Ring expansion and contraction

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Ring expansion and ring contraction reactions expand or contract rings, usually in organic chemistry. The term usually refers to reactions involve making and breaking C-C bonds, [1] Diverse mechanisms lead to these kinds of reactions.

Contents

The bond migration step of the pinacol type rearrangement. Key step of pinacol mechanism.jpg
The bond migration step of the pinacol type rearrangement.

Demyanov ring contraction and expansion

These reactions entail diazotization of aminocyclobutanes and aminocyclopropanes. Loss of N2 from the diazo cations results in secondary carbocations, which tend to rearrange and then undergo hydrolysis. The reaction converts aminocyclobutane into a mixture of hydroxycyclobutane and hydroxymethylcyclopropane. These reactions produce an equilibrating mixture of two carbocations: [2]

C4H+7 ⇌ C3H5CH+2

Carbenoid ring contractions

Mechanism of the Wolff rearrangement used to give a ring contracted product. Generalized Wolf rearrangement mechanism.jpg
Mechanism of the Wolff rearrangement used to give a ring contracted product.

In the Arndt–Eistert reaction, an α-diazoketone is induced to release N2, resulting in a highly reactive sextet carbon center adjacent to the carbonyl. Such species convert by a Wolff rearrangement to give an ester in the presence of alcohols. When applied to cyclic α-diazoketones, ring contraction occurs. [3] [4] In the case of steroids, this reaction has been used to convert cyclopentanone groups to cyclobutanyl derivatives. [5]

Ring expansion reactions

A scheme showing ring expansion by exocyclic bond migration (A) and ring opening of a bicyclic molecule (B). Ring expansion mechanisms.jpg
A scheme showing ring expansion by exocyclic bond migration (A) and ring opening of a bicyclic molecule (B).

Ring expansions can allow access to larger systems that can be difficult to synthesize otherwise. [6] Rings can be expanded by attack of the ring onto an outside group already appended to the ring (a migration/insertion), opening of a bicycle to a single larger ring, or coupling a ring closing with an expansion. [1] These expansions can be further broken down by what type of atom they incorporate (a carbon or a heteroatom) into the expanded ring.

Carbon insertion through migration to an exocyclic group

These reactions have the general features of having an exocyclic leaving group on a carbon adjacent to the ring and an electron donating group on the ring capable of initiating a migration of an endocyclic bond.

A common migration introduction of carbon is a pinacol rearrangement. [1] While this reaction refers specifically to a vicinal dihydroxide rearrangement, there are other pinacol type rearrangements that proceed through the same general mechanism such as the Tiffeneau-Demjanov rearrangement. These "semipinacol rearrangements" occur under milder conditions and are thus preferable in complex syntheses. [7] These reactions are useful beyond simply expanding a ring because the exocyclic group attacked may also have other functionality appended to it besides the leaving group. The group to which the endocyclic bond migrates can also be selectively added to the ring based on the functionality already present, for example 1,2 addition into a cyclic ketone.

Carbon insertion through opening of a bicycle

A generalized mechanism of the Buchner ring expansion. General Buchner ring expansion.jpg
A generalized mechanism of the Buchner ring expansion.

A common method for expanding a ring involves opening cyclopropane-containing bicyclic intermediate. The strategy can start with a Simmons-Smith-like cyclopropanation of a cyclic alkene. [8]

A related cyclopropane-based ring expansion is the Buchner ring expansion. The Buchner ring expansion is used to convert arenes to cycloheptatrienes. The Buchner ring expansion is encouraged to open to the desired product by placing electron withdrawing groups on the carbon added. In order to perform the ring opening on saturated bicyclic molecules the cyclopropane must be introduced such that a neighboring group can facilitate the expansion or the ring must be opened by attackate the expansion [9] or the ring must be opened by attack from an outside group. [10]

Ring opening as a means of ring expansion can also be applied to larger systems to give access to even larger ring syscyclization. The Grob fragmentation can be applied as an example of such an expansion. Like the pinacol type migration the Grob fragmentation relies on an electron donating group to promote the bond migration and encourage the leaving group to be expelled. In this case the electron donating group can be a pseudo electron donating group which is capable of eliminating and donating an electron pair into the carbon with the breaking bond. Working with two smaller rings can allow for elaboration of two parts of the molecule separately before working with the expanded ring. The Dowd-Beckwith ring expansion reaction is also capable of adding several carbons to a ring at a time,e of adding several carbons to a ring at a time, and is a useful tool for making large rings. [11] While it proceeds through an intermediate bicycle the final cyclization and ring opening take place within the same radical reaction. [12] This expansion is useful because it allows the expansion of a beta-ketoester to a large cyclic ketone which can easily be elaborated using either the cyclic ketone or the exocyclic ester.

The bond migration steps in the Baeyer-Villiger oxidation (A) and the Beckmann rearrangement (B). Baeyer-Villiger and Beckmann rearrangement migrations.jpg
The bond migration steps in the Baeyer-Villiger oxidation (A) and the Beckmann rearrangement (B).

Heteroatom insertion reactions

Heteroatom additions to rings can occur through ring expansions if not they are not done through de-novo ring synthesis. [13] These introductions are primarily ring expansions because they often take place through migration/insertion pathways similar to those mentioned above for carbon. Examples include high impact applications of the Beckmann rearrangement (for introduction of nitrogen into codeine) [14] and the Baeyer-Villiger oxidation (introduction of oxygen to cage-annulated ethers) [15] in synthesis. Both occur with the expulsion of a leaving group as the alkyl group migrates onto the exocyclic heteroatom, which is strikingly similar to the pinacol type rearrangement.

Ring contraction reactions

Ring contraction through anionic (A), cationic (B), and carbenoid (C) reactive intermediates. RIng contraction mechanisms.jpg
Ring contraction through anionic (A), cationic (B), and carbenoid (C) reactive intermediates.

Ring contractions are useful for making smaller, more strained rings from larger rings. The impetus for making these rings comes from the difficulty associated with making a fully elaborated small ring when such a ring could more easily be made from an elaborated larger ring, from which an atom can be excised, or that the original larger scaffold is more accessible. [16]

Ring contractions are easily characterized simply by the reactive intermediate which performs the contraction. The standard intermediates are anionic, cationic, and carbenoid. [17]

Favorskii rearrangement

The Favorskii rearrangement is a classic anionic ring contraction. [18] It proceeds through a carbanion that attacks an endocyclic carbon and expels a leaving group (a halide) forming a bicyclic molecule with rings smaller than the original. The bicycle is then opened by nucleophilic attack on the ketone to give the contracted product. [19] This reaction has been used to convert cyclohexanone to the methyl ester of cyclopropanecarboxylic acid.

A generalized mechanism of the Favorskii rearrangement to give a ring contracted product. Note that anion formation has been omitted. Generalized Favorskii rearrangement mechansim.jpg
A generalized mechanism of the Favorskii rearrangement to give a ring contracted product. Note that anion formation has been omitted.

An alternative to the standard Favorskii rearrangement, is to perform what can be thought of as a negative pinacol rearrangement where an anionic group encourages a bond aligned with a leaving group to migrate and expel the leaving group, which has been used in several syntheses. [17] It should also be noted that the so-called "quasi-Favorskii rearrangement" proceeds without an additional nucleophile to form the final contracted product.

A general pinacol type rearrangement to an unequal 5,7 ring system. Pinacol Rearrangment to a 5,7 ring system.jpg
A general pinacol type rearrangement to an unequal 5,7 ring system.

Cation contractions

The cationic rearrangement contraction proceeds through the loss of a leaving group and the migration of an endocyclic bond to the carbocation. Pinacol type rearrangements are often used for this type of contraction. [20] Like the expansion reaction this proceeds with an electron donating group aiding in the migration.

Contraction reactions of one ring can be coupled with an expansion of another to give an unequal bicycle from equally sized fused ring. These cationic rearrangements have found use to synthesize the cores of complex molecules. [21]

Further reading

Related Research Articles

The Baeyer–Villiger oxidation is an organic reaction that forms an ester from a ketone or a lactone from a cyclic ketone, using peroxyacids or peroxides as the oxidant. The reaction is named after Adolf von Baeyer and Victor Villiger who first reported the reaction in 1899.

<span class="mw-page-title-main">Prelog strain</span> Interactions between atomic groups on different parts of a ring molecule

In organic chemistry, transannular strain is the unfavorable interactions of ring substituents on non-adjacent carbons. These interactions, called transannular interactions, arise from a lack of space in the interior of the ring, which forces substituents into conflict with one another. In medium-sized cycloalkanes, which have between 8 and 11 carbons constituting the ring, transannular strain can be a major source of the overall strain, especially in some conformations, to which there is also contribution from large-angle strain and Pitzer strain. In larger rings, transannular strain drops off until the ring is sufficiently large that it can adopt conformations devoid of any negative interactions.

<span class="mw-page-title-main">Wagner–Meerwein rearrangement</span> Organic reaction

A Wagner–Meerwein rearrangement is a class of carbocation 1,2-rearrangement reactions in which a hydrogen, alkyl or aryl group migrates from one carbon to a neighboring carbon. They can be described as cationic [1,2]-sigmatropic rearrangements, proceeding suprafacially and with stereochemical retention. As such, a Wagner–Meerwein shift is a thermally allowed pericyclic process with the Woodward-Hoffmann symbol [ω0s + σ2s]. They are usually facile, and in many cases, they can take place at temperatures as low as –120 °C. The reaction is named after the Russian chemist Yegor Yegorovich Vagner; he had German origin and published in German journals as Georg Wagner; and Hans Meerwein.

<span class="mw-page-title-main">Favorskii rearrangement</span> Chemical reaction

The Favorskii rearrangement is principally a rearrangement of cyclopropanones and α-halo ketones that leads to carboxylic acid derivatives. In the case of cyclic α-halo ketones, the Favorskii rearrangement constitutes a ring contraction. This rearrangement takes place in the presence of a base, sometimes hydroxide, to yield a carboxylic acid, but usually either an alkoxide base or an amine to yield an ester or an amide, respectively. α,α'-Dihaloketones eliminate HX under the reaction conditions to give α,β-unsaturated carbonyl compounds.

<span class="mw-page-title-main">Dakin oxidation</span> Organic redox reaction that converts hydroxyphenyl aldehydes or ketones into benzenediols

The Dakin oxidation (or Dakin reaction) is an organic redox reaction in which an ortho- or para-hydroxylated phenyl aldehyde (2-hydroxybenzaldehyde or 4-hydroxybenzaldehyde) or ketone reacts with hydrogen peroxide (H2O2) in base to form a benzenediol and a carboxylate. Overall, the carbonyl group is oxidised, whereas the H2O2 is reduced.

<span class="mw-page-title-main">Pinacol rearrangement</span> Rearrangement of compound by charge rearrangement.

The pinacol–pinacolone rearrangement is a method for converting a 1,2-diol to a carbonyl compound in organic chemistry. The 1,2-rearrangement takes place under acidic conditions. The name of the rearrangement reaction comes from the rearrangement of pinacol to pinacolone.

<span class="mw-page-title-main">Cyclic compound</span> Molecule with a ring of bonded atoms

A cyclic compound is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where all the atoms are carbon, none of the atoms are carbon, or where both carbon and non-carbon atoms are present. Depending on the ring size, the bond order of the individual links between ring atoms, and their arrangements within the rings, carbocyclic and heterocyclic compounds may be aromatic or non-aromatic; in the latter case, they may vary from being fully saturated to having varying numbers of multiple bonds between the ring atoms. Because of the tremendous diversity allowed, in combination, by the valences of common atoms and their ability to form rings, the number of possible cyclic structures, even of small size numbers in the many billions.

<span class="mw-page-title-main">Tiffeneau–Demjanov rearrangement</span>

The Tiffeneau–Demjanov rearrangement (TDR) is the chemical reaction of a 1-aminomethyl-cycloalkanol with nitrous acid to form an enlarged cycloketone.

The benzilic acid rearrangement is formally the 1,2-rearrangement of 1,2-diketones to form α-hydroxy–carboxylic acids using a base. This reaction receives its name from the reaction of benzil with potassium hydroxide to form benzilic acid. First performed by Justus von Liebig in 1838, it is the first reported example of a rearrangement reaction. It has become a classic reaction in organic synthesis and has been reviewed many times before. It can be viewed as an intramolecular redox reaction, as one carbon center is oxidized while the other is reduced.

The Ramberg–Bäcklund reaction is an organic reaction converting an α-halo sulfone into an alkene in presence of a base with extrusion of sulfur dioxide. The reaction is named after the two Swedish chemists Ludwig Ramberg and Birger Bäcklund. The carbanion formed by deprotonation gives an unstable episulfone that decomposes with elimination of sulfur dioxide. This elimination step is considered to be a concerted cycloelimination.

<span class="mw-page-title-main">Wolff rearrangement</span>

The Wolff rearrangement is a reaction in organic chemistry in which an α-diazocarbonyl compound is converted into a ketene by loss of dinitrogen with accompanying 1,2-rearrangement. The Wolff rearrangement yields a ketene as an intermediate product, which can undergo nucleophilic attack with weakly acidic nucleophiles such as water, alcohols, and amines, to generate carboxylic acid derivatives or undergo [2+2] cycloaddition reactions to form four-membered rings. The mechanism of the Wolff rearrangement has been the subject of debate since its first use. No single mechanism sufficiently describes the reaction, and there are often competing concerted and carbene-mediated pathways; for simplicity, only the textbook, concerted mechanism is shown below. The reaction was discovered by Ludwig Wolff in 1902. The Wolff rearrangement has great synthetic utility due to the accessibility of α-diazocarbonyl compounds, variety of reactions from the ketene intermediate, and stereochemical retention of the migrating group. However, the Wolff rearrangement has limitations due to the highly reactive nature of α-diazocarbonyl compounds, which can undergo a variety of competing reactions.

<span class="mw-page-title-main">Cyclopropanation</span> Chemical process which generates cyclopropane rings

In organic chemistry, 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 pyrethroid insecticides 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.

In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group R3Si−O−CR=CR2, composed of an enolate bonded to a silane through its oxygen end and an ethene group as its carbon end. They are important intermediates in organic synthesis.

The semipinacol rearrangement is a rearrangement reaction in organic chemistry involving a heterosubstituted alcohol of the type R1R2(HO)C–C(X)R3R4. The hetero substituent can be a halogen (Cl, Br, I), a tosylate, a mesylate or a thiol group. This reaction proceeds by removal of the leaving group X forming a carbocation as electron deficient center. One of the adjacent alkyl groups then migrates to the positive carbon in a 1,2-shift. Simultaneously with the shift, a pi bond forms from the oxygen to carbon, assisting in driving the migrating group off its position. The result is a ketone or aldehyde. In another definition all semipinacol rearrangements "share a common reactive species in which an electrophilic carbon center, including but not limited to carbocations, is vicinal to an oxygen-containing carbon and can drive the 1,2-migration of a C–C or C–H bond to terminate the process, generating a carbonyl group ".

<span class="mw-page-title-main">Cyclopropanone</span> Chemical compound

Cyclopropanone is an organic compound with molecular formula (CH2)2CO consisting of a cyclopropane carbon framework with a ketone functional group. The parent compound is labile, being highly sensitive toward even weak nucleophiles. Surrogates of cyclopropanone include the ketals.

The vinylcyclopropane rearrangement or vinylcyclopropane-cyclopentene rearrangement is a ring expansion reaction, converting a vinyl-substituted cyclopropane ring into a cyclopentene ring.

<span class="mw-page-title-main">Basketane</span> Chemical compound

Basketane is a polycyclic alkane with the chemical formula C10H12. The name is taken from its structural similarity to a basket shape. Basketane was first synthesized in 1966, independently by Masamune and Dauben and Whalen. A patent application published in 1988 used basketane, which is a hydrocarbon, as a source material in doping thin diamond layers because of the molecule's high vapor pressure, carbon ring structure, and fewer hydrogen-to-carbon bond ratio.

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.

Rearrangements, especially those that can participate in cascade reactions, such as the aza-Cope rearrangements, are of high practical as well as conceptual importance in organic chemistry, due to their ability to quickly build structural complexity out of simple starting materials. The aza-Cope rearrangements are examples of heteroatom versions of the Cope rearrangement, which is a [3,3]-sigmatropic rearrangement that shifts single and double bonds between two allylic components. In accordance with the Woodward-Hoffman rules, thermal aza-Cope rearrangements proceed suprafacially. Aza-Cope rearrangements are generally classified by the position of the nitrogen in the molecule :

In organic chemistry, the oxy-Cope rearrangement is a chemical reaction. It involves reorganization of the skeleton of certain unsaturated alcohols. It is a variation of the Cope rearrangement in which 1,5-dien-3-ols are converted to unsaturated carbonyl compounds by a mechanism typical for such a [3,3]-sigmatropic rearrangement.

References

  1. 1 2 3 Kantorowski, E.J.; Kurth, M.J. (2000). "Expansion to seven-membered rings" (PDF). Tetrahedron. 56 (26): 4317–4353. doi:10.1016/S0040-4020(00)00218-0. S2CID   34628258. Archived from the original (PDF) on August 18, 2019.
  2. ↑ Smith, Michael B.; March, Jerry (2006). March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. p. 1588-1592. doi:10.1002/0470084960. ISBN   9780470084960.{{cite book}}: CS1 maint: multiple names: authors list (link)
  3. ↑ Smith, Michael B.; March, Jerry (2006). March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. p. 1599. doi:10.1002/0470084960. ISBN   9780470084960.{{cite book}}: CS1 maint: multiple names: authors list (link)
  4. ↑ Kirmse, W. (July 2002). "100 Years of the Wolff Rearrangement". European Journal of Organic Chemistry. 2002 (14): 2193. doi:10.1002/1099-0690(200207)2002:14<2193::AID-EJOC2193>3.0.CO;2-D.
  5. ↑ Thomas N. Wheeler and J. Meinwald (1972). "Formation and Photochemical Wolff Rearrangement of Cyclic α-Diazo Ketones: d-Norandrost-5-en-3β-ol-16-carboxylic Acids". Organic Syntheses. 52: 53. doi:10.15227/orgsyn.052.0053.
  6. ↑ Casadei, M.A.; Calli, C.; Mandolini, L. (February 1, 1984). "Ring-closure reactions. 22. Kinetics of cyclization of diethyl (.omega.-bromoalkyl)malonates in the range of 4- to 21-membered rings. Role of ring strain". Journal of the American Chemical Society. 106 (4): 1051–1056. doi:10.1021/ja00316a039.
  7. ↑ Kurti, L.; Czako, B. (2005). Strategic Applications of Named Reactions. Elsevier. p. 350. ISBN   978-0-12-429785-2. OCLC   1107566236.
  8. ↑ "One-Carbon Ring Expansion of Cycloalkanones to Conjugated Cycloalkenones: 2-Cyclohepten-1-One". Organic Syntheses. 59: 113. 1979. doi:10.15227/orgsyn.059.0113.
  9. ↑ Bieräugel, H.; Akkerman, J. M.; Armande, J. C. L.; Pandit, U. K. (1974). "A specific insertion of carbenes into carbon-carbon bonds". Tetrahedron Letters. 15 (33): 2817–2820. doi:10.1016/S0040-4039(01)91751-4.
  10. ↑ Hoberg, J.O.; Bozell, J.J. (September 1995). "Cyclopropanation and ring-expansion of unsaturated sugars". Tetrahedron Letters. 36 (38): 6831–6834. doi:10.1016/0040-4039(95)01387-W.
  11. ↑ Hierold, J.; Lupton, D.W. (July 2012). "Synthesis of Spirocyclic γ-Lactones by Cascade Beckwith–Dowd Ring Expansion/Cyclization". Organic Letters. 14 (13): 3412–3415. doi:10.1021/ol301387t. PMID   22691029.
  12. ↑ Dowd, P.; Choi; S. C. J. Am. Chem. Soc. 1987, 3493–3494
  13. ↑ McMurry, John (2008). Organic Chemistry 7th Ed. pp. 945–946. ISBN   978-0-495-11258-7.
  14. ↑ White, J. D.; Hrnciar, P.; Stappenbeck, F. (1999). "Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion". Journal of Organic Chemistry. 63 (21): 7871–7884. doi:10.1021/jo990905z.
  15. ↑ Marchand, A. P.; Kumar, V. S.; Hariprakasha, H. K. (2001). "Synthesis of Novel Cage Oxaheterocycles". Journal of Organic Chemistry. 66 (6): 2072–2077. doi:10.1021/jo001611c. PMID   11300903.
  16. ↑ Silva, L.F. Tetrahedron 2002, 9137–9161[ full citation needed ]
  17. 1 2 Myers, Andrew. "Methods for Ring Contraction" (PDF). Retrieved November 30, 2014– via Harvard University Department of Chemistry and Chemical Biology.
  18. ↑ Chenier, Philip J. (1978). "The Favorskii Rearrangement in Bridged Polycyclic Compounds". Journal of Chemical Education. 55 (5): 286–291. Bibcode:1978JChEd..55..286C. doi:10.1021/ed055p286.
  19. ↑ Smith, Michael B.; March, Jerry (2006). March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. p. 1595-1596. doi:10.1002/0470084960. ISBN   9780470084960.{{cite book}}: CS1 maint: multiple names: authors list (link)
  20. ↑ Song, Zhen-Lei; Fan, Chun-An; Tu, Yong-Qiang (2011). "Semipinacol Rearrangement in Natural Product Synthesis". Chemical Reviews. 111 (11): 7523–7556. doi:10.1021/cr200055g. PMID   21851053.
  21. ↑ Büchi, G.; Hofheinz, W.; Paukstelis, J. V. (November 1969). "Synthesis of (-)-aromadendrene and related sesquiterpenes". Journal of the American Chemical Society. 91 (23): 6473–6478. doi:10.1021/ja01051a051.
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