaction, hydrogen bonding, and temperature. Additionally, understanding the mechanistic nature of the singlet- and triplet-excited states of the carbonyl plays an important role in predicting and preparing yields. Further knowledge of the mechanism of the reaction will allow for much more accurate and efficient synthesis.
Improved synthetic methods will lead to additional discoveries and more effective manufacture of important organic compounds. (?)-Oxetin and oxetanocin are two oxetane-containing compounds that can be synthesized using the Paternò–Büchi reaction. However, not all useful compounds created with this reaction are oxetanes. (+)-Preussin, ephedrine, and prostaglandin analogues are alcohols that are synthesized using ring-opening reactions following the Paternò–Büchi process. As chemists at both universities and in the pharmaceutical laboratories gain more knowledge of efficient synthetic techniques, important natural compounds can be more effectively and cheaply made available to their target audience. The Paternò–Büchi reaction has proven useful and effective in the past and as it continues to be studied, it will only enhance the growing arsenal of synthetic chemists.
1. Bach, T. Stereoselective Intermolecular [2+2]-Photocycloaddition Reactions and Their Application in Synthesis. Synthesis 1998, 5, 683–703.
2. Griesbeck, A. G.; Fiege, M.; Bondock, S.; Gudipati, M. S. Spin Directed Stereoselectivity of Carbonyl–Alkene Photocycloadditions. Organic Lett. 2000, 2, 3623–3625.
3. Bach, T.; Bergmann, H.; Brummerhop, H.; Lewis, W.; Harms, K. The [2 + 2]-Photocycloaddition of Aromatic Aldehydes and Ketones to 3,4-Dihydro-2-pyridones: Regioselectivity, Diastereoselectivity, and Reductive Ring Opening of the Product Oxetanes. Chem. Eur. J. 2001, 7, 4512–4521.
4. Bach, T.; Schröder, J. A Short Synthesis of (?)-Oxetin. Liebigs Ann. / Rescueil 1997, 2265–2267.
5. Bach, T. The Paternò–Büchi Reaction of N-Acyl Enamines and Aldehydes – The Development of a New Synthetic Method and its Application to Total Synthesis and Molecular Recognition Studies. Synlett 2000, 12, 1699–1707.
6. Kuteladze, A.G. Conformational Analysis of Singlet–Triplet State Mixing in Paternò–Büchi Diradicals. J. Am. Chem. Soc. 2001, 123, 9279–9282.
7. Adam, W.; Stegmann, V. R. Hydroxy-Group Directivity in the Regioselective and Diastereoselective [2+2] Photocycloaddition (Paternò–Büchi Reaction) of Aromatic Carbonyl Compounds to Chiral and Achiral Allylic Substrates: The Preparation of Oxetanes with up to Three Stereogenic Centers as Synthetic Building Blocks. Synthesis 2001, 8, 1203–1214.
8. Abe, M.; Torii, E.; Nojima, M. Paternò–Büchi Photocyclization of 2-Siloxyfurans and Carbonyl Compounds. Notable Substituent and Carbonyl (Aldehyde vs. Ketone and Singlet- vs. Triplet-Excited State) Effects on the Regioselectivity (Double-Bond Selection) in the Formation of Bicyclic exo-Oxetanes. J. Org. Chem. 2000, 65, 3426–3431.
9. Griesbeck, A.G.; Bondock, S. Paternò–Büchi Reactions of Allylic Alcohols and Acetates with Aldehydes: Hydrogen-Bond Interaction in the Excited Singlet and Triplet States? J. Am. Chem. Soc. 2001, 123, 6191–6192.
10. Bach, T.; Bergmann, H.; Harms, K. High Facial Diastereoselectivity in the Photocycloaddition of a Chiral Aromatic Aldehyde and an Enamide Induced by Intermolecular Hydrogen Bonding. J. Am. Chem. Soc. 1999, 121, 10650–10651.
11. Adam, W.; Stegmann, V. R.; Weinkötz, S. Unusual Temperature-Dependent Diastereoselectivity in the [2+2] Photocycloaddition (Paternò–Büchi Reaction) of Benzophenone to cis- and trans-Cyclooctene through Conformational Control. J. Am. Chem. Soc. 2001, 123, 2452–2453.
12. Bach, T.; Eilers, F. Diastereomerically Pure 1,2-Diols by Nucleophilic Displacement Reactions of 3-Oxetanols – A Study Directed Towards the Identification of Suitable Nucleophiles and the Elucidation of Possible Side Reactions. Eur. J. Org. Chem. 1998, 2161–2169.
13. Bach, T.; Brummerhop, H. Unprecedented Facial Diastereoselectivity in the Paternò–Büchi Reaction of a Chiral Dihydropyrole—A Short Total Synthesis of (+)-Preussin. Angew. Chem. Int. Ed. 1998, 37, 3400–3401.
14. Bach, T.; Brummerhop, H.; Harms, K. The Synthesis of (+)-Preussin and Related Pyrrolidinols by Diastereoselective Paternò–Büchi Reactions of Chiral 2 Substituted 2,3-Dihydropyrroles. Chem. Eur. J. 2000, 6, 3838–3843.
15. Bach, T.; Schröder, J. Photocycloaddition of N-Acyl Enamines to Aldehydes and Its Application to the Synthesis of Diastereomerically Pure 1,2-Amino Alcohols. J. Org. Chem. 1999, 64, 1265–1273.