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{{Short description|Organic compound made by removing substituents from an aromatic ring}}
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'''Arynes'''<ref>{{GoldBookRef|title=Aryne|file=A00465}}</ref> or '''benzynes'''<ref>{{GoldBookRef|title=Benzynes|file=B00634}}</ref> are highly reactive species derived from an [[aromatic ring]] by removal of two [[substituent]]s. The most common arynes are [[ortho-|ortho]] but meta- and para-arynes are also known.<ref name="century"/><ref>{{GoldBookRef|title=Dehydroarenes|file=D01574}}</ref><ref>IUPAC ''[[Gold Book]]'' entry for "benzynes" identifies "''m''-benzyne" and "''p''-benzyne" as erroneous terms for 1,3- and 1,4-didehydrobenzene</ref> ''o''-Arynes are examples of strained [[alkyne]]s.


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In [[organic chemistry]], '''arynes'''<ref>{{GoldBookRef|title=Aryne|file=A00465}}</ref> and '''benzynes'''<ref>{{GoldBookRef|title=Benzynes|file=B00634}}</ref> are a class of highly [[Reactivity (chemistry)|reactive]] chemical [[Chemical species|species]] derived from an [[aromatic ring]] by removal of two [[substituent]]s. Arynes are examples of didehydroarenes (1,2-didehydroarenes in this case), although 1,3- and 1,4-didehydroarenes are also known.<ref name="century"/><ref>{{GoldBookRef|title=Dehydroarenes|file=D01574}}</ref><ref>IUPAC ''[[Gold Book]]'' entry for "benzynes" identifies "''m''-benzyne" and "''p''-benzyne" as erroneous terms for 1,3- and 1,4-didehydrobenzene</ref> Arynes are examples of [[alkyne]]s under high [[Ring strain|strain]].
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==Bonding in ''o''-arynes==

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The alkyne representation of benzyne is the most widely encountered. o-Arynes, or 1,2-didehydroarenes, are usually described as having a strained triple bond.<ref>Anslyn, E. V.; Dougherty, D. A.: ''Modern Physical Organic Chemistry'', University Science Books, 2006, p612.</ref>
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==Bonding in arynes==
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The alkyne representation of benzyne is the most widely encountered. Arynes are usually described as having a strained triple bond.<ref>Anslyn, E. V.; Dougherty, D. A.: ''Modern Physical Organic Chemistry'', University Science Books, 2006, p612.</ref>


[[File:Resonance contributors1.tif|250px|center]]
[[File:Resonance contributors1.tif|250px|center]]


Geometric constraints on the triple bond in ''ortho''-benzyne result in diminished overlap of in-plane p-orbitals, and thus weaker triple bond.<ref>{{cite journal|journal=Angew. Chem. Int. Ed. Engl.|year=2012|volume=51|issue=16|pages=3766–78|doi=10.1002/anie.201107485|pmid=22422638|title= Arynes and Cyclohexyne in Natural Product Synthesis|authors= Gampe, C. M.; Carreira, E. M.}}</ref> The vibrational frequency of the triple bond in benzyne was assigned by Radziszewski to be 1846&nbsp;cm<sup>−1</sup>,<ref>{{cite journal|title=Infrared Spectrum of o-Benzyne: Experiment and Theory|doi=10.1021/ja00027a007|authors=Radziszewski, J. G.; Hess, Jr. B. A.; Zahradnik, R.|journal=J. Am. Chem. Soc.|year=1992|volume=114|page=52}}</ref> indicating a weaker triple bond than in unstrained alkyne with vibrational frequency of approximately 2150&nbsp;cm<sup>−1</sup>. Nevertheless, ''ortho''-benzyne is more like a strained alkyne than a biradical, as seen from the large singlet–triplet gap and alkyne-like reactivity.<ref name=century/>
Geometric constraints on the triple bond in benzyne result in diminished overlap of in-plane p-orbitals, and thus weaker triple bond.<ref>{{cite journal|journal=Angew. Chem. Int. Ed. Engl.|year=2012|volume=51|issue=16|pages=3766–78|doi=10.1002/anie.201107485|pmid=22422638|title= Arynes and Cyclohexyne in Natural Product Synthesis|author1=Gampe, C. M. |author2=Carreira, E. M. }}</ref> The vibrational frequency of the triple bond in benzyne was assigned by Radziszewski to be 1846&nbsp;cm<sup>−1</sup>,<ref>{{cite journal|title=Infrared Spectrum of o-Benzyne: Experiment and Theory|doi=10.1021/ja00027a007|author1=Radziszewski, J. G. |author2=Hess, B. A. Jr. |author3=Zahradnik, R. |journal=J. Am. Chem. Soc.|year=1992|volume=114|page=52}}</ref> indicating a weaker triple bond than in unstrained alkyne with vibrational frequency of approximately 2150&nbsp;cm<sup>−1</sup>. Nevertheless, benzyne is more like a strained alkyne than a diradical, as seen from the large singlet–triplet gap and alkyne-like reactivity.<ref name=century/>


[[File:Geometric constraint2.tif|230px|center]]
[[File:Geometric constraint2.tif|230px|center]]


The [[HOMO and LUMO|LUMO]] of aryne lies much lower than the LUMO of unstrained alkynes, which makes it a better energy match for the HOMO of nucleophiles. Hence, benzyne possesses electrophilic character and undergoes reactions with nucleophiles.<ref>Gilchrist, T. L. Supplement C: ''The Chemistry of Triple Bonded Functional Groups, Part 1''. Patai, S.; Rappaport, Z. Eds., John Wiley & Sons, New York, 1983</ref> A detailed MO analysis of benzyne was presented in 1968.<ref>Hoffmann, R.; Imamura, A.;Hehre, W. J. ''J. Am. Chem. Soc.'' 1968, ''90'', 1499</ref>
The [[HOMO and LUMO|LUMO]] of aryne lies much lower than the LUMO of unstrained alkynes, which makes it a better energy match for the HOMO of nucleophiles. Hence, benzyne possesses electrophilic character and undergoes reactions with nucleophiles.<ref>Gilchrist, T. L. Supplement C: ''The Chemistry of Triple Bonded Functional Groups, Part 1''. Patai, S.; Rappaport, Z. Eds., John Wiley & Sons, New York, 1983</ref> A detailed MO analysis of benzyne was presented in 1968.<ref>{{cite journal | last1 = Hoffmann | first1 = R. | last2 = Imamura | first2 = A. | last3 = Hehre | first3 = W. J. | year = 1968 | title = Benzynes, dehydroconjugated molecules, and the interaction of orbitals separated by a number of intervening sigma bonds| journal = J. Am. Chem. Soc. | volume = 90 | issue = 6| page = 1499 | doi = 10.1021/ja01008a018 }}</ref>


[[File:Homo-lumo gap.tif|290px|center]]
[[File:Homo-lumo gap.tif|290px|center]]


==Generation of ''o''-arynes==
==Generation of arynes==
Due to their extreme reactivity, arynes must be generated ''in situ''. Typical of other [[reactive intermediate]]s, benzyne must be trapped, otherwise it [[dimer (chemistry)|dimerises]] to [[biphenylene]].
Due to their extreme reactivity, arynes must be generated ''in situ''. Typical of other [[reactive intermediate]]s, benzyne must be trapped, otherwise it [[dimer (chemistry)|dimerises]] to [[biphenylene]].


Early routes to benzyne involved [[dehydrohalogenation]] of [[aryl halides]]:
Early routes to benzyne involved [[dehydrohalogenation]] of [[aryl halides]]:
[[File:Benzyne gen1.tif|235px|center]]
[[File:Benzyne gen1.tif|235px|center]]
Such reactions require strong base and high temperatures. Ortho-disubstituted arenes serve as precursors to benzynes under milder conditions.
Such reactions require strong base and high temperatures. 1,2-Disubstituted arenes serve as precursors to benzynes under milder conditions.
Benzyne is generated by the dehalogenation of 2-bromofluorobenzene by magnesium.<ref name=Wittig>{{cite journal | last1 = Wittig | first1 = Georg | year = 1959 | title = Triptycene | journal = Org. Synth. | volume = 39 | issue = | page = 75 | doi = 10.15227/orgsyn.039.0075}}</ref> [[Anthranilic acid]] can be converted to 2-diazoniobenzene-1-carboxylate by diazotization and neutralization. Although explosive,<ref>{{Cite journal|last=Sullivan|first=John M.|date=1971-06-01|title=Explosion during preparation of benzenediazonium-2-carboxylate hydrochloride|journal=Journal of Chemical Education|volume=48|issue=6|pages=419|doi=10.1021/ed048p419.3|issn=0021-9584|doi-access=free}}</ref> this [[zwitterion]]ic species is a convenient and inexpensive precursor to benzyne.<ref name="CV5P0054">{{cite journal|journal=Org. Synth.|year = 1968|volume = 48|pages = 12|last1 = Logullo|first1 = Francis M.|last2 = Seitz|first2 = Arnold M.|last3 = Friedman|first3 = Lester|doi = 10.15227/orgsyn.048.0012|title = Benzenediazonium-2-Carboxylate and Biphenylene (Benzenediazonium, ''o''-carboxy-, hydroxide, inner salt)}}</ref>
Benzyne is generated by the dehalogenation of 1-bromo-2-fluorobenzene by magnesium.<ref name=Wittig>{{cite journal | last1 = Wittig | first1 = Georg | year = 1959 | title = Triptycene | journal = Org. Synth. | volume = 39 | page = 75 | doi = 10.15227/orgsyn.039.0075}}</ref> [[Anthranilic acid]] can be converted to 2-diazoniobenzene-1-carboxylate by diazotization and neutralization. Although explosive,<ref>{{Cite journal|last=Sullivan|first=John M.|date=1971-06-01|title=Explosion during preparation of benzenediazonium-2-carboxylate hydrochloride|journal=Journal of Chemical Education|volume=48|issue=6|pages=419|doi=10.1021/ed048p419.3|bibcode=1971JChEd..48..419S|issn=0021-9584|doi-access=}}</ref> this [[zwitterion]]ic species is a convenient and inexpensive precursor to benzyne.<ref name="CV5P0054">{{cite journal|journal=Org. Synth.|year = 1968|volume = 48|pages = 12|last1 = Logullo|first1 = Francis M.|last2 = Seitz|first2 = Arnold M.|last3 = Friedman|first3 = Lester|doi = 10.15227/orgsyn.048.0012|title = Benzenediazonium-2-Carboxylate and Biphenylene (Benzenediazonium, ''o''-carboxy-, hydroxide, inner salt)}}</ref>


[[File:Benzyne gen2.tif|220px|center]]
[[File:Benzyne gen2.tif|220px|center]]


Another method is based on trimethylsilylaryl [[triflate]]s.<ref name=Tadross/> Fluoride displacement of the trimethylsilyl group induces elimination of triflate and release of benzyne:
Another method is based on trimethylsilylaryl [[triflate]]s.<ref name=Tadross/> This method has seen wide applicability and was reviewed in 2021.<ref>{{Cite journal |last=Shi |first=Jiarong |last2=Li |first2=Lianggui |last3=Li |first3=Yang |date=2021-04-14 |title=o -Silylaryl Triflates: A Journey of Kobayashi Aryne Precursors |url=https://pubs.acs.org/doi/10.1021/acs.chemrev.0c01011 |journal=Chemical Reviews |language=en |volume=121 |issue=7 |pages=3892–4044 |doi=10.1021/acs.chemrev.0c01011 |issn=0009-2665}}</ref> Fluoride displacement of the trimethylsilyl group induces elimination of triflate and release of benzyne:


[[File:Benzyne gen3.tif|260px|center]]
[[File:Benzyne gen3.tif|260px|center]]


A [[hexadehydro Diels-Alder reaction]] (HDDA) involves cycloaddition of 1,3-diyne and alkyne.<ref>Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. ''Nature'', '''2012''', ''490'', 208</ref>
A [[hexadehydro Diels-Alder reaction]] (HDDA) involves cycloaddition of 1,3-diyne and alkyne.<ref>{{cite journal | last1 = Hoye | first1 = T. R. | last2 = Baire | first2 = B. | last3 = Niu | first3 = D. | last4 = Willoughby | first4 = P. H. | last5 = Woods | first5 = B. P. | year = 2012 | title = The hexadehydro-Diels–Alder reaction| journal = Nature | volume = 490 | issue = 7419| pages = 208–212 | doi = 10.1038/nature11518 | pmid = 23060191 | pmc = 3538845 | bibcode = 2012Natur.490..208H }}</ref>


[[File:HDDA rxn.tif|220px|center]]
[[File:HDDA rxn.tif|220px|center]]


''N''-amination of [[benzotriazole|1''H''-benzotriazole]] with [[hydroxylamine-O-sulfonic acid|hydroxylamine-''O''-sulfonic acid]] generates an intermediate which can be oxidised to benzyne in almost quantitative yield with [[lead(IV) acetate]].<ref name="Campbell1969">{{cite journal|first1 = C.D.|last1 = Campbell|author2 = [[Charles Rees|C.W. Rees]]|journal = [[J. Chem. Soc. C]]|title = Reactive intermediates. Part I. Synthesis and oxidation of 1- and 2-aminobenzotriazole|volume = 1969|issue = 5|pages = 742–747|year = 1969|doi = 10.1039/J39690000742}}</ref>
''N''-amination of [[benzotriazole|1''H''-benzotriazole]] with [[hydroxylamine-O-sulfonic acid|hydroxylamine-''O''-sulfonic acid]] generates an intermediate which can be oxidised to benzyne in almost quantitative yield with [[lead(IV) acetate]].<ref name="Campbell1969">{{cite journal|first1 = C.D.|last1 = Campbell|author2 = C.W. Rees|author2-link = Charles Rees|journal = [[J. Chem. Soc. C]]|title = Reactive intermediates. Part I. Synthesis and oxidation of 1- and 2-aminobenzotriazole|volume = 1969|issue = 5|pages = 742–747|year = 1969|doi = 10.1039/J39690000742}}</ref>


[[File:Benzyne Generated from 1H-Benzotriazole.png|442px|center]]
[[File:Benzyne Generated from 1H-Benzotriazole.png|442px|center]]


==Reactions of ''o''-arynes==
==Reactions of arynes==
Even at low temperatures arynes are extremely reactive. Their reactivity can be classified in three main classes: (1) nucleophilic additions, (2) pericyclic reactions, and (3) bond-insertion.
Even at low temperatures arynes are extremely reactive. Their reactivity can be classified in three main classes: (1) nucleophilic additions, (2) pericyclic reactions, and (3) bond-insertion.


===Nucleophilic additions to arynes===
===Nucleophilic additions to arynes===
Upon treatment with basic nucleophiles, aryl halides deprotonate alpha to the leaving group, resulting in [[dehydrohalogenation]]. Isotope exchange studies indicate that for aryl fluorides and, sometimes, aryl chlorides, the elimination event proceeds in two steps, deprotonation, followed by expulsion of the nucleophile. Thus, the process is formally analogous to the E1cb mechanism of aliphatic compounds. Aryl bromides and iodides, on the other hand, generally appear to undergo elimination by a concerted syn-coplanar E2 mechanism.<ref>{{Cite book|title=The Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution|last=Panar|first=Manuel|publisher=California Institute of Technology (Ph.D. Thesis)|year=1961|location=Pasadena, CA|pages=4–5}}</ref><ref>{{Cite book|title=Mechanism and theory in organic chemistry|last=H.|first=Lowry, Thomas|date=1987|publisher=Harper & Row|others=Richardson, Kathleen Schueller|isbn=0060440848|edition=3rd|location=New York|pages=[https://archive.org/details/mechanismtheoryi000321/page/643 643]|oclc=14214254|url-access=registration|url=https://archive.org/details/mechanismtheoryi000321/page/643}}</ref> The resulting benzyne forms addition products, usually by nucleophilic addition and protonation. Generation of the benzyne intermediate is the slow step in the reaction.<ref name="ReferenceB">Anslyn, E. V.; Dougherty, D. A. ''Modern Physical Organic Chemistry.'' University Science Books, '''2006'''</ref>
Upon treatment with basic nucleophiles, aryl halides deprotonate alpha to the leaving group, resulting in [[dehydrohalogenation]]. Isotope exchange studies indicate that for aryl fluorides and, sometimes, aryl chlorides, the elimination event proceeds in two steps, deprotonation, followed by expulsion of the nucleophile. Thus, the process is formally analogous to the E1cb mechanism of aliphatic compounds. Aryl bromides and iodides, on the other hand, generally appear to undergo elimination by a concerted syn-coplanar E2 mechanism.<ref>{{Cite book|title=The Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution|last=Panar|first=Manuel|publisher=California Institute of Technology (Ph.D. Thesis)|year=1961|location=Pasadena, CA|pages=4–5}}</ref><ref>{{Cite book|title=Mechanism and theory in organic chemistry|last=H.|first=Lowry, Thomas|date=1987|publisher=Harper & Row|others=Richardson, Kathleen Schueller|isbn=0-06-044084-8|edition=3rd|location=New York|pages=[https://archive.org/details/mechanismtheoryi000321/page/643 643]|oclc=14214254|url-access=registration|url=https://archive.org/details/mechanismtheoryi000321/page/643}}</ref> The resulting benzyne forms addition products, usually by nucleophilic addition and protonation. Generation of the benzyne intermediate is the slow step in the reaction.<ref name="ReferenceB">Anslyn, E. V.; Dougherty, D. A. ''Modern Physical Organic Chemistry.'' University Science Books, '''2006'''</ref>


[[File:Nuc addn to benzyne.tif|550px|center]]
[[File:Nuc addn to benzyne.tif|550px|center]]
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There are two possible regioisomers of benzyne with substituent (Y): triple bond can be positioned between C2 and C3 or between C3 and C4. Substituents ortho to the leaving group will lead to the triple bond between C2 and C3. Para Y and LG will lead to regioisomer with triple bond between C3 and C4. Meta substituent can afford both regioisomers as described above.
There are two possible regioisomers of benzyne with substituent (Y): triple bond can be positioned between C2 and C3 or between C3 and C4. Substituents ortho to the leaving group will lead to the triple bond between C2 and C3. Para Y and LG will lead to regioisomer with triple bond between C3 and C4. Meta substituent can afford both regioisomers as described above.
Nucleophilic additions can occur with regioselectivity. Although classic explanations to explain regioselectivity refer to carbanion stability following attack by the nucleophile,<ref name="ReferenceB"/> this explanation has been replaced by the aryne distortion model by [[Kendall Houk|Houk]] and [[Neil Garg|Garg]].<ref>{{Cite journal |last=Cheong |first=Paul H.-Y. |last2=Paton |first2=Robert S. |last3=Bronner |first3=Sarah M. |last4=Im |first4=G-Yoon J. |last5=Garg |first5=Neil K. |last6=Houk |first6=K. N. |date=2010-02-03 |title=Indolyne and Aryne Distortions and Nucleophilic Regioselectivites |url=https://pubs.acs.org/doi/10.1021/ja9098643 |journal=Journal of the American Chemical Society |language=en |volume=132 |issue=4 |pages=1267–1269 |doi=10.1021/ja9098643 |issn=0002-7863 |pmc=2819077 |pmid=20058924}}</ref><ref>{{Cite journal |last=Im |first=G-Yoon J. |last2=Bronner |first2=Sarah M. |last3=Goetz |first3=Adam E. |last4=Paton |first4=Robert S. |last5=Cheong |first5=Paul H.-Y. |last6=Houk |first6=K. N. |last7=Garg |first7=Neil K. |date=2010-12-22 |title=Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions |url=https://pubs.acs.org/doi/10.1021/ja1086485 |journal=Journal of the American Chemical Society |language=en |volume=132 |issue=50 |pages=17933–17944 |doi=10.1021/ja1086485 |issn=0002-7863 |pmc=3075889 |pmid=21114321}}</ref><ref>{{Cite journal |last=Medina |first=Jose M. |last2=Mackey |first2=Joel L. |last3=Garg |first3=Neil K. |last4=Houk |first4=K. N. |date=2014-11-05 |title=The Role of Aryne Distortions, Steric Effects, and Charges in Regioselectivities of Aryne Reactions |url=https://pubs.acs.org/doi/10.1021/ja5099935 |journal=Journal of the American Chemical Society |language=en |volume=136 |issue=44 |pages=15798–15805 |doi=10.1021/ja5099935 |issn=0002-7863 |pmc=4221504 |pmid=25303232}}</ref> In this model, substituents cause geometric distortion of the ground state structure of the aryne, leading to regioselective reactions, consistent with reactions proceeding through early transition states.
In case of triple bond located between C2 and C3, electron withdrawing (EWG) substituents, e.g. CF3, will direct the nucleophile addition to place carbanion as close as possible to EWG. However, electron donating (EDG) substituents, e.g. CH3, will provide little selectivity between products.
In the regioisomer where triple bond is located between C3 and C4 the effect of substituent on nucleophile addition is diminished, and mixtures of para and meta products are often obtained.<ref name="ReferenceB"/>

[[File:Regiochemistry2.png|700px|center]]


===Pericyclic reactions of arynes===
===Pericyclic reactions of arynes===
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Benzynes can undergo [[Diels-Alder reaction|[4+2]]] cyclization reactions. When generated in the presence of [[anthracene]], [[trypticene]] results.<ref name=Wittig/> In this method, the concerted mechanism of the Diels-Alder reaction between benzyne and furan is shown below. Other benzyne [4+2] cycloadditions are thought to proceed via a stepwise mechanism.
Benzynes can undergo [[Diels-Alder reaction|[4+2]]] cyclization reactions. When generated in the presence of [[anthracene]], [[trypticene]] results.<ref name=Wittig/> In this method, the concerted mechanism of the Diels-Alder reaction between benzyne and furan is shown below. Other benzyne [4+2] cycloadditions are thought to proceed via a stepwise mechanism.
[[File:4+2 cycloaddition.tif|345px|center]]
[[File:4+2 cycloaddition.svg|345px|center]]


A classic example is the synthesis of [[1,2,3,4-tetraphenylnaphthalene]].<ref>{{cite journal|journal=Organic Syntheses|volume=46|pages=107|year=1966|title=1,2,3,4-Tetraphenylnaphthalene|doi=10.15227/orgsyn.046.0107}}</ref> [[1,2,4,5-Tetrabromobenzene|Tetrabromobenzene]] can react with [[N-Butyllithium|butyllithium]] and [[furan]] to form a tetrahydroanthracene<ref>{{cite journal|journal=Organic Syntheses|volume=75|page=201|title=Use of 1,2,4,5-Tetrabromobenzene as a 1,4-Nenzadiyne Equivalent: Anti- and Syn-1,4,5,8-tetrahydroanthracene 1,4:5,8-diepoxides|year=1998|doi=10.15227/orgsyn.075.0201}}</ref>
A classic example is the synthesis of [[1,2,3,4-tetraphenylnaphthalene]].<ref>{{cite journal|journal=Organic Syntheses|volume=46|pages=107|year=1966|title=1,2,3,4-Tetraphenylnaphthalene|doi=10.15227/orgsyn.046.0107}}</ref> [[1,2,4,5-Tetrabromobenzene|Tetrabromobenzene]] can react with [[N-Butyllithium|butyllithium]] and [[furan]] to form a tetrahydroanthracene<ref>{{cite journal|journal=Organic Syntheses|volume=75|page=201|title=Use of 1,2,4,5-Tetrabromobenzene as a 1,4-Nenzadiyne Equivalent: Anti- and Syn-1,4,5,8-tetrahydroanthracene 1,4:5,8-diepoxides|year=1998|doi=10.15227/orgsyn.075.0201}}</ref>
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[[File:Diaryne reaction.svg|600px|center|diaryne reaction with furan]]
[[File:Diaryne reaction.svg|600px|center|diaryne reaction with furan]]


[4+2] cycloadditions of arynes have been commonly applied to natural product total synthesis. The main limitation of such approach, however, is the need to use constrained dienes, such as furan and cyclopentadiene.<ref name=Tadross/> In 2009 Buszek and co-workers synthesized herbindole A using aryne [4+2]-cycloaddition.<ref>Buszek, K. R.; Brown, N.; Kuo, D. ''Org. Lett.'' 2009, ''11'', 201</ref> 6,7-indolyne undergoes [4+2] cycloaddition with cyclopentadiene to afford complex tetracyclic product.
[4+2] cycloadditions of arynes have been commonly applied to natural product total synthesis. The main limitation of such approach, however, is the need to use constrained dienes, such as furan and cyclopentadiene.<ref name=Tadross/> In 2009 Buszek and co-workers synthesized herbindole A using aryne [4+2]-cycloaddition.<ref>{{cite journal | last1 = Buszek | first1 = K. R. | last2 = Brown | first2 = N. | last3 = Kuo | first3 = D. | year = 2009 | title = Concise Total Synthesis of (±)-cis-Trikentrin A and (±)-Herbindole A via Intermolecular Indole Aryne Cycloaddition| journal = Org. Lett. | volume = 11 | issue = 1 | pages = 201–204 | doi = 10.1021/ol802425m | pmid = 19055375 | pmc = 2723800 }}</ref> 6,7-indolyne undergoes [4+2] cycloaddition with cyclopentadiene to afford complex tetracyclic product.


[[File:Buszek.tif|750px|center]]
[[File:Buszek.tif|750px|center]]


Benzynes undergo [2+2] cycloaddition with a wide range of alkenes. Due to electrophilic nature of benzyne, alkenes bearing electron-donating substituents work best for this reaction.<ref>Pellissier, H.; Santelli, M. ''Tetrahedron,'' 2003, ''59'', 701</ref>
Benzynes undergo [2+2] cycloaddition with a wide range of alkenes. Due to electrophilic nature of benzyne, alkenes bearing electron-donating substituents work best for this reaction.<ref>Pellissier, H.; Santelli, M. ''Tetrahedron,'' 2003; 59, 701</ref>


Due to significant byproduct formation, aryne [2+2] chemistry is rarely utilized in natural product total synthesis.<ref name=Tadross/> Nevertheless, several examples do exist. In 1982, Stevens and co-workers reported a synthesis of taxodione that utilized [2+2] cycloaddition between an aryne and a ketene acetal.<ref>Stevens, R. V.; Bisacchi, G. S. ''J. Org, Chem.'' 1982, ''47'', 2396</ref>
Due to significant byproduct formation, aryne [2+2] chemistry is rarely utilized in natural product total synthesis.<ref name=Tadross/> Nevertheless, several examples do exist. In 1982, Stevens and co-workers reported a synthesis of taxodione that utilized [2+2] cycloaddition between an aryne and a ketene acetal.<ref>Stevens, R. V.; Bisacchi, G. S. ''J. Org, Chem.'' 1982; 47, 2396</ref>


[[File:Stevens.tif|750px|center]]
[[File:Stevens.tif|750px|center]]


Mori and co-workers performed a palladium-catalyzed [2+2+2]-cocyclization of aryne and diyne in their total synthesis of taiwanins C.<ref>Sato, Y.; Tamura,T.; Mori, M. ''Angew. Chem. Int. Ed.'' 2004, ''43'', 2436</ref>
Mori and co-workers performed a palladium-catalyzed [2+2+2]-cocyclization of aryne and diyne in their total synthesis of taiwanins C.<ref>Sato, Y.; Tamura, T.; Mori, M. ''Angew. Chem. Int. Ed.'' 2004; 43, 2436</ref>


[[File:Mori.tif|825px|center]]
[[File:Mori.tif|825px|center]]


===Bond-insertion reactions of arynes===
===Bond-insertion reactions of arynes===
The first example of aryne σ-bond insertion reaction is the synthesis of melleine in 1973.<ref>Guyot, M.; Molho, D. ''Tetrahedron Lett.'' '''1973''', 1''4'', 3433</ref>
The first example of aryne σ-bond insertion reaction is the synthesis of melleine in 1973.<ref>Guyot, M.; Molho, D. ''Tetrahedron Lett.'' 1973; 14, 3433</ref>
[[File:Guyot.tif|700px|center]]
[[File:Guyot.tif|700px|center]]


==Other dehydrobenzenes==
==Other dehydrobenzenes==
If benzyne is 1,2-didehydrobenzene, two further isomers are possible: 1,3-didehydrobenzene and 1,4-didehydrobenzene.<ref name="century">{{cite journal|journal=Angew. Chem. Int. Ed.|year=2003|volume=42|issue=5|pages=502–528|title=One Century of Aryne Chemistry|authors=Hans Henning Wenk, Michael Winkler, Wolfram Sander|doi=10.1002/anie.200390151|pmid=12569480}}</ref> Their energies [[in silico]] are, respectively, 106, 122, and 138 kcal/mol (444, 510 and 577 kJ/mol).<ref name=Bartlett/> The 1,2- and 1,3- isomers have singlet ground states, whereas for 1,4-benzyne the gap is smaller.
If benzyne is 1,2-didehydrobenzene, two further isomers are possible: 1,3-didehydrobenzene and 1,4-didehydrobenzene.<ref name="century">{{cite journal|journal=Angew. Chem. Int. Ed.|year=2003|volume=42|issue=5|pages=502–528|title=One Century of Aryne Chemistry |author=Hans Henning Wenk |author2=Michael Winkler |author3=Wolfram Sander |doi=10.1002/anie.200390151|pmid=12569480}}</ref> Their energies [[in silico]] are, respectively, 106, 122, and 138 kcal/mol (444, 510 and 577 kJ/mol).<ref name=Bartlett/> The 1,2- and 1,3- isomers have singlet ground states, whereas for 1,4-didehydrobenzene the gap is smaller.


[[File:Benzyne o,p,m1.tif|385px|center]]
[[File:Benzynes o, m, and p.svg|385px|center]]


The interconversion of the 1,2-, 1,3- and 1,4-didehydrobenzenes has been studied.<ref name=Bartlett>A m-Benzyne to o-Benzyne Conversion Through a 1,2-Shift of a Phenyl Group. Blake, M. E.; Bartlett, K. L.; Jones, M. Jr. J. Am. Chem. Soc. '''2003''', 125, 6485. {{DOI|10.1021/ja0213672}}</ref><ref>A p-Benzyne to m-Benzyne Conversion Through a 1,2-Shift of a Phenyl Group. Completion of the Benzyne Cascade, Polishchuk, A. L.; Bartlett, K. L.; Friedman, L. A.; Jones, M. Jr. J. Phys. Org. Chem. '''2004''', Volume 17, Issue 9 , Pages 798 - 806. {{DOI|10.1002/poc.797}}</ref> A 1,2- to 1,3-didehydrobenzene conversion has been postulated to occur in the [[pyrolysis]] (900&nbsp;°C) of the [[phenyl]] substituted aryne precursors<ref name=Bartlett/> as shown below. Extremely high temperatures are required for benzyne interconversion.
The interconversion of the 1,2-, 1,3- and 1,4-didehydrobenzenes has been studied.<ref name=Bartlett>{{cite journal | last1 = Blake | first1 = M. E. | last2 = Bartlett | first2 = K. L. | last3 = Jones | first3 = M. Jr | year = 2003 | title = A m-Benzyne to o-Benzyne Conversion Through a 1,2-Shift of a Phenyl Group | journal = J. Am. Chem. Soc. | volume = 125 | issue = 21| pages = 6485–90 | doi = 10.1021/ja0213672 | pmid = 12785789 }}</ref><ref>{{cite journal | last1 = Polishchuk | first1 = A. L. | last2 = Bartlett | first2 = K. L. | last3 = Friedman | first3 = L. A. | last4 = Jones | first4 = M. Jr | year = 2004 | title = A p-Benzyne to m-Benzyne Conversion Through a 1,2-Shift of a Phenyl Group. Completion of the Benzyne Cascade | journal = J. Phys. Org. Chem. | volume = 17 | issue = 9| pages = 798–806 | doi = 10.1002/poc.797 }}</ref> A 1,2- to 1,3-didehydrobenzene conversion has been postulated to occur in the [[pyrolysis]] (900&nbsp;°C) of the [[phenyl]] substituted aryne precursors<ref name=Bartlett/> as shown below. Extremely high temperatures are required for benzyne interconversion.


[[File:Interconversion.tif|375px|center]]
[[File:Interconversion.tif|375px|center]]
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[[File:Bergman.tif|600px|center]]
[[File:Bergman.tif|600px|center]]


Two states were proposed for 1,4-didehydrobenzene: singlet and triplet, with the singlet state lower in energy.<ref>Clauberg, H.; Minsek, D. W.; Chen, P. ''J. Am. Chem. Soc.'' '''1992''', ''114'', 99.</ref><ref>Blush, J. A.; Clauberg, H.; Kohn, D. W.; Minsek, D. W.; Zhang, X.; Chen, P. ''Acc. Chem. Res.'' '''1992''', ''25'', 385</ref> Triplet state represents two noninteracting radical centers, and hence should abstract hydrogens at the same rate as phenyl radical. However, singlet state is more stabilized than the triplet, and therefore some of the stabilizing energy will be lost in order to form the transition state for hydrogen cleavage, leading to slower hydrogen abstraction. Chen proposed the use of 1,4-didehydrobenzene analogues that have large singlet-triplet energy gaps to enhance selectivity of enediyne drug candidates.<ref>Chen, P. ''Angew. Chem. Int. Ed. Engl.'' '''1996''', ''35'', 1478.</ref>
Two states were proposed for 1,4-didehydrobenzene: singlet and triplet, with the singlet state lower in energy.<ref>{{cite journal | last1 = Clauberg | first1 = H. | last2 = Minsek | first2 = D. W. | last3 = Chen | first3 = P. | year = 1992 | title = Mass and photoelectron spectroscopy of C3H2. .DELTA.Hf of singlet carbenes deviate from additivity by their singlet-triplet gaps| journal = J. Am. Chem. Soc. | volume = 114 | page = 99 | doi = 10.1021/ja00027a014 }}</ref><ref>{{cite journal | last1 = Blush | first1 = J. A. | last2 = Clauberg | first2 = H. | last3 = Kohn | first3 = D. W. | last4 = Minsek | first4 = D. W. | last5 = Zhang | first5 = X. | last6 = Chen | first6 = P. | year = 1992 | title = Photoionization mass and photoelectron spectroscopy of radicals, carbenes, and biradicals| journal = Acc. Chem. Res. | volume = 25 | issue = 9| page = 385 | doi = 10.1021/ar00021a001 }}</ref> Triplet state represents two noninteracting radical centers, and hence should abstract hydrogens at the same rate as phenyl radical. However, singlet state is more stabilized than the triplet, and therefore some of the stabilizing energy will be lost in order to form the [[transition state]] for hydrogen cleavage, leading to slower hydrogen abstraction. Chen proposed the use of 1,4-didehydrobenzene analogues that have large singlet-triplet energy gaps to enhance selectivity of enediyne drug candidates.<ref>{{cite journal | last1 = Chen | first1 = P | year = 1996 | title = Design of Diradical-based Hydrogen Abstraction Agents| journal = Angew. Chem. Int. Ed. Engl. | volume = 35 | issue = 1314| page = 1478 | doi = 10.1002/anie.199614781 | doi-access = free }}</ref>


== History ==
== History ==
The first evidence for arynes came from the work of Stoermer and Kahlert. In 1902 they observed that upon treatment of 3-bromobenzofuran with base in ethanol 2-ethoxybenzofuran is formed. Based on this observation they postulated an aryne intermediate.<ref>{{cite journal |doi=10.1002/cber.19020350286 |title=Ueber das 1- und 2-Brom-cumaron |journal=Berichte der Deutschen Chemischen Gesellschaft |volume=35 |issue=2 |pages=1633–1640 |year=1902 |last1=Stoermer |first1=R. |last2=Kahlert |first2=B. |url=https://zenodo.org/record/1426054 }}</ref>
The first evidence for arynes came from the work of Stoermer and Kahlert. In 1902 they observed that upon treatment of 3-bromobenzofuran with base in ethanol 2-ethoxybenzofuran is formed. Based on this observation they postulated an aryne intermediate.<ref>{{cite journal |doi=10.1002/cber.19020350286 |title=Ueber das 1- und 2-Brom-cumaron |journal=Berichte der Deutschen Chemischen Gesellschaft |volume=35 |issue=2 |pages=1633–1640 |year=1902 |last1=Stoermer |first1=R. |last2=Kahlert |first2=B. |url=https://zenodo.org/record/1426054 }}</ref>


[[File:Stoermer - benzyne.tif|440px|center|First indication of benzyne.]]
[[File:Stoermer - benzyne.svg|440px|center|First indication of benzyne.]]


[[Georg Wittig|Wittig]] et al. invoked zwitterionic intermediate in the reaction of fluorobenzene and phenyllithium to give biphenyl.<ref>Wittig, G., Pieper, G. and Fuhrmann, G. (1940), Über die Bildung von Diphenyl aus Fluorbenzol und Phenyl-lithium (IV. Mitteil. über Austauschreaktionen mit Phenyl-lithium). Berichte der deutschen chemischen Gesellschaft (A and B Series), 73: 1193–1197. {{doi|10.1002/cber.19400731113}}</ref><ref name="Phenyl-lithium 1942, Pages 696-703">''Phenyl-lithium, der Schlüssel zu einer neuen Chemie metallorganischer Verbindungen'' Georg Wittig Naturwissenschaften, 1942, Volume 30, Numbers 46-47, Pages 696-703 {{DOI|10.1007/BF01489519}}</ref><ref>Wittig, G. (1954), Fortschritte auf dem Gebiet der organischen Aniono-Chemie. Angewandte Chemie, 66: 10–17. {{doi|10.1002/ange.19540660103}}</ref> This hypothesis was later confirmed.<ref name="OF CHLOROBENZENE-1-C14 WITH POTASSIUM AMIDE John D 1953">''rearrangement in the reaction of chlorobenzene-1-C14 with potassium amid'' John D. Roberts, Howard E. Simmons Jr., L. A. Carlsmith, C. Wheaton Vaughan J. Am. Chem. Soc., 1953, 75 (13), pp 3290–3291 {{DOI| 10.1021/ja01109a523}}</ref><ref>''The Mechanism of Aminations of Halobenzenes'' John D. Roberts, Dorothy A. Semenow, Howard E. Simmons Jr., L. A. Carlsmith J. Am. Chem. Soc., 1956, 78 (3), pp 601–611 {{DOI|10.1021/ja01584a024}}</ref><ref>''Orientation in Aminations of Substituted Halobenzenes'' John D. Roberts, C. Wheaton Vaughan, L. A. Carlsmith, Dorothy A. Semenow J. Am. Chem. Soc., 1956, 78 (3), pp 611–614 {{DOI|10.1021/ja01584a025}}</ref><ref>''Modern Arylation Methods''. Edited by Lutz Ackermann 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim {{ISBN|978-3-527-31937-4}}</ref><ref>''The Benzyne and Related Intermediates''. H. Heaney Chem. Rev., 1962, 62 (2), pp 81–97 {{DOI|10.1021/cr60216a001}}</ref>
[[Georg Wittig|Wittig]] et al. invoked zwitterionic intermediate in the reaction of fluorobenzene and phenyllithium to give biphenyl.<ref>{{cite journal | last1 = Wittig | first1 = G. | last2 = Pieper | first2 = G. | last3 = Fuhrmann | first3 = G. | year = 1940 | title = Über die Bildung von Diphenyl aus Fluorbenzol und Phenyl-lithium (IV. Mitteil. über Austauschreaktionen mit Phenyl-lithium) | journal = Berichte der Deutschen Chemischen Gesellschaft (A and B Series) | volume = 73 | issue = 11| pages = 1193–1197 | doi = 10.1002/cber.19400731113 }}</ref><ref name="Phenyl-lithium 1942, Pages 696-703">{{cite journal | doi = 10.1007/BF01489519 | volume=30 | title=Phenyl-lithium, der Schlüssel zu einer neuen Chemie metallorganischer Verbindungen | year=1942 | journal=Die Naturwissenschaften | pages=696–703 | last1 = Wittig | first1 = Georg| issue=46–47 | bibcode=1942NW.....30..696W | s2cid=37148502 }}</ref><ref>{{cite journal | last1 = Wittig | first1 = G | year = 1954 | title = Fortschritte auf dem Gebiet der organischen Aniono-Chemie | journal = Angewandte Chemie | volume = 66 | issue = 1 | pages = 10–17 | doi = 10.1002/ange.19540660103 | bibcode = 1954AngCh..66...10W }}</ref> This hypothesis was later confirmed.<ref name="OF CHLOROBENZENE-1-C14 WITH POTASSIUM AMIDE John D 1953">{{cite journal | doi = 10.1021/ja01109a523 | volume=75 | year=1953 | journal=Journal of the American Chemical Society | pages=3290–3291 | last1 = Roberts | first1 = John D.| title=Rearrangement in the Reaction of Chlorobenzene-1-C14With Potassium Amide1 | issue=13 }}</ref><ref>{{cite journal | doi = 10.1021/ja01584a024 | volume=78 | title=The Mechanism of Aminations of Halobenzenes 1 | year=1956 | journal=Journal of the American Chemical Society | pages=601–611 | last1 = Roberts | first1 = John D.| issue=3 }}</ref><ref>{{cite journal | doi = 10.1021/ja01584a025 | volume=78 | title=Orientation in Aminations of Substituted Halobenzenes 1 | year=1956 | journal=Journal of the American Chemical Society | pages=611–614 | last1 = Roberts | first1 = John D.| issue=3 }}</ref><ref>''Modern Arylation Methods''. Edited by Lutz Ackermann 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim {{ISBN|978-3-527-31937-4}}</ref><ref>{{cite journal | doi = 10.1021/cr60216a001 | volume=62 | title=The Benzyne and Related Intermediates. | year=1962 | journal=Chemical Reviews | pages=81–97 | last1 = Heaney | first1 = H.| issue=2 }}</ref>


[[File:Wittig.tif|536px|center]]
[[File:Wittig.tif|536px|center]]
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[[File:Roberts 1953.png|460px|center|<sup>14</sup>C labeling experiment shows equal distribution of products.]]
[[File:Roberts 1953.png|460px|center|<sup>14</sup>C labeling experiment shows equal distribution of products.]]


Wittig and Pohmer found that benzyne participate in [4+2] cycloaddition reactions.<ref>Wittig, G.; Pohmer, L. ''Angew. Chem.'' '''1955''', ''67(13)'', 348.</ref>
Wittig and Pohmer found that benzyne participate in [4+2] cycloaddition reactions.<ref>Wittig, G.; Pohmer, L. ''Angew. Chem.'' 1955; 67(13), 348.</ref>


[[File:Wittig 1955.png|300px|center|Capture of benzyne as dienophile in Diels-Alder reaction.]]
[[File:4+2 cycloaddition.svg|300px|center|Capture of benzyne as dienophile in Diels-Alder reaction.]]


Additional evidence for the existence of benzyne came from spectroscopic studies.<ref name="century"/> Benzyne has been observed in a "molecular container".<ref>Warmuth, R.; Yoon, ''Acc. Chem. Res.'' '''2001''', ''34'', 96</ref>
Additional evidence for the existence of benzyne came from spectroscopic studies.<ref name="century"/> Benzyne has been observed in a "molecular container".<ref>{{cite journal | last1 = Warmuth | first1 = R. | last2 = Yoon | year = 2001 | title = Recent highlights in hemicarcerand chemistry| journal = Acc. Chem. Res. | volume = 34 | issue = 2| page = 96 | doi = 10.1021/ar980082k | pmid = 11263868 }}</ref>


In 2015, a single aryne molecule was imaged by [[Scanning tunneling microscope|STM]].<ref>On-surface generation and imaging of arynes by atomic force microscopy, D.Pérez, E.Guitián, D.Peña, L.Gross, ''Nature Chemistry'', '''2015''', 7, 623</ref>
In 2015, a single aryne molecule was imaged by [[Scanning tunneling microscope|STM]].<ref>{{cite journal | last1 = On-surface | last2 = Pérez | first2 = E.Guitián | last3 = Peña | first3 = L.Gross | year = 2015 | title = On-surface generation and imaging of arynes by atomic force microscopy| journal = Nature Chemistry | volume = 7 | issue = 8| pages = 623–8| doi = 10.1038/nchem.2300| pmid = 26201737| bibcode = 2015NatCh...7..623P}}</ref>


''m''-Benzyne was first demonstrated in the 1990s when it was generated from 1,3-disubstituted benzene derivatives, such as the peroxy ester 1,3-C<sub>6</sub>H<sub>4</sub>(O<sub>2</sub>C(O)CH<sub>3</sub>)<sub>2</sub>.<ref name="century"/>
1,3-Didehydroarenes was first demonstrated in the 1990s when it was generated from 1,3-disubstituted benzene derivatives, such as the peroxy ester 1,3-C<sub>6</sub>H<sub>4</sub>(O<sub>2</sub>C(O)CH<sub>3</sub>)<sub>2</sub>.<ref name="century"/>


Breakthroughs on ''p''-benzynes came in the 1960s, followed from studies on the [[Bergman cyclization]].<ref name=Berg>{{cite journal| title=p-Benzyne. Generation as an intermediate in a thermal isomerization reaction and trapping evidence for the 1,4-benzenediyl structure|doi=10.1021/ja00757a071|author1=Richard R. Jones |author2=Robert G. Bergman |journal=[[J. Am. Chem. Soc.]]|year=1972|volume= 94|issue=2|pages= 660–661}}</ref> This theme became topical with the discovery of enediyne "cytostatics", such as [[calicheamicin]], which generates a 1,4-didehydrobenzene.<ref>{{cite journal |last1=Galm |first1=U |last2=Hager |first2=MH |last3=Van Lanen |first3=SG |last4=Ju |first4=J |last5=Thorson |first5=JS |last6=Shen |first6=B |title=Antitumor antibiotics: bleomycin, enediynes, and mitomycin |journal=Chemical Reviews |date=Feb 2005 |volume=105 |issue=2 |pages=739–58 |pmid=15700963 |doi=10.1021/cr030117g}}</ref>
Breakthroughs on 1,4-didehydrobenzene came in the 1960s, followed from studies on the [[Bergman cyclization]].<ref name=Berg>{{cite journal| title=p-Benzyne. Generation as an intermediate in a thermal isomerization reaction and trapping evidence for the 1,4-benzenediyl structure|doi=10.1021/ja00757a071|author1=Richard R. Jones |author2=Robert G. Bergman |journal=[[J. Am. Chem. Soc.]]|year=1972|volume= 94|issue=2|pages= 660–661}}</ref> This theme became topical with the discovery of enediyne "cytostatics", such as [[calicheamicin]], which generates a 1,4-didehydrobenzene.<ref>{{cite journal |last1=Galm |first1=U |last2=Hager |first2=MH |last3=Van Lanen |first3=SG |last4=Ju |first4=J |last5=Thorson |first5=JS |last6=Shen |first6=B |title=Antitumor antibiotics: bleomycin, enediynes, and mitomycin |journal=Chemical Reviews |date=Feb 2005 |volume=105 |issue=2 |pages=739–58 |pmid=15700963 |doi=10.1021/cr030117g}}</ref>


==Examples of benzynes in total synthesis==
==Examples of benzynes in total synthesis==
A variety of natural products have been prepared using arynes as intermediates.<ref name="Tadross">{{cite journal|authors=Tadross, P. M.; Stoltz, B. M.|title=A Comprehensive History of Arynes in Natural Product Total Synthesis|journal=Chem. Rev.|year=2012|volume=112|issue=6|pages=3550–3577|doi=10.1021/cr200478h|pmid=22443517}}</ref>
A variety of natural products have been prepared using arynes as intermediates.<ref name="Tadross">{{cite journal|author1=Tadross, P. M. |author2=Stoltz, B. M. |title=A Comprehensive History of Arynes in Natural Product Total Synthesis|journal=Chem. Rev.|year=2012|volume=112|issue=6|pages=3550–3577|doi=10.1021/cr200478h|pmid=22443517}}</ref> Nucleophilic additions to arynes have been widely used in natural product total synthesis. Indeed, nucleophilic additions of arynes are some of the oldest known applications of aryne chemistry.<ref name="Tadross" /> Nucleophilic addition to aryne was used in the attempted synthesis of cryptaustoline (1) and cryptowoline (2).<ref>Kametani, T.; Ogasawara, K. J. ''J. Chem. Soc., C'' 1967, 2208</ref>
Nucleophilic additions to arynes have been widely used in natural product total synthesis. Indeed, nucleophilic additions of arynes are some of the oldest known applications of aryne chemistry.<ref name="Tadross" /> Nucleophilic addition to aryne was used in the attempted synthesis of cryptaustoline (1) and cryptowoline (2).<ref>Kametani, T.; Ogasawara, K. J. ''J. Chem. Soc., C'' 1967, 2208</ref>
[[File:Kametani1.tif|800px|center]]
[[File:Kametani1.tif|800px|center]]


The synthesis of the tetracyclic meroterpenoid (+)-liphagal involved an aryne intermediate.<ref>Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.; Stoltz, B. M. ''Angew. Chem. Int. Ed.'' 2011, ''50'', 6814.</ref> Their approach employed an aryne cyclization to close the final ring of the natural product.<ref name="Tadross" />
The synthesis of the tetracyclic meroterpenoid (+)-liphagal involved an aryne intermediate.<ref>{{cite journal | last1 = Day | first1 = J. J. | last2 = McFadden | first2 = R. M. | last3 = Virgil | first3 = S. C. | last4 = Kolding | first4 = H. | last5 = Alleva | first5 = J. L. | last6 = Stoltz | first6 = B. M. | year = 2011 | title = The catalytic enantioselective total synthesis of (+)-liphagal| journal = Angew. Chem. Int. Ed. | volume = 50 | issue = 30| pages = 6814–8 | doi = 10.1002/anie.201101842 | pmid = 21671325 | pmc = 3361906 }}</ref> Their approach employed an aryne cyclization to close the final ring of the natural product.<ref name="Tadross" />


[[File:Stoltz Liphagal.tif|750px|center]]
[[File:Stoltz Liphagal.tif|750px|center]]


Multicomponent reactions of arynes are powerful transformations that allow for rapid formation of 1,2-disubsituted arenes. Despite their potential utility, examples of multicomponent aryne reactions in natural product synthesis are scarce.<ref name="Tadross" /> A four-component aryne coupling reaction was employed in the synthesis of dehydroaltenuene B.<ref>{{cite journal|authors=Soorukram, D.; Qu, T.; Barrett, A. G. M.|title=Four-Component Benzyne Coupling Reactions: A Concise Total Synthesis of Dehydroaltenuene B|journal=Org. Lett.|year= 2008|volume=10|issue=17|pages=3833–3835|doi=10.1021/ol8015435|pmid=18672878}}</ref>
Multicomponent reactions of arynes are powerful transformations that allow for rapid formation of 1,2-disubstituted arenes. Despite their potential utility, examples of multicomponent aryne reactions in natural product synthesis are scarce.<ref name="Tadross" /> A four-component aryne coupling reaction was employed in the synthesis of dehydroaltenuene B.<ref>{{cite journal|author1=Soorukram, D. |author2=Qu, T. |author3=Barrett, A. G. M. |title=Four-Component Benzyne Coupling Reactions: A Concise Total Synthesis of Dehydroaltenuene B|journal=Org. Lett.|year= 2008|volume=10|issue=17|pages=3833–3835|doi=10.1021/ol8015435|pmid=18672878}}</ref>


[[File:Barrette synthesis.tif|750px|center]]
[[File:Barrette synthesis.tif|750px|center]]
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==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

==External links==
*{{Commons category-inline|Arynes}}


{{Authority control}}
{{Authority control}}


[[Category:Reactive intermediates]]
[[Category:Reactive intermediates]]
[[Category:Cycloalkynes]]
[[Category:Aromatic hydrocarbons]]

Latest revision as of 04:03, 9 November 2024

In organic chemistry, arynes[1] and benzynes[2] are a class of highly reactive chemical species derived from an aromatic ring by removal of two substituents. Arynes are examples of didehydroarenes (1,2-didehydroarenes in this case), although 1,3- and 1,4-didehydroarenes are also known.[3][4][5] Arynes are examples of alkynes under high strain.

Bonding in arynes

[edit]

The alkyne representation of benzyne is the most widely encountered. Arynes are usually described as having a strained triple bond.[6]

Geometric constraints on the triple bond in benzyne result in diminished overlap of in-plane p-orbitals, and thus weaker triple bond.[7] The vibrational frequency of the triple bond in benzyne was assigned by Radziszewski to be 1846 cm−1,[8] indicating a weaker triple bond than in unstrained alkyne with vibrational frequency of approximately 2150 cm−1. Nevertheless, benzyne is more like a strained alkyne than a diradical, as seen from the large singlet–triplet gap and alkyne-like reactivity.[3]

The LUMO of aryne lies much lower than the LUMO of unstrained alkynes, which makes it a better energy match for the HOMO of nucleophiles. Hence, benzyne possesses electrophilic character and undergoes reactions with nucleophiles.[9] A detailed MO analysis of benzyne was presented in 1968.[10]

Generation of arynes

[edit]

Due to their extreme reactivity, arynes must be generated in situ. Typical of other reactive intermediates, benzyne must be trapped, otherwise it dimerises to biphenylene.

Early routes to benzyne involved dehydrohalogenation of aryl halides:

Such reactions require strong base and high temperatures. 1,2-Disubstituted arenes serve as precursors to benzynes under milder conditions. Benzyne is generated by the dehalogenation of 1-bromo-2-fluorobenzene by magnesium.[11] Anthranilic acid can be converted to 2-diazoniobenzene-1-carboxylate by diazotization and neutralization. Although explosive,[12] this zwitterionic species is a convenient and inexpensive precursor to benzyne.[13]

Another method is based on trimethylsilylaryl triflates.[14] This method has seen wide applicability and was reviewed in 2021.[15] Fluoride displacement of the trimethylsilyl group induces elimination of triflate and release of benzyne:

A hexadehydro Diels-Alder reaction (HDDA) involves cycloaddition of 1,3-diyne and alkyne.[16]

N-amination of 1H-benzotriazole with hydroxylamine-O-sulfonic acid generates an intermediate which can be oxidised to benzyne in almost quantitative yield with lead(IV) acetate.[17]

Reactions of arynes

[edit]

Even at low temperatures arynes are extremely reactive. Their reactivity can be classified in three main classes: (1) nucleophilic additions, (2) pericyclic reactions, and (3) bond-insertion.

Nucleophilic additions to arynes

[edit]

Upon treatment with basic nucleophiles, aryl halides deprotonate alpha to the leaving group, resulting in dehydrohalogenation. Isotope exchange studies indicate that for aryl fluorides and, sometimes, aryl chlorides, the elimination event proceeds in two steps, deprotonation, followed by expulsion of the nucleophile. Thus, the process is formally analogous to the E1cb mechanism of aliphatic compounds. Aryl bromides and iodides, on the other hand, generally appear to undergo elimination by a concerted syn-coplanar E2 mechanism.[18][19] The resulting benzyne forms addition products, usually by nucleophilic addition and protonation. Generation of the benzyne intermediate is the slow step in the reaction.[20]

"Aryne coupling" reactions allow for generation of biphenyl compounds which are valuable in pharmaceutical industry, agriculture and as ligands in many metal-catalyzed transformations.[21]

The metal–arene product can also add to another aryne, leading to chain-growth polymerization. Using copper(I) cyanide as the initiator to add to the first aryne yielded polymers containing up to about 100 arene units.[22]

When leaving group (LG) and substituent (Y) are mutually ortho or para, only one benzyne intermediate is possible. However, when LG is meta to Y, then regiochemical outcomes (A and B) are possible. If Y is electron withdrawing, then HB is more acidic than HA resulting in regioisomer B being generated. Analogously, if Y is electron donating, regioisomer A is generated, since now HA is the more acidic proton.

There are two possible regioisomers of benzyne with substituent (Y): triple bond can be positioned between C2 and C3 or between C3 and C4. Substituents ortho to the leaving group will lead to the triple bond between C2 and C3. Para Y and LG will lead to regioisomer with triple bond between C3 and C4. Meta substituent can afford both regioisomers as described above. Nucleophilic additions can occur with regioselectivity. Although classic explanations to explain regioselectivity refer to carbanion stability following attack by the nucleophile,[20] this explanation has been replaced by the aryne distortion model by Houk and Garg.[23][24][25] In this model, substituents cause geometric distortion of the ground state structure of the aryne, leading to regioselective reactions, consistent with reactions proceeding through early transition states.

Pericyclic reactions of arynes

[edit]

Benzyne undergoes rapid dimerization to form biphenylene. Some routes to benzyne lead to especially rapid and high yield of this subsequent reaction.[13][17] Trimerization gives triphenylene.[26]

Benzynes can undergo [4+2] cyclization reactions. When generated in the presence of anthracene, trypticene results.[11] In this method, the concerted mechanism of the Diels-Alder reaction between benzyne and furan is shown below. Other benzyne [4+2] cycloadditions are thought to proceed via a stepwise mechanism.

A classic example is the synthesis of 1,2,3,4-tetraphenylnaphthalene.[27] Tetrabromobenzene can react with butyllithium and furan to form a tetrahydroanthracene[28]

diaryne reaction with furan
diaryne reaction with furan

[4+2] cycloadditions of arynes have been commonly applied to natural product total synthesis. The main limitation of such approach, however, is the need to use constrained dienes, such as furan and cyclopentadiene.[14] In 2009 Buszek and co-workers synthesized herbindole A using aryne [4+2]-cycloaddition.[29] 6,7-indolyne undergoes [4+2] cycloaddition with cyclopentadiene to afford complex tetracyclic product.

Benzynes undergo [2+2] cycloaddition with a wide range of alkenes. Due to electrophilic nature of benzyne, alkenes bearing electron-donating substituents work best for this reaction.[30]

Due to significant byproduct formation, aryne [2+2] chemistry is rarely utilized in natural product total synthesis.[14] Nevertheless, several examples do exist. In 1982, Stevens and co-workers reported a synthesis of taxodione that utilized [2+2] cycloaddition between an aryne and a ketene acetal.[31]

Mori and co-workers performed a palladium-catalyzed [2+2+2]-cocyclization of aryne and diyne in their total synthesis of taiwanins C.[32]

Bond-insertion reactions of arynes

[edit]

The first example of aryne σ-bond insertion reaction is the synthesis of melleine in 1973.[33]

Other dehydrobenzenes

[edit]

If benzyne is 1,2-didehydrobenzene, two further isomers are possible: 1,3-didehydrobenzene and 1,4-didehydrobenzene.[3] Their energies in silico are, respectively, 106, 122, and 138 kcal/mol (444, 510 and 577 kJ/mol).[34] The 1,2- and 1,3- isomers have singlet ground states, whereas for 1,4-didehydrobenzene the gap is smaller.

The interconversion of the 1,2-, 1,3- and 1,4-didehydrobenzenes has been studied.[34][35] A 1,2- to 1,3-didehydrobenzene conversion has been postulated to occur in the pyrolysis (900 °C) of the phenyl substituted aryne precursors[34] as shown below. Extremely high temperatures are required for benzyne interconversion.

1,4-Didehydroarenes

[edit]

In classical 1,4-didehydrobenzene experiments, heating to 300 °C, [1,6-D2]-A readily equilibrates with [3,2-D2]-B, but does not equilibrate with C or D. The simultaneous migration of deuterium atoms to form B, and the fact that none of C or D is formed can only be explained by a presence of a cyclic and symmetrical intermediate–1,4-didehydrobenzene.[36]

Two states were proposed for 1,4-didehydrobenzene: singlet and triplet, with the singlet state lower in energy.[37][38] Triplet state represents two noninteracting radical centers, and hence should abstract hydrogens at the same rate as phenyl radical. However, singlet state is more stabilized than the triplet, and therefore some of the stabilizing energy will be lost in order to form the transition state for hydrogen cleavage, leading to slower hydrogen abstraction. Chen proposed the use of 1,4-didehydrobenzene analogues that have large singlet-triplet energy gaps to enhance selectivity of enediyne drug candidates.[39]

History

[edit]

The first evidence for arynes came from the work of Stoermer and Kahlert. In 1902 they observed that upon treatment of 3-bromobenzofuran with base in ethanol 2-ethoxybenzofuran is formed. Based on this observation they postulated an aryne intermediate.[40]

First indication of benzyne.
First indication of benzyne.

Wittig et al. invoked zwitterionic intermediate in the reaction of fluorobenzene and phenyllithium to give biphenyl.[41][42][43] This hypothesis was later confirmed.[44][45][46][47][48]

In 1953 14C labeling experiments provided strong support for the intermediacy of benzyne.[44] John D. Roberts et al. showed that the reaction of chlorobenzene-1-14C and potassium amide gave equal amounts of aniline with 14C incorporation at C-1 and C-2.

14C labeling experiment shows equal distribution of products.
14C labeling experiment shows equal distribution of products.

Wittig and Pohmer found that benzyne participate in [4+2] cycloaddition reactions.[49]

Capture of benzyne as dienophile in Diels-Alder reaction.
Capture of benzyne as dienophile in Diels-Alder reaction.

Additional evidence for the existence of benzyne came from spectroscopic studies.[3] Benzyne has been observed in a "molecular container".[50]

In 2015, a single aryne molecule was imaged by STM.[51]

1,3-Didehydroarenes was first demonstrated in the 1990s when it was generated from 1,3-disubstituted benzene derivatives, such as the peroxy ester 1,3-C6H4(O2C(O)CH3)2.[3]

Breakthroughs on 1,4-didehydrobenzene came in the 1960s, followed from studies on the Bergman cyclization.[36] This theme became topical with the discovery of enediyne "cytostatics", such as calicheamicin, which generates a 1,4-didehydrobenzene.[52]

Examples of benzynes in total synthesis

[edit]

A variety of natural products have been prepared using arynes as intermediates.[14] Nucleophilic additions to arynes have been widely used in natural product total synthesis. Indeed, nucleophilic additions of arynes are some of the oldest known applications of aryne chemistry.[14] Nucleophilic addition to aryne was used in the attempted synthesis of cryptaustoline (1) and cryptowoline (2).[53]

The synthesis of the tetracyclic meroterpenoid (+)-liphagal involved an aryne intermediate.[54] Their approach employed an aryne cyclization to close the final ring of the natural product.[14]

Multicomponent reactions of arynes are powerful transformations that allow for rapid formation of 1,2-disubstituted arenes. Despite their potential utility, examples of multicomponent aryne reactions in natural product synthesis are scarce.[14] A four-component aryne coupling reaction was employed in the synthesis of dehydroaltenuene B.[55]

See also

[edit]

References

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