| Buchner ring expansion | |
|---|---|
| Named after | Eduard Buchner |
| Reaction type | Rearrangement reaction |
The Buchner ring expansion is a two-step organic C-C bond forming reaction used to access 7-membered rings. The first step involves formation of a carbene from ethyl diazoacetate, which cyclopropanates an aromatic ring. The ring expansion occurs in the second step, with an electrocyclic reaction opening the cyclopropane ring to form the 7-membered ring.
The Buchner ring expansion reaction was first used in 1885 by E. Buchner and T. Curtius [1] [2] who prepared a carbene from ethyl diazoacetate for addition to benzene using both thermal and photochemical pathways in the synthesis of cycloheptatriene derivatives. The resulting product was a mixture of four isomeric carboxylic acids. Variations in the reaction arise from methods of carbene preparation. Advances in organometallic chemistry have resulted in increased selectivity of cycloheptatriene derivatives. In the 1980s it was found that dirhodium catalysts provide single cyclopropane isomers in high yields. [3] Applications are found in medicine (drug syntheses) [4] [5] [6] [7] [8] and material science (fullerene derivatives). [9] [10] [11]
Preparation of ethyl-diazoacetate:
Buchner's first synthesis of cycloheptatriene derivatives in 1885 used photolysis and thermal conditions to generate the carbene. A procedure for preparation of the hazardous starting material needed for carbene generation in the Buchner reaction, ethyl-diazoacetate, is available in Organic Syntheses. [12] In the procedure provided, Searle includes cautionary instructions due to the highly explosive nature of diazoacetic esters.
Preparation of the metal carbenoid:
Synthesis of the carbene in the 1960s was focused on using copper catalysts for stereoselective propanation. [13] In the 1980s, dirhodium catalysts have been used to generate the carbenoid for cyclopropanation. The advent of metallochemistry has improved the selectivity of the product ratios of the cyclohexatriene derivatives through choice of ligand on the carbenoid catalyst. [14]
Step 1:
The reaction mechanism of a Buchner ring expansion begins with carbene formation from ethyl-diazoacetate generated initially through photochemical or thermal reactions with extrusion of nitrogen.
The generated carbene adds to one of the double bonds of benzene to form the cyclopropane ring.
The advent of transition metal catalyzed reagents provides alternative stereospecific methods for cyclopropanation. The choices for metals include Cu, Rh and Ru with a variety of ligands. [13] The use of rhodium catalysts in the Buchner reaction for carbene generation reduces the number of products by producing predominantly the kinetic cycloheptatrienyl esters. [14] Product mixtures of Buchner reactions resulting from thermal Rhodium II-catalysts are less complicated. Wyatt et al. have studied the regioselectivity of the thermal Buchner reaction using Rh2(O2CCF3)4 and demonstrated that the electrophilic character of the rhodium carbene prefers reaction at the more nucleophilic π-bonds of the aromatic ring. [15]
The accepted carbene catalytic cycle [16] was proposed by Yates [17] in 1952. Initially the diazo compound oxidatively adds to the metal ligand complex. Following the extrusion of nitrogen the metal carbene is generated and reacts with an electron rich aromatic substance to reductively regenerate the metal catalyst completing the catalytic cycle.
Step 2:
The second step of the Buchner reaction involves a pericyclic concerted ring expansion. Based on Woodward–Hoffmann rules, the electrocyclic opening of norcaradiene derivatives is a 6-electron disrotatory (π 4s + σ 2s), thermally allowed process.
The norcaradiene-cycloheptatriene equilibrium has been studied extensively. [18] The position of the equilibrium depends upon steric, electronic and conformational effects. Due to conformational strain in the cyclopropane ring of the norcaradiene the equilibrium lies on the side of the cycloheptatriene. The equilibrium may be shifted toward the norcaradiene by destabilization of the cycloheptatriene by bulky substitution (large sterically hindered groups i. e. t-butyl) at C1 and C6.
Equilibrium may be altered by varying substitution at C7. Electron donating groups (EDG) favor the norcaradiene, while electron withdrawing groups (EWG) favor the cycloheptatriene.
The tautomerism of the norcaradiene and cycloheptatriene can be understood based on the Walsh cyclopropane molecular orbitals of the norcaradiene cyclopropane ring. Electronic rationalization for stabilization of the Walsh orbitals [18] is possible for both electron withdrawing and electron donating groups at the C7 carbon. The molecular orbitals of electron withdrawing groups at C7 overlap with the HOMO Walsh orbitals of the cyclopropane ring causing a shortening of the C1-C6 bond. In the case of electron donating groups, orbital overlap is again possible now in the LUMO, resulting in an increase in antibonding character destabilizing the norcaradiene tautomer. The position of the equilibrium may be controlled depending on the carbene substituents.
Medicine:
The importance of the Buchner ring expansion annulation chemistry is evident in the application of this synthetic sequence in the synthesis of biological compounds.
While studying an analogous reaction of carbene addition to thiophene, Stephen Matlin and Lam Chan applied the Buchner ring expansion method in 1981 to generate spiro derivatives of Penicillin. [7]
In 1998, Mander et al. synthesized the diterpenoid tropone, Harringtonolide [6] using the Buchner intramolecular ring expansion annulation chemistry. A rhodium catalyst (Rh2(mandelate)4) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) were used to generate the carbene. This natural product was found to have antineoplastic and antiviral properties.
Danheiser et al. utilized intramolecular carbenoid generation to produce substituted azulenes through a Buchner type ring expansion. The anti-ulcer drug, Egualen (KT1-32) [4] [5] was synthesized using this ring expansion-annulation strategy with a rhodium catalyst (Rh2(OCOt-Bu)4) in ether.
Material Science:
The Buchner ring expansion method has been used to synthesize starting materials for applications in material science involving photovoltaic cells. The development of a donor-acceptor (D-A) interface composed of conducting polymer donors and buckminsterfullerene derivative acceptors create a phase-separated composite that enhances photoconductivity (available with only polymer donors) in the photoinduced charge transfer process of photovoltaic cells. [19] The fullerene compounds can be functionalized for miscibility of C60 to increase efficiency of the solar cell depending upon the polymeric thin film synthesized. [11]
The disadvantages of the reaction involve side reactions of the carbene moiety. The choice of solvent for the reaction needs to be considered. In addition to the potential for carbon-hydrogen bond insertion reactions, carbon-halogen carbene insertion is possible when dichloromethane is used as the solvent. [20]
Control for regioselectivity during the carbene addition is necessary to avoid side products resulting from conjugated cycloheptatriene isomers. Noels et al. used Rh(II) catalysts for carbene generation under mild reaction conditions (room temperature) to obtain regioselectively the kinetic non-conjugated cycloheptatriene isomer. [3] [8] [21]
Cyclopropene is an organic compound with the formula C3H4. It is the simplest cycloalkene. Because the ring is highly strained, cyclopropene is difficult to prepare and highly reactive. This colorless gas has been the subject for many fundamental studies of bonding and reactivity. It does not occur naturally, but derivatives are known in some fatty acids. Derivatives of cyclopropene are used commercially to control ripening of some fruit.
In chemistry, a carbene is a molecule containing a neutral carbon atom with a valence of two and two unshared valence electrons. The general formula is R-(C:)-R' or R=C: where the R represent substituents or hydrogen atoms.
The diazogroup is an organic moiety consisting of two linked nitrogen atoms (azo) at the terminal position. Overall charge neutral organic compounds containing the diazo group bound to a carbon atom are called diazo compounds or diazoalkanes and are described by the general structural formula R2C=N+=N–. The simplest example of a diazo compound is diazomethane, CH2N2. Diazo compounds (R2C=N2) should not be confused with azo compounds of the type R-N=N-R or with diazonium compounds of the type R-N2+.
The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen. Hence, the reaction is sometimes referred to as the Huisgen cycloaddition. 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives. The dipolarophile is typically an alkene or alkyne, but can be other pi systems. When the dipolarophile is an alkyne, aromatic rings are generally produced.
The Simmons–Smith reaction is an organic cheletropic reaction involving an organozinc carbenoid that reacts with an alkene to form a cyclopropane. It is named after Howard Ensign Simmons, Jr. and Ronald D. Smith. It uses a methylene free radical intermediate that is delivered to both carbons of the alkene simultaneously, therefore the configuration of the double bond is preserved in the product and the reaction is stereospecific.
The Bamford–Stevens reaction is a chemical reaction whereby treatment of tosylhydrazones with strong base gives alkenes. It is named for the British chemist William Randall Bamford and the Scottish chemist Thomas Stevens Stevens (1900–2000). The usage of aprotic solvents gives predominantly Z-alkenes, while protic solvent gives a mixture of E- and Z-alkenes. As an alkene-generating transformation, the Bamford–Stevens reaction has broad utility in synthetic methodology and complex molecule synthesis.
A transition metal carbene complex is an organometallic compound featuring a divalent organic ligand. The divalent organic ligand coordinated to the metal center is called a carbene. Carbene complexes for almost all transition metals have been reported. Many methods for synthesizing them and reactions utilizing them have been reported. The term carbene ligand is a formalism since many are not derived from carbenes and almost none exhibit the reactivity characteristic of carbenes. Described often as M=CR2, they represent a class of organic ligands intermediate between alkyls (−CR3) and carbynes (≡CR). They feature in some catalytic reactions, especially alkene metathesis, and are of value in the preparation of some fine chemicals.
Ring expansion and ring contraction reactions in the course of organic synthesis refer to a set of reactions which can lead to the expansion or contraction of an existing ring. This often makes it possible to access structures that would be difficult if not impossible to synthesise with single cyclization reactions. Ring expansions are valuable because they allow access to larger systems that are difficult to synthesize through a single cyclization due to the slow rate of formation. Ring contractions are useful for making smaller, more strained rings from larger rings. Expansions are classified by the mechanism of expansion and the atom(s) added; contractions are characterized simply by the reactive intermediate which performs the contraction.
Cycloheptatriene (CHT) is an organic compound with the formula C7H8. It is a closed ring of seven carbon atoms joined by three double bonds (as the name implies) and four single bonds. This colourless liquid has been of recurring theoretical interest in organic chemistry. It is a ligand in organometallic chemistry and a building block in organic synthesis. Cycloheptatriene is not aromatic, as reflected by the nonplanarity of the methylene bridge (-CH2-) with respect to the other atoms; however the related tropylium cation is.
Cyclopropanation refers to any chemical process which generates cyclopropane rings. It is an important process in modern chemistry as many useful compounds bear this motif; for example pyrethroids and a number of quinolone antibiotics. However the high ring strain present in cyclopropanes makes them challenging to produce and generally requires the use of highly reactive species, such as carbenes, ylids and carbanions. Many of the reactions proceed in a cheletropic manner.
Rhodium(II) acetate is the coordination compound with the formula Rh2(AcO)4, where AcO− is the acetate ion (CH
3CO−
2). This dark green powder is slightly soluble in polar solvents, including water. It is used as a catalyst for cyclopropanation of alkenes. It is a widely studied example of a transition metal carboxylate complex.
Carbene C−H insertion in organic chemistry concerns the insertion reaction of a carbene into a carbon–hydrogen bond. This organic reaction is of some importance in the synthesis of new organic compounds.
Intramolecular reactions of diazocarbonyl compounds include addition to carbon–carbon double bonds to form fused cyclopropanes and insertion into carbon–hydrogen bonds or carbon–carbon bonds.
Metal-catalyzed intermolecular carbenoid cyclopropanations are organic reactions that result in the formation of a cyclopropane ring from a metal carbenoid specie and an alkene. In the Simmons–Smith reaction the metal involved is zinc.
An insertion reaction is a chemical reaction where one chemical entity interposes itself into an existing bond of typically a second chemical entity e.g.:
Carbene dimerization is a type of organic reaction in which two carbene or carbenoid precursors react in a formal dimerization to an alkene. This reaction is often considered an unwanted side-reaction but it is also investigated as a synthetic tool. In this reaction type either the two carbenic intermediates react or a carbenic intermediate reacts with a carbene precursor. An early pioneer was Christoph Grundmann reporting on a carbene dimerisation in 1938. In the domain of persistent carbenes the Wanzlick equilibrium describes an equilibrium between a carbene and its alkene.
The Doyle–Kirmse reaction is an organic reaction in which in the original scope an allyl sulfide reacts with trimethylsilyldiazomethane to form the homoallyl sulfide compound. The reaction was first reported by W. Kirmse in 1968 and modified by M.P. Doyle in 1981.
Cycloisomerization is any isomerization in which the cyclic isomer of the substrate is produced in the reaction coordinate. The greatest advantage of cycloisomerization reactions is its atom economical nature, by design nothing is wasted, as every atom in the starting material is present in the product. In most cases these reactions are mediated by a transition metal catalyst, in few cases organocatalysts and rarely do they occur under thermal conditions. These cyclizations are able to be performed with excellent levels of selectivity in numerous cases and have transformed cycloisomerization into a powerful tool for unique and complex molecular construction. Cycloisomerization is a very broad topic in organic synthesis and many reactions that would be categorized as such exist. Two basic classes of these reactions are intramolecular Michael addition and Intramolecular Diels–Alder reactions. Under the umbrella of cycloisomerization, enyne and related olefin cycloisomerizations are the most widely used and studied reactions.
Cobalt(II)–porphyrin catalysis is a process in which a Co(II) porphyrin complex acts as a catalyst, inducing and accelerating a chemical reaction.
In organometallic chemistry, the activation of cyclopropanes by transition metals is a research theme with implications for organic synthesis and homogeneous catalysis. Being highly strained, cyclopropanes are prone to oxidative addition to transition metal complexes. The resulting metallacycles are susceptible to a variety of reactions. These reactions are rare examples of C-C bond activation. The rarity of C-C activation processes has been attributed to Steric effects that protect C-C bonds. Furthermore, the directionality of C-C bonds as compared to C-H bonds makes orbital interaction with transition metals less favorable. Thermodynamically, C-C bond activation is more favored than C-H bond activation as the strength of a typical C-C bond is around 90 kcal per mole while the strength of a typical unactivated C-H bond is around 104 kcal per mole.