Arynes

see: Han, W.; Lu, Y.; Zhao, H.; Dutt, M.; Biehl, E. R.  The Reaction of Halogeno-Substituted N,N-Dimethylanalines and Polycyclic Aromatic Hydrocarbons with Certain Arylacetonitriles or ?-Cyano-o-tolunitrile Under Aryne-Forming Conditions.  Synthesis., 1996, 1, 59-63.
 

Introduction:
 Arynes are highly reactive aromatic intermediates containing a formally drawn C-C triple bond.  The first and most well studied aryne is benzyne (1), shown in figure 1.1  More complicated arynes are known, including all carbon multiple ring conjugated species, and species containing heteroatoms within the aromatic ring (figure 1, molecules 2 and 3 respectively are examples).  3 is an example of a hetaryne, which is the nomenclature used for a aryne with a heteroatom incorporated into the ring structure.2


Figure 1.  Examples of arynes.

  Benzyne was almost certainly the first aryne formed, most likely generated as early as 1866 from the pyrolysis of benzene in a red-hot porcelain tube.  Since benzyne is an unstable intermediate and not a product of this reaction, however, benzyne was not recognized as an intermediate until almost 100 years later. Though proposed as an intermediate in many reactions since the turn of the century, the benzyne intermediate was first clearly demonstrated by Bottini and Roberts through 14C labeling experiments.  They inferred an aryne intermediate through the reaction of strong base with labeled chlorobenzene (Figure 2).3  The mechanism and details of this type of reaction will be discussed later.


Figure 2.  Rearrangement of products through a benzyne intermediate.

 Aromatic nucleophilic substitution reactions generally proceed slowly enough to render them synthetically unfeasible.  However, there are four methods which make reactions of this type possible:  nucleophilic aromatic substitution can be activated by ortho and para electron withdrawing groups, by electron donors, by reaction in which a diazonium salt is replaced by a nucleophile, and by catalysis by a strong base proceeding through an aryne intermediate.4  The aryne reactions and associated mechanisms will be the focus of this paper.

Structure:
 Of all arynes, the benzyne structure has been the most studied in the literature, but the general features of the benzyne structure discussed here also apply to other arynes.  First, one should note that the formal triple bond drawn in benzyne is not conjugated.  The orbitals of this bond are perpendicular  to the p-system in benzene, so the interaction is localized (Figure 3).5  The orbitals of the formally drawn triple bond are highlighted in black in Figure 3.


Figure 3.  Benzyne, showing the delocalized p-system and the localized C-C "triple bond".

 A great deal of computational work on the structure and orbital energies of benzyne has been done, the results of which seem to correlate with benzyne's high electrophilicity.   Calculations have shown that benzyne has a very small HOMO-LUMO gap when compared to a linear alkyne.  In a computational study by Rondan et al. using ab initio methods (4-31G), 2-butyne and distorted 2-butynes were compared to benzyne.  The frontier orbitals were compared, showing a general decrease in the energy of the LUMO as the structure became more like benzyne, while the HOMO stayed at approximately the same energy (Figure 4).6


Figure 4.  Frontier Orbital energies (in eV) for 2-butyne, distorted 2-butynes, and benzyne.

The relatively low energy of the LUMO in benzyne has been attributed to mixing of the p* orbital with a s* orbital which lies just slightly higher in energy. The electrophilic character of benzyne (and therefore, other arynes as well) can be attributed to the low-lying LUMO.  This orbital will be much closer in energy, compared to linear alkynes, to the HOMO of a nucleophile, making nucleophilic reactions much more facile.7

Generation of Arynes
 Aryne chemistry is observed with aromatic rings lacking ortho and para electron withdrawing groups.  These groups activate aromatic rings towards addition-elimination reactions.  An example of this type of reaction is formation of 2-nitrophenol from 2-nitrochlorobenzene (Figure 5).8


Figure 5.  Addition-elimination reaction scheme.

 Nucleophilic aromatic substitution on aryl halides that have no activating groups can take place in the presence of strong bases.  Substitution in this case will follow the elimination-addition mechanism (aryne formation) as shown in Figure 6.8


Figure 6.  Elimination-addition reaction scheme.

There are several methods for generation of arynes. Initially, arynes were mostly formed using the aryl-halide-strong base route (Figure 7).1,9  A variety of base-solvent combinations can be used to eliminate a hydrogen halide from a halobenzene.  The ones most commonly used are alkali metal aryls/alkyls in ether solvents or amides in liquid ammonia.9  More on formation of arynes using this method will be discussed later.


Figure 7.  Formation of arynes through strong base route.

 A very useful method in aryne formation is diazotization of o-aminobenzoic acids.  After diazotization, loss of nitrogen and carbon dioxide generates benzyne (Figure 8).  A major disadvantage of this method is the explosive nature of diazonium compounds.10,11


Figure 8.  Formation of arynes through diazonium salt.

Arynes can also be generated by oxidative decomposition of 1-aminobenzotriazole (Figure 9).  The oxidized intermediate decomposes with elimination of two molecules of nitrogen.12,13


Figure 9.  Formation of arynes through oxidative decomposition.

 The o-dihaloaromatic precursors can also be used to generate arynes (Figure 10).  Metal-halogen exchange of the precursor with lithium amalgam or magnesium results in formation of a transient organometalic compound that decomposes with elimination of lithium halide.14


Figure 10.  Formation of arynes through an o-dihaloaromatic.

Effects of Substituents
The slow step in the formation of benzyne from halobenzene can either be the removal of a hydrogen or the loss of halide.  The relative rates depend on the solvent and on  the halogen.  The ease of halide expulsion from 5 is I > Br > Cl > F (Figure 11).  This order reflects the ease of carbon-halogen bond breaking.  The rates of initial proton removal are in the reverse order, F > Cl > Br > I.  This is due to the inductive effect favoring proton removal from the carbon adjacent to the more electronegative atom.1


Figure 11.  Formation of arynes through strong base route.

Reaction of aryl halides with KNH2 in liquid ammonia shows the order Br > I > Cl > F.15  This indicates that carbon-halogen bond breaking is the part of the rate determining step.  On the other hand reaction of aryl halides with organolithium reagents in aprotic solvents shows the reverse order F > Cl > Br > I.16  Here the rate determining step is governed by the acidity of the ortho hydrogen.

 In m-substituted halides, aryne formation can take place at two different sites.  If the m-substituent is electron withdrawing, more of anion 8 than 10 will be formed (Figure 12).  When the substituent is electron releasing, 10 will be formed preferentially. Ratio of 8 to 10, however may not necessarily be the same as the ratio of 9 to 11.  If the rate determining step in the reaction is loss of halide from the anion, then the ease of halide loss from two possible anions will determine the ratio of arynes formed.1


Figure 12.  Work done by Roberts et al.

An example comes from the experiments done by Roberts et al.  They reacted m-bromo- and m-chloro-toluene with potassium amide and looked for formation of arynes.  The rate determining step in aryne formation from m-bromo-toluene is the loss of hydrogen because Br- is a better leaving group than Cl- and the protons ortho to the bromine are less acidic.  In the case of m-chloro-toluene, rate is governed by the loss of chloride from the anions. Because the methyl group is electron releasing the rate of formation of the anion 10 is faster than formation of 8.  Thus, m-bromo toluene mainly forms aryne 11. Since the rate determining step for aryne formation from m-chloro-toluene is chloride loss, the anion which eliminates chloride faster will be the one dominating the product distribution.  Anion 10 is more destabilized than 8 due to the proximity of negative charge to the electron releasing methyl group.  Thus this anion will eliminate chloride faster and produce aryne 9.17

Generation of Hetarynes
Generation of hetarynes has proven to be much more difficult than that of other arynes.  This is because reacting heteroaromatic ring species are either "more labile toward non-aryne reactions or more stable toward aryne formation.18
 For example, in the Diels-Alder reaction of 3-bromobenzofuran with tetraphenylcyclopentadienone, an addition-elimination reaction occurs instead of the aryne elimination-addition reaction.  The penalty for breaking aromaticity in addition elimination reactions is less for hetarynes than arynes due to their  lower resonance energy.18


Figure 13. Diels-Alder Reaction.

Another example is the attempted hetaryne generation from a diazonium carboxylate.18


Figure 14.  Attempted Generation of Hetaryne from Diazonium Carboxylate.

For oxygen and sulfur containing heteroaromatic rings, hetarynes are not usually observed.  However, hetaryne formation is favored in some nitrogen containing heteroaromatic ring systems.  Heavier halogen substituents and use of a bulky base seem to promote nitrogen hetaryne formation, because heavier halogens are better leaving groups and bulky bases are less nucleophilic.5


Figure 15.  Nitrogen Hetaryne Formation.18

Reactivity
 Arynes participate almost exclusively in two different reactivity pathways: a) nucleophilic addition to the triple bond b) pericyclic reactions and c) radical reactions. However, aryne radical chemistry has not been deeply explored due to its limited scope. The large enthalpy of formation of these intermediates (around 120 kcal/mol) is partially responsible for the high reactivity of arynes in both types of processes.19  Also, the strong electrophilic character of the formal triple bond in benzyne has been explained by observing that the LUMO in this species is much lower in energy compared to the energy of the LUMO of acetylene.20 This leads to a smaller energy gap with respect to the HOMO of a


Figure 16.  Relative reactivity of nucleophiles towards addition to benzyne.

incoming nucleophile, resulting in enhanced reactivity. Another general trend in aryne chemistry is the ease of polarization of the triple bond. As a consequence of this behavior, arynes are classified as "soft" electrophiles and show some selectivity (Figure 16) towards hard/soft nucleophiles.9
From the synthetic point of view an important feature of aryne chemistry is the regioselectivity of the addition to the triple bond in unsymmetrically substituted arynes.


Figure 17.  Effect of substituents on addition to benzyne.

 Useful selectivity is observed when the incoming nucleophile is not very reactive and is susceptible to a strong regiochemical bias by the electronic distribution of the triple bond. Since the p orbitals forming the triple bond of a typical aryne are orthogonal to the aromatic system, the polarization of the triple bond is governed exclusively by the inductive effect of the substituents. Taking benzyne as an example, Figure 17 summarizes the expected regiochemical outcomes of the addition to monosubstituted benzyne rings depending on the nature of the substituent. Factors like sterics or the type of nucleophile employed also play a role in determining the regiochemical outcome of the reaction. In general, the more reactive nucleophiles will show reduced selectivities. Steric hindrance is specially important for cases where the favored addition to the aryne is ortho to the substituent.


Figure 18.  Regiochemical control in 1,2-napthalyne.

An illustrative example of this behavior is the selectivity (Figure 18) in the nucleophilic addition to 1,2-naphthalyne.21 The selectivity in this system is attributed to the shielding of the 1 position by the peri H atom.

 A brief word will be mentioned on the regioselectivity of the addition of nucleophiles to hetarynes, in particular to pyridyne systems (Figure 19). For the 2,3-didehydro pyridine system, addition occurs exclusively at the 2 position, possibly due to the fact that the 3-pyridyl anion is more stable than the 2-pyridyl anion.22


Figure 19.  Regioselectivity of addition to pyridyne.

Electronic repulsion with the lone pair on the nitrogen has also been argued as a possible cause for the observed regioselectivity. On the other hand, for 3,4-didehydropyridine the selectivity seems to be strongly affected by the nucleophile (Table 1).23
 
 
 
Nucleophile
Solvent
C-3:C-4
KNH2
NH3 (l)
35:65
KOtBu
DMSO
33:67
NaSCH3
NH3 (l)
50:50
KSPh
DMSO
50:50
KSPh
NH3
50:50
LiNC5H10
HNC5H10
48:52

Table 1.  Effect of nucleophile on addition to pyridyne.

While soft nucleophiles are completely unselective, hard bases show a slight preference for attack at the 4 position. This is expected on grounds of electron density distribution across the triple bond and the stability of the resulting anion.
 Perhaps one of the most useful synthetic applications that spring from this type of processes is the ability to trap the aryne intramolecularly and, thus, form potentially complex


Figure 20.  Benzoxazole formation.

fused cyclic structures. The formation of the 7-lithio benzoxazoles through an aryne intermediate (Figure 20) constitutes a fine example of this type of chemistry.24

 Reactions in which the triple bond of an aryne acts as a dienophile or a dipolarophile constitute the other major set of chemical processes that arynes can undergo. Especially useful from the synthetic point of view is the Diels-Alder reaction of arynes with dienes. The reaction works better with electron rich dienes as expected from the fact that the aryne reactivity is dominated by the electrophilicity of these systems. Synthetically, this reaction has been put to use as the key step in the formation of the tetracyclic core of several lycorine alkaloids (Figure 21).25  The high reactivity of the arynes promotes a competitive [2+2] cycloaddition pathway, which can be avoided through the use of cyclic dienes like cyclopentadiene, furan or anthracene. Arynes can


Figure 21.  Lycorine alkaloid skeleton formation.

react with olefins to yield [2+2] cycloaddition adducts, however, the yields of these reactions are rarely above 40%, thus, limiting the synthetic utility of these processes.  Arynes can also undergo 1,3 dipolar cycloadditions with several 1,3 dipoles (nitrones, diazo compounds, allyl anions). A rather simple route to substituted  benzofurans comes from the work of Reid.26 The reaction of benzyne with  several benzenediazonium-2-oxides gives the benzofuran adducts in fair yield (Figure 22).


Figure 22.  Benzofuran formation.

Results:  The Reaction of Halogeno-Substituted N,N-Dimethylanalines and Polycyclic Aromatic Hydrocarbons with Certain Arylacetonitriles or a-Cyano-o-tolunitrile Under Aryne-Forming Conditions.

The reactions of arynes with preformed a-lithio arylacetonitriles has been shown to yield two types of products arising from two competitive pathways: i) product 1 being the result of a typical nucleophilic addition to the electrophilic triple bond of the aryne and ii) product 2, which is formed by an initial addition of 3 to the aryne, followed by an


Scheme 1.
intramolecular ring closure to produce intermediate 4. This upon protonation yields 2. Biehl and coworkers have been studying ways to maximize the rearrangement process as an effective entry into trisubstituted aromatic rings. In earlier work, Biehl demostrated excellent meta regioselectivity in the addition of aryl methyl nitriles to 2,3-arynes possessing electron withdrawing groups.27  This can potentially afford good control in the preparation of 1,2,3-trisubstituted aromatic rings, being this the major focus of the case study at hand.

In this work Biehl et al. treated different substituted 2,3-arynes with various arylacetonitriles.   By varying the substituent on the 2,3-aryne, different products could be formed.  The following reactions were reported.


Figure 23.  Reactions reported by Biehl et al28

In the first reaction, a tandem addition-rearrangement reaction occurred, where the arylacetonitrile was first added ortho to the dimethylamino substituent.  The same reaction was observed in the second reaction, however, the arylacetonitrile was initially added meta to the methoxy substituent.  A different reaction pathway occurred in the third reaction.  A [4+2] cycloaddition was observed in this reaction.

Discussion:
 It has been argued that electron releasing groups (alkyl chains) will favor the addition-rearrangement pathway through a destabilizing effect on the precursor to the benzocyclobutane intermediate. Indeed compounds 5 and 6 gave exclusively products where the rearrangement has taken place in poor to fair yields. Interestingly enough, no comment is made on the paper to the fact that initial addition to the aryne derived from 5 occurs ortho to the dimethylamine function. This is contrary to the expected meta preferred site of attack if one considers that CH3- is electron donating and the amine will be electron withdrawing (by induction).
 The first reaction is believed to proceed through the following mechanism:


Figure 24.  Reaction 1 Mechanism.28
On the other hand, reaction B takes place with addition at the meta position with respect to the methoxy subsituent, as would be expected based on iductive effect considerations. In the second reaction, this mechanism is believed to occur:
 
 


Figure 25.  Reaction 2 Mechanism.28

Unfortunately, the authors did not attempt to test their ideas concerning the control of the competitive pathways. That is, no examples where the alkyl chains in compounds 5 and 6 have been replaced by electron withdrawing subsituents are presented. If their initial assumption was to be correct, one would expect to see some of the simple addition product.

Finally the authors present a new reactivity pathway observed when arynes are treated with compound 11. The third reaction does not proceed by the tandem addition rearrangement but by a [4+2] cycloaddition.  The mechanism is thought to be the following:


Figure 26.  Reaction 3 Mechanism.28

It is suggested by the authors that electron withdrawing substituents favor the 4+2 cycloaddition pathway.  This is due to the belief that not enough negative charge is present to attack the arylacetonitrile.

 These reactions are examples of the usefulness of aryne chemistry in synthesis.  The tandem addition-rearrangement reaction is a novel reaction to add cyano groups to aromatic rings.  Also, arynes can be used in Diels-Alder reactions to form new ring structures.

Conclusions:
 Arynes have been shown to be highly reactive intermediates that occur under highly basic conditions with aromatic rings without electron withdrawing groups.  Their reactivity towards nucleophiles is a direct result of the low-lying LUMO all arynes possess.  Nucleophilic addition as well as pericyclic reactions of arynes have been shown to be synthetically relevant.  The addition of nucleophiles to unsymmetrically substituted arynes can be rationalized by considering the nature of the substituents on the aromatic ring.

References
1)  Fields, E. K.  Organic Reactive Intermediates., McManus, S. P., Ed.; Academic Press, New York, 1973.
2)  Kauffmann, T.; Wirthwein, R.  Progress in the Hetaryne Field.  Angew. Chem. Internat. Ed., 1971, 10, 20-33.
3)  Bottini, A. T.; Roberts, J. D.  Mechanisms for Liquid Phase Hydrolyses of Chlorobenzene and Halotoluenes.  J. Am. Chem. Soc., 1957, 79, 1458-1462.
4)  March, J.  Advanced Organic Chemistry.  4th Ed., John Wiley and Sons, New York, 1992.
5)  Hoffmann, R.  Dehydrobenzenes and Cycloalkynes.  Academic Press, New York, 1967.
6)  Rondan, N.; Domelsmith, N.; Houk, K. N.; Bowne, A. T.; Levin, R. H.  The Relative Rates of Electron-Rich and Electron-Deficient Alkene Cycloadditions to Benzyne.  Enhanced Electrophilicity as a Consequence of Alkyne Bending Distortions.  Tetrahedron Letters, 1979, 35, 3237-3240.
7)  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.
8)  McMurry, J.  Organic Chemistry., Brooks/Cole Publishing Company, Belmont, California, 1992.
9)  Kessar, S. V. Comprehensive Organic Chemistry., Trost, B. M., Ed., Pergamon Press, Oxford, U. K., 1991.
10)  Stiles, M.; Miller, R. G.; Burckhardt, U.  Reactions of Benzyne Intermediates in Non-basic Media. J. Am. Chem. Soc., 1963, 85, 1792-1797.
11)  Friedman, L.; Logullo, F. M. Arynes Via Aprotic Diazotization of Anthranilic Acids.  J. Org. Chem., 1969, 34, 3089-3092.
12)  Campbell, C. D.; Rees, C. W.  Reactive Intermediates.  Part III.  Oxidation of 1-aminobenzotriazole With Oxidants other than Lead Tetra-acetate.  J. Chem. Soc. Part C:  Organic., 1969, 742, 752-756.
13)  Whitney, S. E.;  Rickborn, B.  Isolation of 1:1 Oxazole-Benzyne Cycloadduct:  An Improved Method for Generating Benzyne and a New Approach to Isobenzofuran.  J. Org. Chem., 1988, 53, 5595-5596.
14)  Wittig, G.; Hoffmann, R. W.  1,2,3-Benzothiodiazole. Org. Synth, 1967, 47, 4-10.
15)  Bergstrom, F. W.; Wright, R. E.; Chandler, C.; Gilkey, W. A.  The Action of Bases on Organic Halogen Compounds.  J. Org. Chem., 1936, 1, 170-178.
16)  Huisgen, R.; Sauer, J.  Nucleophile Artomatische Substitutionen Uber Arine.  Angew. Chem., 1960, 72, 91-108.
17)  Roberts, J. D.; Vaughan, C. W., Carlsmith, L. A.; Semenow, D. A.  Orientation in Aminations of Substituted Halobenzenes. J. Am. Chem. Soc., 1956, 78, 611-614.
18)   Reinecke, M.  Hetarynes. Tetrahedron, 1982, 38, 427-498.
19)  Pollack, S. K.; Hehre, W. J.; Determination of the Heat of Formation of o-benzyne by Ion Cyclotron Resonance Spectroscopy.  Tetrahedron Letters, 1980, 21, 2483-2486.
20)  Houk, K. N.; Levin, R. H.; The Relative Rates of Electron Rich and Electron Deficient Alkene Cycloadditions to Benzyne. Enhanced Electrophilicity as a Consequence of Alkyne Bending Distortions. Tetrahedron Letters., 1979, 20, 3237-3240.
21)  Kauffmann, K.; Fischer, H.; Nürnberg R.; Withwein, R.; Über die Selektivität hetero- und carbocyclischer Arine gegenüber Basen; Justus Liebigs Ann. Chem., 1970, 731, 23-26.
22)  Abramovitch, R. A.; Singer, G. M.; Vinutha, A. R.; Base-catalysed Deprotonation in Pyridine N-Oxides and Pyridinium Salts; J. Chem. Soc. Chem. Comm., 1967, 55.
23)  Van der Plas, H. C.; Roeterdink, F.; "Six Membered Didehydroheteroarenes" in The Chemistry of Functional Groups, Supplement C (Ed. by Patai S. and Rapaport Z.), 1983, John Wiley and Sons Ltd., New York.
24)  Clark, R. D.; Caroon, J. M.; Preparation and Electrophilic Trapping of 7-Lithiated Benzoxazoles Generated via Benzyne Cyclization; J. Org. Chem., 1982, 47, 2804-2806.
25)  González, C.; Guitián, E.; Castedo, L.; A New Intramolecular Cycloaddition Approach to Lycorines; Tetrahedron Letters, 1996, 37, 405-406.
26)  Ried, W.; Tan Sio Eng, J.; o-Chinondiazide und o-Chinone als Dehydrobenzol-Fänger; Justus Liebigs Ann. Chem., 1969, 727, 219-221.
27)  Biehl, E. R.; Khanapure, S. P.; Acc. Chem. Res., 1989, 22, 275.
28)  Han, W.; Lu, Y.; Zhao, H.; Dutt, M.; Biehl, E.;  The Reaction of Halogeno-Substituted N,N-Dimethylanalines and Polycyclic Aromatic Hydrocarbons with Certain Arylacetonitriles or a-Cyano-o-tolunitrile Under Aryne-Forming Conditions.  Synthesis., 1996, 1, 59-63.
 

Questions
1) Wotiz and Huba (J. Org. Chem., 1959, 24, 595) observed the following results while studying the addition of metal amides to substituted aromatic rings. Rationalize the regiochemistry of the products (Be sure to indicate any type of intermediates formed under the reaction conditions).

Answer.
 Under the reaction conditions aryne formation is very likely and, more important, aryne intermediacy provides with a clear rationale for the regiochemistry of the products observed.

Compounds 1 and 5 can only form one aryne each, A and B respectively. Intermediate A would be preferentially attacked at the meta position as that would bring the negative charge close to the electron withdrawing chlorine. As for intermediate B, the preferred site of attack would be para with respect to the chlorine for the same reasons explained earlier.

 On the other hand, compound 3 can form both intermediates A and B. One would predict A to be formed preferentially due to the greater acidity of the proton between the two chlorines. Indeed, the observed product has the amine function meta to the chlorine, which means that the intermediate formed must be A.

2)  In another paper by Biehl et al. (Heterocycles 1998, 48, 303-309) another reaction pathway was observed.
Describe a plausible mechanism for this reaction.

Answer.