CSIRO PUBLISHING Essay
www.publish.csiro.au/journals/ajc Aust. J. Chem. 2010,63, 979–986
The Benzyne Story
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane,
Qld 4072, Australia. Email: email@example.com
The history of o-benzyne from its early beginnings as an unobservable reactive intermediate until its present status as a
very well characterized but still theoretically challenging molecule with important applications in synthesis is reviewed.
The m- and p-benzynes, tridehydrobenzenes, and benzdiynes are also known, and p-benzyne is a key intermediate in the
action of a potent class of ene-diyne anti-tumour compounds.
Manuscript received: 2 May 2010.
Manuscript accepted: 3 June 2010.
Benzyne (C6H4) was first proposed as a reactive intermedi-
ate by Bachmann and Clarke at the Eastman Kodak Co., who
investigated the reaction of sodium with boiling chlorobenzene
(a Wurtz–Fittig reaction), which produces benzene, biphenyl,
a trace of p-diphenylbenzene, and significant amounts of
o-diphenylbenzene, triphenylene, and o,o-diphenylbiphenyl.
While the formation of the first three products could be explained
by means of ionic reactions of the types
C6H5Cl +2Na=C6H5Na +NaCl
C6H5Na +C6H5Cl =C6H5–C6H5+NaCl
C6H5–C6H4Na +C6H5Cl =C6H5–C6H4–C6H5+NaCl
the formation of the last three, in particular triphenylene, was
taken as ‘decisive in favour of the free radical explanation’:
whereby C6H5– is the phenyl radical, and C6H4<was named
free phenylene. It was clear from the presentation that the free
phenylene was meant to be the biradical 1(Scheme 1).
Compelling experimental evidence was provided by Georg
Wittig, then at the University of Freiburg and soon afterwards
at Tübingen, in 1942. Wittig and his students discovered
that the formation of biphenyl by reaction of the haloben-
zenes with phenyllithium was the fastest with fluorobenzene,
which was contrary to the expected difficulty of displacing
fluoride directly in a nucleophilic substitution reaction. A di-
polar form 2of benzyne was proposed as an intermediate in
the formation of biphenyl (Scheme 2a) because, in contrast
to the corresponding olefinic zwitterions, which would give
rise to open-chain acetylenes, ‘the zwitterion  would not
be able to form dehydrobenzene’, dehydrobenzene being the
triple-bonded molecule 3. The trimerization of this zwitterion to
triphenylene ‘under certain conditions’ was noted. In the same
year, Morton et al. at Massachusetts Institute of Technology
(MIT) had also proposed the ‘dipolar phenylene’ intermediate
, which ‘cannot be stabilized by double bond formation’ in
their investigation of the Wurtz reaction of chlorobenzene with
pentylsodium (Scheme 2b). Schubert invoked o-phenylene to
explain the formation of triphenylene in the reactions of diphenyl
ethers with phenylpotassium in 1950 (Scheme 2c).
In 1953, John D. Roberts and coworkers, then at MIT and soon
afterwards at CalTech, reported a classic 14C labelling exper-
iment, which necessitated the involvement of a symmetrical,
electrically neutral intermediate – formulated as benzyne 3–in
the reaction of chlorobenzene with potassium amide in liquid
ammonia (Scheme 3). These authors also estimated that the
bent acetylene structure would lead to a strain energy comparable
to that of cyclopropene.[5b] In fact, the current values for these
(a) X ⫽ F, RM ⫽ PhLi
(b) X ⫽ Cl, RM ⫽ C5H11Na
(c) X ⫽ OPh, RM ⫽ PhK
© CSIRO 2010 10.1071/CH10179 0004-9425/10/070979
980 C. Wentrup
Br or Mg
strain energies are 54 (cyclopropene) and 50kcalmol−1(ben-
zyne) (1 cal =4.184 J).[6,7] The enthalpy of formation of benzyne
is ∼107 kcal mol−1.
Huisgen and Rist (University of Munich) provided further
evidence for the benzyne structure (3-methoxybenzyne 4)by
demonstrating that identical mixtures of carboxylic acids were
obtained on treatment of ortho- and meta-fluoroanisole with
phenyllithium followed by carboxylation with CO2(Scheme 4).
The existence of 1,2-naphthyne 5was demonstrated analogously
(Scheme 4). Nevertheless, Huisgen expressed uncertainty as
to whether the symmetrical intermediates implied by the results
were really free arynes, and, at any rate, ‘an isolation is out of
Further advances were made when it was discovered
that benzyne could be generated from o-dihalobenzenes (e.g.
o-bromofluorobenzene) with lithium amalgam or by forming the
Grignard reagent with magnesium.[10–12] The first Diels–Alder
reaction of benzyne, with furan, was performed in this manner,
giving a 76% yield of the adduct 6, which was converted to
1-naphthol with acid (Scheme 5). In the absence of the furan
trapping agent, biphenylene and triphenylene were obtained in
yields of 24 and 3%, respectively.
The concept of mesomerism (resonance) had been developed
by Slater, Ingold, Hückel, Pauling, and Wheland in 1931–33
and was slowly being adopted by organic chemists. Qualitative
valence bond theory was accepted fairly readily, but molecular
orbital (MO) theory only took hold in the 1950s. Huisgen and
Rist formulated benzyne 3with a (weakened) in-plane πbond.
Lüttringhaus and Schubert were the first to explicitly formulate
mesomerism between the three limiting valence structures of
benzyne, i.e. the zwitterion 2, the biradical o-phenylene 1, and
the ‘acetylene’ 3(Eqn 1).[4b] Wittig used the two equivalent zwit-
terionic structures 2in mesomerism with the ‘cyclohexadienyne’
3(Eqn 2) at this time (1955) and continued to do so for many
years (the term cyclohexadienyne is incorrect, as it implies that
benzyne lacks the resonance stabilization of benzene). Eugen
Müller considered resonance between the singlet biradical
and the zwitterion, 1↔2, and Heaney, Mann, and Millar
formulated a resonance between the zwitterion and the aryne,
In an early application of MO theory, Coulson estimated
the structure of o-benzyne with a pronounced and localized but
rather too short C1C2triple bond (122 pm) and a too long C2C3
bond (144 pm) (the modern experimental values are 125.5 and
138.3 pm, respectively; see below). Clearly, in 1958 MO the-
ory was not yet capable of providing a satisfactory description
of benzyne. At the same time, Roberts admitted to not know-
ing the state of the two electrons formally forming the triple
bond. The first detailed MO study of benzyne by Hoffmann,
Imamura, and Hehre was published in 1968. An account by
Radom et al. in 1986 stressed that very little was still known about
the level of theory needed for a proper description of benzynes
but concluded from two-configurational calculations that while
the triple-bonded valence structure 3dominates, o-benzyne pos-
sesses non-negligible biradical character,i.e. 3↔1; accordingly,
single-configuration descriptions are inadequate. This theme
is developed thoroughly in this issue’s Research Front.[8,19,20]
An important experimental advance was made in 1960, when
Stiles and Miller discovered that o-benzenediazonium carboxy-
late 7is an excellent precursor of benzyne in organic solvents
at 40–60◦C. This precursor, easily obtained by diazotization of
anthranilic acid, allowed benzyne chemistry to move out of the
organometallic domain for the first time (Scheme 6). A 30%
yield of biphenylene can be obtained by thermal decomposition
of 7in boiling 1,2-dichloroethane (∼84◦C). The first UV
spectrum of gaseous benzyne (λmax =242 ±3 nm) was obtained
by photolysis of 7. Fur ther details of the UV spectrum of ben-
zyne are reviewed herein. A mass spectrum of benzyne (or
most likely a ring-opened C6H•+
4ion) was obtained in the
same manner. Compound 7 continues to be an important
preparative source of benzyne.
Diphenyliodonium carboxylate 8requires a higher tempera-
ture, 160◦C in diglyme, to form benzyne, iodobenzene, and CO2.
The Benzyne Story 981
The benzyne was trapped with anthracene, giving triptycene
(Scheme 6). Flash vacuum pyrolysis (FVP) of 8at 325◦C yielded
biphenylene and iodobenzene. Much later, the three-phase
test was used to demonstrate the occurrence of free o-benzyne
in the thermolysis of 8in solution.
As more and more solid evidence for the existence of ben-
zyne accumulated, further efforts were made to demonstrate the
existence of the free molecule in the gas phase. Schüler and
coworkers generated benzyne from the monohalobenzenes and
even from benzene and phenylacetylene in an electrical glow
discharge, the evidence being the observation of biphenylene
by means of its gas-phase UV spectrum. They assumed that
benzyne existed in a biradical state (1) in the plasma. This
method of benzyne generation languished for many years, but a
modern variation has risen to prominence recently: high quality
microwave spectra of benzyne have been produced by pulsed
electrical discharges (0.8–1.4 kV) in benzene vapour seeded in
neon, which had been cooled to a few degrees K in a free jet
Wittig and Ebel found that iodophenylmercuric iodide 9and
bis(2-iodophenyl)mercury 10 yielded biphenylene on gas phase
pyrolysis. Ebel and Hoffmann reported detailed experi-
ments on the gas-phase flow pyrolysis of 10 (Ar carrier gas,
60 hPa, 700◦C; residence time in the hot zone ∼8.5 ×10−3s),
where the benzyne so produced was trapped downstream with
furan vapour. Although the furan adduct 6was isolated in only
0.1% yield, these experiments demonstrated the existence of free
benzyne with a lifetime of at least 20 ms under the reaction condi-
tions. FVP of compound 10 was used later by Grützmacher to
obtain the mass spectrum and an approximate ionization poten-
tial of benzyne (or most likely a ring-opened C6H•+
whereas Fisher and Lossing used FVP of o-diiodobenzene
for the same purpose. Günther demonstrated that FVP of
o-diiodobenzene over Zn at 500–550◦C(2hPaN
2carrier gas at a
rate of 120 cm s−1) afforded a 21% yield of biphenylene and 10%
of triphenylene. The relatively high yields of triphenylene in
some of these reactions indicate that it is not (only) formed by
free benzyne trimerizing in the gas phase. With H2as carrier gas
a 3–5% yield of benzene and 7% of biphenylene were obtained.
Co-pyrolysis with anthracene afforded the Diels–Alder trapping
product triptycene in 8% and biphenylene in 10% yields.
Monitoring of the dimerization of gaseous benzyne produced by
flash photolysis of solid benzene diazonium carboxylate 5in an
evacuated tube by both UV and mass spectrometry permitted the
determination of a preliminary rate of dimerization to bipheny-
lene as equal to or greater than 8 ±108l mol−1s−1. This value
was considered to be within a factor of 3 of the true bimolecular
rate constant, which is just a little short of a rate measured a few
years later by flash photolysis of phthalic anhydride vapour in
Ne and Ar, 4.6 ±1.2 ×109l mol−1s−1.
The photolysis of either 9,10, or phthaloyl peroxide 11
in the presence of tetraphenylcyclopentadienone (tetracyclone)
or hnor hn
m 61%, p 39%
yielded 1,2,3,4-tetraphenylnaphthalene, formed via Diels–Alder
addition of benzyne followed by cheletropic extrusion of CO
(Scheme 7). The fact that the reactions took place photo-
chemically caused the authors to propose a biradical state
(1; singlet or triplet) of dehydrobenzene. Benzyne is now rec-
ognized to be a ground state singlet molecule, and the currently
accepted singlet-triplet splitting is 37.5 kcal mol−1.
Wittig and Hoffmann introduced yet another, convenient
albeit explosive, benzyne precursor, 1,2,3-benzothiadiazole S,S-
dioxide 12, which decomposes to benzyne at 10–20◦Cin
solution. Benzyne was trapped in Diels–Alder cycloaddition
reactions (Scheme 8). When 12 was allowed to decompose
in substance in an evacuated flask at 60◦C, biphenylene was iso-
lated in 38–52% yield together with 2% triphenylene. Köbrich
provided evidence for a symmetrical benzyne intermediate in
the pyrolysis of the silver salts of o-chlorobenzoic acids 13 in a
sealed tube (Scheme 8).
Huisgen and Knorr built a solid foundation for mechanis-
tic benzyne chemistry by using competition experiments to
demonstrate that the same reactive intermediate – interpreted as
benzyne – was formed from three different precursors, namely
thermolysis of 7and 10 and treatment of o-bromofluorobenzene
with Li(Hg). The competition constant for the Diels–Alder
cycloadditions with furan and 1,3-cyclohexadiene was ∼21.5
for all precursors under a variety of conditions.
982 C. Wentrup
or NiO22 N2
The oxidation of 1-aminobenzotriazole with lead tetraacetate
or nickel peroxide constitutes an extremely mild method for gen-
erating benzyne by loss of two molecules of N2. In this way
benzyne chemistry can be carried out well below room temper-
ature (Scheme 9). This continues to be an important method
in preparative benzyne chemistry. It is interesting to note
that benzyne undergoes click chemistry; thus, the cycloaddition
of azides to benzynes is a convenient method of synthesis of
Three groups reported the formation of benzyne by pyrolysis
of carbonyl compounds in 1965–66: the gas-phase pyrolysis
of indanetrione (FVP over quartz tubings at 600◦C/0.2 hPa)
yielded up to 40% of biphenylene and ∼4% of triphenylene,
the solution-phase pyrolysis of phthalic anhydride in benzene
afforded 1% biphenylene and ∼1% triphenylene, and flow
pyrolysis of phthalic anhydride (N2carrier gas, 50 hPa, ∼800◦C)
yielded 10–15% biphenylene. In the latter work, a 30% yield
of octachlorobiphenylene was isolated from a similar pyrolysis
of tetrachlorophthalic anhydride. The formation of benzyne
by microwave flash pyrolysis of phthalic anhydride is reviewed
herein. The mechanism of the deceptively simple forma-
tion of benzyne in the thermal reactions (Eqn 3) is still under
Δ or hn
CO2, CO (3)
The photolysis of phthalic anhydride in the gas phase and in
matrices also affords benzyne. The measurement of the rate of
dimerization of gaseous benzyne formed by microsecond flash
photolysis was mentioned above. The reaction is reported to
take place via a hot, highly vibrationally excited, ground state of
phthalic anhydride when using ArF laser photolysis at 193 nm
on the nanosecond timescale.
The first matrix-isolation experiments with IR-spectroscopic
observation of benzyne were reported in 1973 using phthaloyl
proxide and benzocyclobutenedione as precursors.
o-Benzyne has now been characterized very thoroughly by
IR spectroscopy in noble gas matrices, which is reviewed
herein,[19,25] as are the gas-phase microwave,[31,50] photoelec-
tron and UV spectroscopic, and mass spectrometric inves-
tigations. Also the 1,2-naphthyne 5and 2,3-naphthyne have been
characterized by IR and UV spectroscopy. Moreover, the 13C
dipolar NMR spectrum of benzyne-1,2-13C2was obtained in
an Ar matrix at ∼20K and yielded the important acetylenic
C1C2distance as 124 ±2 pm, which is in agreement with
the more accurate value obtained by microwave spectroscopy,
125.5 pm.[31,50] This bond distance lies between the values for
ethyne (120.3pm) and ethene (133.2pm), being closer to the
ethyne value, and the C2C3bonds (138.3pm) are a little shorter
than the CC bonds in benzene (139.1 pm). The 1H and 13C
NMR spectra of benzyne in solution were obtained after gen-
erating the molecule inside a hemi-carcerand, a large molecular
container. In this environment benzyne is stable at −100◦C
for several hours, sufficiently for the recording of its NMR spec-
tra. At higher temperatures it reacts irreversibly with the hemi-
carcerand host via Diels–Alder addition to benzene moieties.
The combined evidence from microwave,[31,50] NMR,[53a] and
IR spectroscopy[48,49] as well as theoretical calculations[17,53b]
indicates that o-benzyne can be described as a resonance hybrid
of the acetylene 3and the cumulene 14, being closer to the
acetylenic structure (Eqn 4).
Stable transition metal complexes of benzyne have been pre-
pared and investigated by X-ray crystallography.They have much
more normal bond lengths than benzyne itself, e.g. C1C2is
ethene-like (133–136 pm), all other CC bonds are very much
benzene-like (138–140 pm) in the Zr and Ni complexes, and
they are best described as metallacyclopropenes (e.g. the Ni(0)
complex shown in Eqn 5).
The m- and p-benzynes 15 and 16,[8,19,55] tridehydrobenzenes
17–19, and tetradehydrobenzenes (benzdiynes), e.g. 20
(Scheme 10) are described herein. Several resonance struc-
tures can be formulated for these species as illustrated for 20
as an example (Scheme 10). Therefore, for a proper quantum-
mechanical description, it is preferable to use multireference
methods.[8,19,20,56] Sato and Niino present experimental evi-
dence for the multireference character of benzdiynes. Also
the highly reactive 1,4-benzdiynes can be stabilized by com-
plexation with transition metals, thus turning them into isolable
compounds.[54,57] X-ray crystallography of such complexes
indicate that the C1C2and C4C5bonds are ethene-like (131–
135 pm), and the C2C3bonds are benzene-like (139–140 pm).
The cyclic C6(hexadehydrobenzene), which according to cal-
culations has D3h symmetry (structure similar to that shown for
m-benzyne in Fig. 1), is also known,[20,58] as are linear C6and
other carbon chain clusters.
The structure of m-benzyne has been the subject of much
debate, partly because there is experimental evidence for the
17 18 19
The Benzyne Story 983
Fig. 1. m-Benzyne. Calculated bond distances at the CCSD(T)/cc-pVDZ
(upright numbers) and CAS-RS2/cc-pVDZ (italics).
existence of an isomer, bicyclo[3.1.0]hexatriene 22 as a reac-
tive intermediate formed by base treatment of the bicyclohexene
21 (Scheme 11). Similarly, there is good experimental evi-
dence for the existence of butalene 23, an isomer of p-benzyne
(Scheme 11). However, both these reactions are complex and
not fully understood. Similar experiments on a benzologue of 21
indicated that a m-naphthyne was formed rather than a benzo-
logue of 22. Early Hückel MO calculations indicated, not
surprisingly, that 22, being a non-alternant ‘azulenoid’ 6πelec-
tron system, retains a major portion of the benzenoid resonance
energy. In spite of its high strain energy, it is, therefore, a rea-
sonable intermediate. In contrast, butalene 23 is a cyclobutadiene
derivative with antiaromatic character and consequential high
energy. MINDO/3 calculations indicated the separate existence
of m- and p-benzynes 15 and 16 as well as the bicyclic structures
22 and 23. General valence bond calculations predicted that
the lowest energy forms of the 1,3- and 1,4-dehydrobenzenes
are not bicyclic but monocyclic structures with considerable
biradical character. However, the m-isomer 15 collapses to the
bicyclic structure 22 at the single-determinant level. Thus,
again, multireference theoretical methods are required in order
to handle these systems correctly. Recent calculations reveal a
1,3-bonding interaction resulting in an interradical distance of
200–210 pm for the singlet state of m-benzyne, depending on
the computational method used (Fig. 1).[19,66] Due to this bond-
ing interaction, m-benzyne has much less biradical character
and a larger singlet-triplet splitting than p-benzyne. The calcu-
lated IR spectra of m-benzyne and tetrafluoro-p-benzyne at the
CCSD(T) level are in very good agreement with the matrix-
isolation IR spectra. To summarize, the species observed in
matrix isolation as well as gas phase experiments definitely
possess the monocyclic aryne structures 15 and 16, although
they are not regular hexagons.The bicyclic structures 22 and 23
do not correspond to the observed species. The natures of the
OH O OH 25 Dynemicin A
intermediates generated in the reactions shown in Scheme 11
remain to be clarified.
The Bergman-cyclization of 3-hexene-1,5-diynes(e.g. 24)
to p-benzynes (e.g. 16) (Scheme 12) is biologically important
because several natural products with powerful anti-tumour,
and/or antibiotic properties such as the calicheamicins, esperam-
icins, lidamycin, and dynemicins (e.g. 25, Scheme 12) con-
tain such enediyne moieties, and their biological activity can
be ascribed to formation of transient p-benzynes. Hydrogen
abstraction by the p-benzyne generates a more reactive phenyl
radical, which abstract a second H atom from DNA, resulting
in DNA cleavage.[68,69] There is a related cyclization of enyne-
allenes 26 to α,3-didehydrotoluenes 27 or 1,4-didehydroindenes,
known as the Myers–Saito cyclization, which is involved in
the mechanism of action of the neocarcinostatin anti-cancer
agents. Examples of photochemically triggered Bergman and
Myers–Saito rearrangements are reviewed herein.[68d]
The possible interconversion of the o-,m-, and p-benzynes
has been evaluated theoretically. Experiments using femto-
second gas-phase laser irradiation to generate the o-,m-, and
p-benzynes from the corresponding dibromobenzenes, together
with femtosecond mass spectrometric product observation, indi-
cate lifetimes of ∼400 ps for each benzyne isomer under the
reaction conditions used. The experiments also suggested that
the o- and m-isomers may rearrange to the p-isomer by H-atom
tunnelling; the p-isomer then undergoes the Bergman ring
Several reviews of benzyne chemistry have been published
In spite of extensive experimentation, many challenges remain
in benzyne-related chemistry.A better experimental and theoret-
ical understanding of m- and p-benzynes and their relationships
with the bicyclic isomers 22 and 23 is needed. It is an exper-
imental challenge but highly desirable to obtain microwave
spectra and hence exact geometrical parameters of m- and p-
benzynes. The benzynes have always been a testing ground
for computational methods (as have carbenes and nitrenes,
for example) and continue to be so; their multireference
character puts serious demands on the theoretical methods.
The interplay between experiment and theory will undoubt-
edly continue, and systems such as α,n-didehydrotoluenes
27 and 1,n-didehydroindenes involved in Myers–Saito and
related rearrangements, didehydrophenyl cations,[67b] and
984 C. Wentrup
hetarynes need further characterization by matrix-isolation
spectroscopy and computational methods. A deeper insight
into the mechanisms of rearrangement and interconversion
of arynes[25,43c,46,56a] will require exacting experimental and
computational investigations. Benzynes continue to be applied
widely in synthesis by using classical procedures as well as mod-
ern methods, such as the CsF-induced reactions of o-(trimethyl-
silyl)aryl triflates and o-(trimethylsilyl)aryliodonium triflates,
described in this issue. New chemotherapeutic drugs based
on enediyne/p-benzyne chemistry are being developed, and
their modes of action are being investigated experimentally and
computationally. There is fascinating potential for synthetic
applications of aryne and cycloalkyne transition metal com-
plexes either as isolable compounds or reactive intermediates
under stoichiometric,[54d,74] or catalytic conditions.
 (a) W. E. Bachmann, H. T. Clarke, J. Am. Chem. Soc. 1927,49, 2089.
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