Alkyne trimerisation
Encyclopedia
An alkyne trimerisation reaction is a 2+2+2
Cycloaddition
A cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...

 cyclization reaction
Organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...

 in which three alkyne
Alkyne
Alkynes are hydrocarbons that have a triple bond between two carbon atoms, with the formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature...

 molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...

s react to form an aromatic
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...

 compound. The reaction is 'pseudo' pericyclic since it has not been observed to occur without the assistance of metal catalysis; and the metal catalyst assembles the ring stepwise via intermediates which are not directly in between (in a geometric sense) the starting material and products.

Introduction

In 1866, Berthelot reported the first example of cyclotrimerization leading to aromatic products, the cyclization of acetylene
Acetylene
Acetylene is the chemical compound with the formula C2H2. It is a hydrocarbon and the simplest alkyne. This colorless gas is widely used as a fuel and a chemical building block. It is unstable in pure form and thus is usually handled as a solution.As an alkyne, acetylene is unsaturated because...

 to benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....

. The reaction required very high temperatures to proceed (400 °C) and produced a complex mixture of products, and research in the field remained dormant until the late 1940s. In 1948, Reppe
Walter Reppe
Walter Julius Reppe was a German chemist. He is notable for his contributions to the chemistry of acetylene.-Education and career:...

 discovered that nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...

 could catalyze the formation of substituted benzenes from acetylenic compounds; since his initial discovery, cyclotrimerizations to produce substituted benzenes have been catalyzed by no less than seventeen transition metal
Transition metal
The term transition metal has two possible meanings:*The IUPAC definition states that a transition metal is "an element whose atom has an incomplete d sub-shell, or which can give rise to cations with an incomplete d sub-shell." Group 12 elements are not transition metals in this definition.*Some...

s, including:
  • Group 4
    Group 4 element
    The Group 4 elements are a group of chemical elements in the periodic table. In the modern IUPAC nomenclature, Group 4 of the periodic table contains titanium , zirconium , hafnium and rutherfordium . This group lies in the d-block of the periodic table...

     (Ti, Zr)
  • Group 5
    Group 5 element
    A Group 5 element is a chemical element in the fifth group in the periodic table. In the modern IUPAC nomenclature, Group 5 of the periodic table contains vanadium , niobium , tantalum and dubnium . This group lies in the d-block of the periodic table...

     (V, Nb)
  • Group 6
    Group 6 element
    A Group 6 element is one in the series of elements in group 6 in the periodic table, which consists of the transition metals chromium , molybdenum , tungsten , and seaborgium ....

     (Mo, W)
  • Group 8
    Group 8 element
    A Group 8 element is one in the series of elements in group 8 in the periodic table, which consists of the transition metals iron , ruthenium , osmium and hassium ....

     (Fe, Ru, Os)
  • Group 9
    Group 9 element
    In modern IUPAC nomenclature, Group 9 of the periodic table contains the elements cobalt , rhodium , iridium , and meitnerium . These are all d-block transition metals...

     (Co, Rh, Ir)
  • Group 10
    Group 10 element
    A Group 10 element is one in the series of elements in group 10 in the periodic table, which consists of the transition metals nickel , palladium , platinum , and darmstadtium ....

     (Pd)
  • Group 11
    Group 11 element
    A Group 11 element is one in the series of elements in group 11 in the periodic table, consisting of transition metals which are the traditional coinage metals of copper , silver , and gold...

     (Cu)

Advantages: Control of the substitution pattern of the aromatic product is good in many cases, and cyclotrimerization can be used in cases when functionalization of pre-formed aromatic materials (through electrophilic aromatic substitution
Electrophilic aromatic substitution
Electrophilic aromatic substitution EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile...

, for instance) is not selective. The reaction is highly chemoselective for triple bonds and can tolerate a wide variety of functional groups on the starting materials.

Disadvantages: For cotrimerizations involving two or three different acetylenes, a variety of regioisomers may form. Operationally, these reactions usually require elevated temperatures (>60 °C) and sometimes require irradiation to facilitate the dissociation of strongly binding carbon monoxide
Carbon monoxide
Carbon monoxide , also called carbonous oxide, is a colorless, odorless, and tasteless gas that is slightly lighter than air. It is highly toxic to humans and animals in higher quantities, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal...

 ligands. Catalyst deactivation can occur through the formation of stable, 18-electron η4-complexes incorporating cyclobutadiene
Cyclobutadiene
Cyclobutadiene is the smallest [n]-annulene , an extremely unstable hydrocarbon having a lifetime shorter than five seconds in the free state. It has chemical formula 44 and a rectangular structure verified by infrared studies. This is in contrast to the square geometry predicted by simple Hückel...

, cyclohexadiene
Cyclohexadiene
-See also:* Benzene or its theoretical isomer 1,3,5-Cyclohexatriene* Cyclohexene...

, and arene
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...

 ligands. The most problematic side products of the reaction are due to cyclotetramerization (leading to cyclooctatetraene
Cyclooctatetraene
1,3,5,7-Cyclooctatetraene is an unsaturated derivative of cyclooctane, with the formula C8H8. It is also known as [8]annulene. This polyunsaturated hydrocarbon is a colorless to light yellow flammable liquid at room temperature...

s) and alkyne dimerization (leading to enyne
Enyne
An enyne is a functional group in organic chemistry consisting of a conjugated alkyne and alkene group....

s).

Prevailing Mechanism

The most common mechanism for the cyclotrimerization of acetylenes begins with the formation of a metallocyclopentadiene complex. Oxidative cyclization of two coordinated alkyne units produces either metallocycle
Metallocycle
In organometallic chemistry, a metallacycle is a derivative of a carbocyclic compound wherein a metal has replaced at least one carbon center. Metallacycles appear frequently as reactive intermediates in catalysis, e.g. olefin metathesis and alkyne trimerization. In organic synthesis, directed...

 3 or 4. After dissociation of a third ligand and coordination of a third alkyne, two pathways are possible. Either alkyne insertion
Migratory insertion
A migratory insertion is a type of reaction in organometallic chemistry wherein two ligands on a metal complex combine. It is a subset of reactions that very closely resembles the insertion reactions, and both are differentiated by the mechanism that leads to the resulting stereochemistry of the...

 generates metallocycloheptatriene 5, or [4+2] cycloaddition generates bridged bicycle 6. The former pathway is questionable however, as reductive elimination from a metallocycloheptatriene to form an arene is symmetry forbidden. A third pathway proposed for ruthenium
Ruthenium
Ruthenium is a chemical element with symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to most chemicals. The Russian scientist Karl Ernst Claus discovered the element...

 catalysts involves formal [2+2] cycloaddition of the alkyne followed by rearrangement, reductive elimination, and arene decomplexation. The intermediacy of bicycle 7 was supported by DFT calculations.

For cyclotrimerization reactions of asymmetrically substituted acetylenes, a number of regioisomeric products are possible. The substitution pattern about the product arene depends on two events: formation of the metallocyclopentadiene intermediate and incorporation of the third equivalent of alkyne
Alkyne
Alkynes are hydrocarbons that have a triple bond between two carbon atoms, with the formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature...

. Although both head-to-head and tail-to-tail metallocyclopentadienes lead to 1, a number of acetylenic substrates selectively form regioisomers of type 2. Steric bulk on the alkyne
Alkyne
Alkynes are hydrocarbons that have a triple bond between two carbon atoms, with the formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature...

 coupling partners and catalyst have been invoked as the controlling elements of regioselectivity.

Enantioselective Variants

Chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 catalysts have been employed in combination with arynes to produce non-racemic amounts of atropisomer
Atropisomer
Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The word atropisomer is derived from the Greek a, meaning not, and tropos, meaning turn...

ic products. Selective cyclotrimerization of one of a pair of enantiotopic
Topicity
In chemistry, topicity is the stereochemical relationship of substituents relative to the structure to which they are attached. Depending on the relationship, such groups can be heterotopic, homotopic, enantiotopic, or diastereotopic....

 alkynes has also been facilitated by a chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 catalyst.

Scope and Limitations

Catalysts for cyclotrimerization are highly selective for triple bonds, which gives the reaction a fairly wide substrate scope. Alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

s, ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...

s, amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

s, and carbonyl compounds (ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...

s, ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

s, amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...

s, and carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...

s) are well tolerated. Other than carbonyl compounds, the reaction is not generally compatible with unsaturated functionality. Nitrile
Nitrile
A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...

s, for instance, can react to form pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...

s.

The reaction is limited in some cases by catalyst deactivation due to the formation of stable, 18-electron η4-complexes. Cyclobutadiene
Cyclobutadiene
Cyclobutadiene is the smallest [n]-annulene , an extremely unstable hydrocarbon having a lifetime shorter than five seconds in the free state. It has chemical formula 44 and a rectangular structure verified by infrared studies. This is in contrast to the square geometry predicted by simple Hückel...

, cyclohexadiene
Cyclohexadiene
-See also:* Benzene or its theoretical isomer 1,3,5-Cyclohexatriene* Cyclohexene...

, and arene
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...

 complexes have all been observed as off-cycle, inactivate catalyst forms. In addition to high-order polymers and dimers and trimers, which originate from low regio- and chemoselectivities, enyne
Enyne
An enyne is a functional group in organic chemistry consisting of a conjugated alkyne and alkene group....

 side products derived from alkyne dimerization have been observed. Rhodium catalysts are particularly adept at enyne formation (see below). For nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...

 catalysis, formation of larger rings (particularly cyclooctatetraene
Cyclooctatetraene
1,3,5,7-Cyclooctatetraene is an unsaturated derivative of cyclooctane, with the formula C8H8. It is also known as [8]annulene. This polyunsaturated hydrocarbon is a colorless to light yellow flammable liquid at room temperature...

) can be a problem.

Synthetic Applications

Cyclization of diynes with a separate alkyne can provide fused ring systems with high atom economy. In a striking example in the synthesis of estrone, diyne 8 was combined with di(trimethylsilyl)acetylene to produce benzocyclobutane 9. Upon heating, ring-opening produced a quinone methide that participated in a subsequent intramolecular Diels-Alder reaction.
If the third alkyne unit is tethered to the first two, three rings can be created in a single step. In the example below in the synthesis of calomelanolactone, Wilkinson's catalyst
Wilkinson's catalyst
Wilkinson's catalyst is the common name for chlorotrisrhodium, a coordination compound with the formula RhCl3 . It is named after the late organometallic chemist and 1973 Nobel Laureate, Sir Geoffrey Wilkinson who popularized its use.-Structure and basic properties:The compound is a square planar,...

 was used to catalyze an intramolecular cotrimerization of triyne 10.
Crowded triynes can cyclize to products exhibiting helical chirality. In one example, highly favorable due to the formation of three new aromatic rings in one step, triyne 12 transforms to helical product 13 in the presence of cyclopentadienylcobalt dicarbonyl
Cyclopentadienylcobalt dicarbonyl
Cyclopentadienylcobalt dicarbonyl is an organocobalt compound with formula Co2, abbreviated CpCo2. It is an example of a half-sandwich complex. It is a dark red air sensitive liquid. This compound features one cyclopentadienyl ring that is bound in an η5-manner and two carbonyl ligands...

. As of 2004, this process had yet to be rendered asymmetric, but the products could be separated through chiral HPLC
High performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...

.

Comparison with Other Methods

Cyclotrimerization presents an alternative to the functionalization of pre-formed aromatic compounds through electrophilic
Electrophilic aromatic substitution
Electrophilic aromatic substitution EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile...

 or nucleophilic
Nucleophilic aromatic substitution
right|300px|Aromatic nucleophilic substitutionA nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring...

 substitution, the regioselectivity
Regioselectivity
In chemistry, regioselectivity is the preference of one direction of chemical bond making or breaking over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base will abstract from an organic molecule, or where...

 of which can sometimes be difficult to control.

Other methods for the direct formation of aromatic rings from substituted, unsaturated precursors include the Dötz reaction
Dötz reaction
The Wulff-Dötz reaction is the chemical reaction of an aromatic or vinylic alkoxy pentacarbonyl chromium carbene complex with an alkyne and carbon monoxide to give a Cr3-coordinated substituted phenol. Several reviews have been published...

, palladium-catalyzed [4+2] benzannulation of enynes with alkynes, and Lewis-acid-mediated [4+2] cycloaddition of enynes with alkynes. Cyclization of transient benzyne species with alkynes, catalyzed by palladium, can also produce substituted aromatic compounds.

Typical Conditions

Although various experimental conditions have been used to perform this reaction, commercially available CpCo(CO)2
Cyclopentadienylcobalt dicarbonyl
Cyclopentadienylcobalt dicarbonyl is an organocobalt compound with formula Co2, abbreviated CpCo2. It is an example of a half-sandwich complex. It is a dark red air sensitive liquid. This compound features one cyclopentadienyl ring that is bound in an η5-manner and two carbonyl ligands...

 remains the most common catalyst used. High temperatures and irradiation with light are often required in order to facilitate the dissociation of carbon monoxide
Carbon monoxide
Carbon monoxide , also called carbonous oxide, is a colorless, odorless, and tasteless gas that is slightly lighter than air. It is highly toxic to humans and animals in higher quantities, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal...

 from the catalyst.

Example Procedure

1,2-Bis(propiolyl)benzene (350 mg, 2.3 mmol) was dissolved in diglyme
Diglyme
Diglyme, or bis ether, is a solvent with a high boiling point. It is an organic compound which is the dimethyl ether of diethylene glycol. It is a clear, colorless liquid with a slight ether-like odor...

 (8 mL) and added over a period of 36 hours (with a syringe pump) to a refluxing solution of bis(trimethylsilyl)acetylene
Bis(trimethylsilyl)acetylene
Bisacetylene is an organosilicon compound with the formula C22. It is a colorless liquid that is soluble in organic solvents...

 (5 mL) and CpCo(CO)2
Cyclopentadienylcobalt dicarbonyl
Cyclopentadienylcobalt dicarbonyl is an organocobalt compound with formula Co2, abbreviated CpCo2. It is an example of a half-sandwich complex. It is a dark red air sensitive liquid. This compound features one cyclopentadienyl ring that is bound in an η5-manner and two carbonyl ligands...

 (60 µL) in n-octane
Octane
Octane is a hydrocarbon and an alkane with the chemical formula C8H18, and the condensed structural formula CH36CH3. Octane has many structural isomers that differ by the amount and location of branching in the carbon chain...

 (70 mL), under a dry N2
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

 atmosphere. Removal of the solvent and unreacted BTMSA by vacuum transfer followed by column chromatography
Column chromatography
Column chromatography in chemistry is a method used to purify individual chemical compounds from mixtures of compounds. It is often used for preparative applications on scales from micrograms up to kilograms.The main advantage of column chromatography is the relatively low cost and disposability...

 on silica gel (100 g) (pentane:ether = 80:20) gave a yellow oil which solidified on standing. Recrystallization of the crude solid from methanol gave orange crystals of the title anthraquinone (120 mg, 15 %), mp
Melting point
The melting point of a solid is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depends on pressure and is usually specified at standard atmospheric pressure...

 69–71.5°: IR
Infrared spectroscopy
Infrared spectroscopy is the spectroscopy that deals with the infrared region of the electromagnetic spectrum, that is light with a longer wavelength and lower frequency than visible light. It covers a range of techniques, mostly based on absorption spectroscopy. As with all spectroscopic...

 (CCl4
Carbon tetrachloride
Carbon tetrachloride, also known by many other names is the organic compound with the formula CCl4. It was formerly widely used in fire extinguishers, as a precursor to refrigerants, and as a cleaning agent...

) 2900, 1670, 1540, 1320, 1290, 1250, 1005, 980, 952, 932 cm–1; 1H NMR δ 1.50 (s, 2H), 1.70 (m, 2H), 2.23 (m, 2H), 9.51 (s, 18H); EIMS
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...

m/z (relative intensity): M+ 352 (14), 337 (17), 73 (67), 57 (79), 55 (77), 43 (100), 41 (67).
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