Aryne

Arynes are uncharged, short-lived, highly reactive and cyclic intermediates in chemistry. They are derived from aromatic, where two mostly ortho, adjacent substituents were cleaved while two atomic orbitals results in two electrons, which are distributed to these two carbon atoms. Formally comprise ortho- didehydro - arynes at this point is a carbon- carbon triple bond. Due to the strained triple bond have such arynes energetically very low-lying LUMO. Therefore arynes are correspondingly reactive and prone to addition reactions. In analogy with carbenes and nitrenes arynes have a singlet and a triplet state.

• 2.1 ortho- benzyne
• 2.2 meta- benzyne
• 2.3 para- benzyne

• 5.1 Nucleophilic aromatic reactions
• 5.2 Ring -closure reactions
• 5.3 Diels -Alder reactions
• 5.4 arylation
• 5.5 Insertion Reactions
• 5.6 dehydrobenzene conversions
• 5.7 Tumortheraphie
• 5.8 Further possibilities

History

1902 postulated R. Stoermer and B. Kahlert, who worked at the University of Rostock, that the formation of 2- Ethoxybenzofuran from the implementation of 3- bromobenzofuran runs with bases in ethanol via the reactive intermediate of the 2,3- Didehydrobenzofurans. Also WE Bachmann and HT Clarke suspected in 1927 benzyne as a reactive intermediate of the Wurtz synthesis. Further investigations were carried out in 1953 by John Dombrowski Roberts, which the existence of arynes by the reaction of 14C-labeled chlorobenzene with potassium amide and subsequent reaction with ammonia was detected. Here, Roberts discovered that the newly introduced NH2 group at both the 14C - carbon atom and the adjacent carbon atom was located ( cine- substitution). The formation of the two products in equal amounts can only be explained by the existence of the symmetric intermediate, since the classical nucleophilic aromatic substitution which proceeds via an addition - elimination pathway, provides only the isomer in which the NH 2 group is bound to the 14C atom is.

1960 confirmed Rolf Huisgen and Jürgen Sauer these results; However, they found an isomer ratio of 48 percent to 52 percent, which can be attributed to the isotope effect. Erwin. F. Jenny and John D. Roberts found in the reaction of 14C-labeled fluorobenzene with phenyllithium similar results. After hydrolysis, they received a biphenyl with a rearrangement rate of 53 percent.

Georg Wittig succeeded in 1956, the verification of reactive aryne intermediates by trapping with furan in various Diels- Alder reactions. IP Fisher and FP Lossing found in mass spectrometric investigations in 1963, the peak of benzyne and were able to determine its ionization potential. 1969 succeeded the first mass-spectroscopic detection of 9,10- Dehydrophenanthren by Hans -Friedrich Joachim Griitzmacher and Lohmann. The first infrared spectroscopic detection of benzyne succeeded OL Chapman et al. by photolysis of phthaloyl, Benzocyclobutadienon or phthalic anhydride and matrix isolation spectroscopy at low temperatures. Here, Chapman ordered the stretching vibration of the carbon-carbon triple bond erroneously a band at 2085 cm -1, which was later confirmed by other research groups. Only in 1992 succeeded Juliusz G. Radziszewski et al. the final proof that the stretching vibration of the carbon-carbon triple bond gives a band at 1846 cm -1. This corresponds to the expectation that the (formal ) carbon-carbon triple bond is weaker by the ring strain than in unstressed alkynes, which show a band at 2150 cm -1. By trapping with furan in a Diels -Alder reaction Hans F. Ebel and Reinhard W. Hoffmann was the life of benzyne in a vacuum to a maximum of 20 msec calculate. Ralf Warmuth et al. finally succeeded in isolating 1,2- benzyne in a molecular container and examine 1H and 13C NMR spektrospokisch. By comparison with the NMR data benzene could be calculated as follows: 1H- NMR δ ( D8THF ) = 7.69 ppm and 7.01 ppm; 13C -NMR δ ( D8THF ) = 182.7 ppm, 126.8 ppm and 138.2 ppm.

The discovery of the aryne intermediate

The postulate of a Arinzwischenstufe was established on the basis of a series of experiments with chlorobenzene ( C6H5Cl ). Chlorobenzene, a rather electron-rich aromatic ( M effect of the chlorine ), proves to most nucleophiles such as hydroxide ion (OH - ) to be very slow to react; there are temperatures above 200 ° C required to generate a response at all. With sodium amide ( NaNH2 ) in liquid ammonia chlorobenzene will be converted at -33 ° C in aniline.

Considering as the starting compound not chlorobenzene, but p -chlorotoluene (p- CH3C6H4Cl ) and puts them on the same terms as to the chlorobenzene with amide ions, one finds two products: an expected amino acid substitution product and unexpected. Thus, the chlorine atom may not have been directly substituted by the amino group. In addition, you can always find in the reaction of chlorotoluene with amide ions only the meta- and para- Aminoprodukte, but never the ortho isomer.

Reaction mechanism

Known from H / D exchange reactions is that the amide anion can abstract protons of benzene in liquid ammonia. This is particularly surprising in the ortho position to ( I ) substituents, such as chlorine. From these facts it can be concluded that not primarily the chlorine- substituted carbon atom of the aromatic compound is under attack. The deprotonated amide ion as a strong base an alpha- hydrogen atom of chlorotoluene, which. An carbanion to a triple bond intermediate, the aryne leads,

In the following the addition of NH 3, both the m- isomer and p- isomer forms.

2,6- dimethylchlorobenzene not react under these conditions to the corresponding aniline derivative. 2,6- dimethylchlorobenzene has no alpha- hydrogen atoms. Thus, no proton can be abstracted, the aryne not develops.

Didehydrobenzene

The simplest Arin, C6H4 (with 1 in the right image) is, is sometimes called in reference to the English name Benzyn. However, the description must be viewed critically, since it implies a special triple bond. A better name is usually abbreviated Didehydrobenzen or benzyne as benzyne. Benzyne is resonance stabilized, as the structures in Figures 1 and 2. The actual distribution of the electrons can be better seen in Figure 3. The additional π - bond is located in Figure 4a and is perpendicular to the π - bond ( in Figure 4B ) of the aromatic system. Benzyne can be described as diradical: The " extra " π bond in 2, 3, 4a and 4b is then cleaved homolytically, where one electron is in the atom that was previously involved in the " extra" π bond.

Benzyne is highly reactive due to the triple bond and therefore has a very short life. In solution, it reacts very quickly with existing partners and reaction in the gas phase with itself to form di- or triphenylene. While in alkynes ( in the simplest case ethyne ) normally unhybridized p orbitals are orthogonal to the top and back to the molecular axis, which causes an optimum overlap of the orbitals in the aryne the p orbital becomes distorted to accommodate the triple bond in the ring system. This reduces the optimum overlap of the orbitals.

There are three possible diradicals of benzyne: 1,2 -, 1,3 - and 1,4- benzyne. The binding energies are in silico 106, 122, and 138 kcal / mol ( 444, 510, and 577 kJ / mol). Maitland Jones in Princeton has the possible rearrangements of the 1,2 - and 1,4- examined Didehydrobenzole -, 1,3.

Ortho- benzyne

The ortho- Didehydrolbenzol is the best studied isomer from the group of the three possible Didehydrobenzole. On the representation and his reactions will be discussed in accordance with the following. How is the high number of publications shows, this is undoubtedly linked to the relatively simple experimental accessibility through a variety of possible formation reactions together, but also with the fact that mate the two electrons and thus can achieve the energetically favorable singlet state. Armin Schweig et al. calculated the bond length for the C-C triple bond in the ortho- benzyne (depending on the computer model ) to 122-126 pm. Anita M. Orendt et al. determined a value of 124 ± 2 pm. This is a value that is close to a normal carbon-carbon triple bond, such as ethyne ( 120.3 pm ) is located. By η 2 - coordination of the carbon-carbon triple bond in the metal complexes, ortho- Didehydrobenzole and even Tetradehydrobenzol be stabilized and used as target for catalyzed organic syntheses.

Meta- benzyne

In contrast to the ortho- Didehydroarinen the meta -and para- isomers are significantly more unstable and reactive. Accordingly, working groups succeeded only in 1992 by Wolfram Sander and Dieter Cremer, the first IR spectroscopic evidence of the existence of 2,4- Didehydrophenol after photolysis of matrix- quinone diazide at 10 K.

The first isolation of 1,3- Didehydrobezol succeeded in 1996 by the group of Wolfram Sander by photolysis of meta-para - cyclophane -9 ,10 -dione or by gas-phase thermolysis of diacetyl. Other preparative routes for meta- benzyne are the pyrolysis of 1,3- diiodobenzene or flash vacuum pyrolysis of 1,3- dinitrobenzene. The 1,3- benzyne is under the chosen conditions is not very stable and rearranges ,5 -diyne by a ring-opening reaction of 3-hexene -1 at.

Para- benzyne

1974 could Richard Jones and Robert Bergman show that at the positions C-1 and C-6 deuterated (Z)- Hex -3-en -1 ,5 -diyne by thermolysis at 300 ° C in a mixture of 3,4 - and 1,6- deuterated (Z)- Hex -3-en -1 ,5 -diyne passes, but no 1,3 - or 1,4- isomers are formed deuterated. The result can only be a symmetric and cyclic intermediate, the 1,4- benzyne explain.

The ring closure reaction is named after its discoverer as Bergman cyclization. The fact that the 1,4- benzyne actually forms could be detected in the presence of carbon tetrachloride by appropriate trapping, for example, by the formation of 1,4- dichlorobenzene. Through works by Kyriacos Costa Nicolaou could be shown that the rate of Bergmann cyclization is dependent on how close the two terminal carbon atoms (C- 1 and C- 6). In the (Z)- Hex -3-en -1 ,5 -diyne the two terminal carbon atoms at a distance of 412 pm, and the cyclization proceeds at 200 ° C with a half -life of 30 seconds. If the ends of the En - diyne, for example, brought by a ring closure closer together, thus increasing the reaction rate. In 3- cyclodecene -1 ,5 -diyne, the distance between C-1 and C-6 only 325 pm, and the Bergman cyclization is already at room temperature with a half-life of 18 h. However, the presence of substituents has an influence on the rate of Bergmann cyclization.

In the Bergman cyclization is a reversible reaction, in which the 1,4- benzyne is converted by a retro- Bergman reaction again in the (Z) - hex-3 -ene-1 ,5 -diyne. Since the En -diyne compared to the 1,4- benzyne also the energetically more stable product, the direct detection and isolation of the 1,4- benzyne designed correspondingly difficult. Thermolysis of 1,4- diiodobenzene supplies only hex-3 -ene-1 ,5 -diyne, 1,4- benzyne can not be detected spectroscopically. In a by Juliusz G. Radziszewski et al. developed photolysis method was 1,4- benzyne but are presented and characterized in a Ne matrix at 6 K of 1,4- diiodobenzene by irradiation at 248 nm.

Hetarynes

As hetarynes be arynes in which a carbon atom has been replaced formally by a hetero atom, respectively. The Preparation and Reactions of hetarynes have been studied in many research papers. Hetarynes be the arynes often formed similarly on Elimierungsreaktionen halogenated heteroaromatics. Even in their reactions behave similarly substituted hetarynes arynes, wherein the heteroatom may have a stronger directing effect. Interestingly enough, the position of the heteroatom in the aromatic ring system plays a decisive role. A working group led by Thomas Kauffmann could show that halogenated quinolines chlorine and bromine in the 5 -, 6 - or 7- position after the elimination-addition mechanism via arynes are cleaved, while 8 -position chlorine, bromine or iodine after addition - elimination pathway is replaced. Known representatives of hetarynes are about 3.4 - pyridyne, 3,4- Didehydrochinolin or the already mentioned above 2,3- Didehydrobenzofuran. Formal formation of the triple bond can with halogen derivatives of the pyridine in the 2,3 - or 3,4- position take place to the nitrogen atom.

Representation

Arynes are mostly prepared from aryl halides by reaction with strong bases according to equation ( a). However, other reaction pathways are described. So examined Georg Wittig and Reinhard W. Hoffmann, the formation of benzyne by decomposition of Benzothiadiazoldoxid at room temperature according to equation (b). Martin Stiles and Roy G. Miller reported a similar reaction pathway by thermolysis of Benzoldiazonioum -o -carboxylate in boiling furan according to equation ( c). Next Georg Wittig and Hans F. Ebel reported on the thermolysis of phthaloyl peroxide in vacuum at 600 ° C according to equation ( d).

Thermolysis of Benzoldiazonioum -o -carboxylate as diazotized anthranilic acid, according to equation ( c ) is carried out via a concerted mechanism:

By reaction of 1,2- fluorobromobenzene with lithium, photolysis or Gignard compounds having aromatic residues arynes be represented.

Studies on the formation of arynes from aryl halides by reaction with phenyllithium in diethyl ether show that this is done via a two-step mechanism. In the first step an ortho- hydrogen atom (which is directly adjacent to the halogen atom ) is cleaved and replaced by an alkali metal. After that, Arin formed in the second step by elimination of lithium halide.

Rolf Huisgen et al. could show that under appropriately selected conditions ( phenyllithium in diethyl ether) the fluorobenzene about 10 times faster responding than the other aryl halides ( fluorine >> bromine > chlorine > iodine). Georg Wittig and Liselotte Pohmer could also show that the formation of benzyne is easier the more electronegative the halogen and the more electropositive the metal.

Amines are added to the reaction mixture (for example as lithium piperidide / piperidine ), the reaction rate as a function of amine concentration change. When bromobenzene, the reaction rate increases, otherwise it decreases inversely with fluorobenzene. By reducing the activation energy of the metalation reaction ( 1 step ) in this reversible fluoroaromatics is increasingly resulting in the formation of the aryne slows accordingly, or is prevented. In the reaction of fluoronaphthalene with lithium piperidide / piperidine substitution reaction then proceeds in accordance with increasing Piperidingehalt increasingly the addition -elimination mechanism instead of the aryne intermediate from. The resistance of fluorobenzene to a substitution reaction with potassium amide in ammonia can thus be explained. Studies performed on deuterated fluorobenzene could be shown that the Metallierungschritt can run normally. The intermediate is thereafter converted by the high concentration of ammonia, but again to the ( then entdeuterierten ) fluorobenzene. Rolf Huisgen et al. were able to show that the reaction rate at the Arinbildung bromobenzene also depends on additional ring substituents. Thus Reaktionsgeschwindingkeit is 140-fold and 34- fold to a fluoro, alkyl residues while reducing the rate of reaction at a (further) bromo substituent in the ortho position. The other substituent is in the meta position to the bromine, the Reaktionggeschwindigkeit with bromine 600 times, with fluorine is even 1700 times as high. In a further substituent in the para position relative to the change of the bromine reaction rate is lowest.

Reactions / Applications

Nucleophilic aromatic reactions

Arynes can react either as electrophiles or as nucleophiles depending on the reaction partner. When electron-deficient, ie electrophilic intermediates they react readily with nucleophiles. Rolf Huisgen and Jürgen Sauer showed that nucleophilic aromatic reactions often proceed via aryne intermediates. The reaction pathway via arynes competes with by way of an addition- elimination reaction. In this case, decide, among other things, the reaction conditions and the ring substituents about which expires preferred of the two paths. As running in the reaction of p -halo- toluenes (halogen is chlorine, bromine and iodine ) and 4 molar sodium hydroxide solution at 340 ° C to cresol practically completely over an elimination reaction with an aryne intermediate, while even at 250 ° C of addition mechanism has a significant share. An important indication that the reaction mechanism proceeds at an aromatic substitution, there is a change of the substitution pattern. The new group is exclusively occurred on the same ring atom, one can start from a classical nucleophilic aromatic reaction. In this entering and leaving group in the transition state at the same time are bonded to the same ring atom. In an elimination reaction on arynes the ortho ( adjacent ) ring atoms are instead involved, so it always comes to a partial rearrangement. John D. Roberts et al. For this purpose, the reactions studied in substituted aryl halide with sodium or potassium amide in liquid ammonia to give the substituted anilines.

Potassium amide can also function as a catalyst and to accelerate the formation of the aryne. Thus, reactions such as the reaction of chlorobenzene with the less reactive Kaliumanilid to di-or triphenyl at all possible. Albert T. Bottini and John D. Roberts studied the alkaline hydrolysis of chlorobenzene [1- 14C ] and found that, under the conditions of the technical process (15 percent NaOH, 370 ° C), the reaction is preferably about the elimination process with a Arin occurs as an intermediate. Depending on the selected reaction conditions result in varying amounts, in addition to phenol, also diphenyl ether and o-and p -hydroxybiphenyl.

Ring -closure reactions

Rolf Huisgen and H. King reported intramolecular ring-closure reactions on Arinzwischenstufen. Here, a alkylarylamine for example with phenyllithium ( C6H5Li ) was implemented. On the corresponding aryne N -methyl-2 ,3 -dihydro -indole formed in this case in 58 percent yield. In contrast, forming the output from the equivalent compound in which to one another, the alkyl group and the chlorine atom in otho position, and which should provide the N-methyl -2 ,3 -dihydro -indol limited to, a substantially lower amount of product.

Contains the amino group of an additional aromatic residue, so you can be synthesized via the aryne intermediate phenanthridines.

Similarly extend cyclization of o- or m -halogen or - thioacylaniliden acylanilides with potassium ( KNH 2 ) to form an aromatic oxazole or thiazole ring.

Diels- Alder reactions

A reaction with arynes as an intermediate is the Diels -Alder reaction with dienes. Within a few years reported Georg Wittig et al. over a number of Diels -Alder reaction of arynes, including with cyclopentadiene ( a), furan ( b ) pyrrole ( c ), benzene ( d), anthracene (s) and cyclohexadiene (f). Anthracene is converted by Diels -Alder reaction of benzyne with the central benzene ring of triptycene. The pentiptycene the anthracene analogs during the reaction with 1,2,4,5- tetrabromobenzene and butyllithium.

By palladium catalysts 1,2- Didehydrobenzole can be trimerizes with high regioselectivity to triphenylenes. Alkenes or alkynes in the presence of analogous successful, the palladium -catalyzed synthesis of substituted phenanthrene derivatives. With vinylindoles arynes respond appropriately to form carbazoles. 1,2,4,5- tetrabromobenzene reacts with butyllithium and furan to 1,4,5,8- diepoxy -1 ,4,5,8 - tetrahydroanthracene. The syn-and anti - stereoisomers can be separated due to the different solubilities of methanol.

Arylation

Is an aryl halide, such as chlorobenzene, is reacted with phenyl lithium in boiling diethyl ether, it is formed of biphenyl, wherein the reaction rate and the yield is relatively low. As listed earlier, showing that Arin with lithium piperidide is formed much faster. Is added to the mixture of aryl halide and phenyllithium according lithium piperidide as a catalyst, the reaction is significantly accelerated and the yield improved.

By variation of the aryl chloride ( Aryl1Cl ) and lithium aryl compound ( Aryl2Li ) opens up the opportunity to synthesize a number of unusual part bisaryls.

By arylation reactions via arynes can be obtained in good yields very bulky aryldialkylamines such as N- Naphthyldiisopropylamin, represent, which are not accessible by other means.

Insertion reactions

With 2 - aryl triflates ( trimethylsilyl ) are quite mild Arinvorstufen are available that can perform with which selective insertion reactions. Thus, the following equation shows an insertion into a CC bond of malonate.

Eiji Shirakawa et al. showed the possibility for insertion of arynes in the CN bonds of urea derivatives and Akkattu T. Biju Frank Glorius and reported 2010 highly selective insertion reactions of arynes in the CH bond of aldehydes. So 4 -bromobenzaldehyde was reacted with a yield of 98 percent to 4 - bromobenzophenone. Substituting 1,2- benzyne with Magnesiumthiolaten order, one obtains the corresponding aryl thiolates. The magnesium group on the ring can be replaced with appropriate electrophiles.

Dehydrobenzene conversions

The reaction of 1,2 - to 1,3- Didehydrobenol has been postulated to explain the pyrolysis ( at 900 ° C) of the phenyl-substituted 1 to Arinvorstufe acenaphthylene 7.

The reaction proceeds via multiple, reactive intermediates: The Arin 2 is shown for the phenyl-substituted phthalic anhydride 1 and rearranges with ring contraction, ie reduction of cyclohexanone on the cyclopentane ring, for 3 to vinylidene. The resultant carbene -insertion undergoes CH pentalene to 4, and subsequent cleavage of a bond to vinylidene After 5 cis-trans - isomerisation to 6 followed by a final insertion reaction for the formation of the acenaphthylene. The proof of the Phenylmigration in Arin 2 from the 1,2- benzyne to 1,3 - benzyne based on isotope hike. If the ipso- carbon atom replaced by a 13C in the intermediate stage, it is found in the mechanism shown in acenaphthylene at the ipso- Arinposition again. The presence of 13C in the bridge position can only be explained if 15 percent isomerization of 2 to 1,3- benzyne A.

Tumortheraphie

The Bilung of para- benzyne by the Bergman cyclization of ene- diynes is of particular research interest, as they may explain the mechanism of the ene -diyne cytostatics. The calicheamicins, esperamicins and dynemicins used in cancer treatment act via the reactive intermediates of para- Didehydrobenzolderivaten and can be targeted to disrupt in vivo the sugar chains of the DNA double strands, leading to cell death. Due to their special molecular structure of the Bergmann cyclization can take place even at room temperature. Since the naturally occurring en- diynes are highly toxic derivatives must be developed that have a maximum toxicity against cancer cells with low toxicity to healthy cells.

More options

Chemistry arynes was used to synthesize novel arylamines in a tandem reaction including two Diels -Alder reactions with three Dehydrobenzolmolekülen responsive to an imidazole: