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Proc. NatL Acad. Sci. USA Vol. 79, pp. 4487-4494, July 1982 Review

Recent aspects of : New preparative methods and mechanistic studies (A Review) GEORGE A. OLAH, SUBHASH C. NARANG, JUDITH A. OLAH, AND KooP LAMMERTSMA Research Institute and Department of , University of Southern California, Los Angeles, California 90007 Contributed by George A. Olah, April 13, 1982

ABSTRACT New preparative methods of electrophilic nitra- 1700C, without subliming, into its components-i.e., NO2F tion and transfer nitration are reviewed, including reactions re- + BF3. The hexafluoroantimonate salt is even more stable. The lating to the ambident reactivity of the nitronium . Recent as- higher thermal stability may be partially a consequence of the pects of the mechanism of electrophilic aromatic substitution are higher boiling point of the corresponding Lewis fluoride discussed. compared to boron trifluoride. Nitronium salts can be stored at room temperature indefi- Nitration is one ofthe most studied and best understood ofor- nitely without decomposition. Refrigeration is generally un- ganic reactions (for reviews, see refs. 1-4). Both aromatic and necessary and no other special precautions are required. How- aliphatic compounds can be nitrated by various methods such ever, all nitronium salts are very hygroscopic and must be stored as heterolytic (electrophilic and nucleophilic) and nitra- and handled with precautions to avoid moisture. tions. Aromatic nitration is most frequently electrophilic; ali- Nitronium tetrafluoroborate and related nitronium salts are phatic is free radical. Nitroaromatic compounds are ofsubstan- extremely active nitrating agents for aromatics: tial use as intermediates in the synthesis of plastics, phar- maceuticals, dyestuffs, , insecticides, etc.; nitro- ArH + NOQBF- -- ArNO2 + HF + BF3. aliphatics are used as solvents and synthons in . In regard to aromatic nitration, Ingold and his associates pub- The are carried out under anhydrous conditions. lished a series of papers in 1950 which ever since have been This is of special advantage in dealing with compounds which, considered the most fundamental study in our understanding under the usual strongly acidic nitration conditions, may under- of electrophilic nitration reactions (for a review, see ref. 5). go or oxidation. Aryl , for example, are easily Despite this, many questions remained unanswered and many hydrolyzed under nitration conditions and no direct dinitration, new aspects of nitration reactions have been discovered. Nu- requiring forceful conditions, was previously possible. The ni- cleophilic and free radical nitration ofaromatics is considerably tronium fluoroborate method enabled us to carry out mono- and less studied. Aliphatic nitration, most frequently carried out in dinitration of aryl in high yields without any hydrolysis the phase under free radical conditions, is of increasing of the -CN group. interest. Typical results of preparative nitrations of arenes, nitroar- In the 1980s, the subject ofnitration is still ofsubstantial in- enes, ary1carboxylic acid and halides, and arylnitriles are terest and activity. This is the case concerning new preparative summarized in Tables 1-4. aspects as well as mechanistic aspects with particular emphasis In mono- or dinitration of aromatics, nitronium salts gener- on the nature of the reactive intermediates involved. The fol- ally react under quite mild conditions, and yields are 80-100%. lowing review summarizes results of our ongoing research on Trinitration of aromatics, particularly of , repre- nitration in recent years. sented a challenging problem. Although the preparation of 1,3,5-trinitrobenzene from rn-dinitrobenzene has been re- PREPARATIVE ASPECTS ported in low yield (11), 1,3,5-trinitrobenzene is usually pre- Nitration with Nitronium Salts. The Ingold group (5) clari- pared by indirect methods (12). The nitration ofm-dinitroben- fied the nature of the salt obtained by Hantsch (6, 7) from the zene to 1,3,5-trinitrobenzene with nitronium tetrafluoroborate reaction ofnitric and perchloric as a mixture ofnitronium in fluorosulfuric acid solution in contrast could be carried out perchiorate and . They subsequently with ease (62% yield). prepared and studied (by Raman spectroscopy) pure nitronium Nitronium salts in strongly acidic solvents (such as FS03H perchlorate (5). This wvas a significant step because it directly or HF) are thus capable of effecting an efficient preparative proved the existence of the suggested by their nitration ofbenzene to 1,3,5-trinitrobenzene which, due to its kinetic studies. However, was unstable increased stability relative to TNT, can be of significance. () and therefore it was not further studied. Nitronium salts also readily aliphatics. and Preparation of stable nitronium salts as nitrating reagents cycloalkanes, such as cyclohexane or adamantane, give high necessitated the use of counterions that could give no unstable yields. The difficulty is not in lack of reactivity but due to the esters. Olah and Kuhn reported the preparation of nitronium fact that tertiary (and reactive secondary) nitroalkanes them- tetrafluoroborate and its application as a nitrating agent (8-10). selves can react further under acidic conditions via cleavage of Nitronium tetrafluoroborate is most conveniently prepared the C-,N bond. Thus, reaction conditions must be found to byadding anhydrous HF to HNO3 in a solvent such as CH3NO2, minimize further reaction; in contrast, this is not the case in CH2C12, or the like and then saturating the solution with BF3: aromatic nitrations. Primary nitroalkanes are less susceptible HNO3 20 but nitration of their less reactive C-H bonds is also more + HF + 2BF3 -* NOCBF.7 + BF3 difficult. The nitration ofmethane, for example, is feasible only Nitronium salts are colorless, crystalline, stable compounds. in strongly acidic solution (such as FSO3H). NOtBF- decomposes at atmospheric pressure only above Nitronium salts also add readily to oilefins in the presence of 4487 Downloaded by guest on September 28, 2021 AAM Review: Olah et aL Proc. Nat/. Acad. Sci. USA 79 (1982)

Table 1. Nitration of arenes with NO'BF4 pared to ClH3NO3 for the synthesis of various ring-substituted Yield of phenyl nitromethanes (15). The incipient negative charge upoon isolated the formation ofthe nitronium ion is stabilized to a large extent Reaction mononitro by the ready expulsion ofcyanide ion, thus providing the nec- time, product, essary driving force for the reaction to proceed: Substrate Product min % CN: (N:BF3 Benzene 10 93 CH3-Co-0-NO2 + BF -0 NO Nitrotoluenes 10 95 C o-Xylene Nitroxylenes 10 91 I3- B3 -*CH3-C-ON2 m-Xylene Nitroxylenes 10 90 CH3 CH3 p-Xylene Nitro-p-xylene 10 93 Mesitylene Nitromesitylene 10 89 Using acetone cyanohydrin nitrate has certain practical ad- Ethylbenzene Nitroethylbenzenes 10 93 vantages over other procedures that use alkyl . The for- n-Propylbenzene Nitro-n- 10 91 mer is more stable than CH3N03 and is stored easily for longer propylbenzenes periods of time. BF3 etherate is easier to handle than the BF3 iso-Propylbenzene Nitro-iso- 10 93 gas used in other methods. Under similar conditions, this meth- propylbenzenes and than a n-Butylbenzene Nitro-n- 10 90 od provides cleaner products higher yields does butylbenzenes mixture of CH3NO3 and BF3 etherate; only small amounts of sec-Butylbenzene Nitro-sec- 10 92 BF3 etherate are required. butylbenzenes Alklylbenzenes and anisole have been nitrated (16) by this tert-Butylbenzene Nitro-tert- 10 88 method. Table 6 summarizes the data. butylbenzenes Nitration with Silver Nitrate. Topchiev et al nitrated aro- Naphthalene Nitronaphthalenes 25 79 matic with metal nitrates in the presence of var- Anthracene 9-Nitro- 25 85 ious Lewis acids under heterogeneous conditions (17). A max- anthracene imum yield of 58% of nitrobenzene was obtained with silver nitrate. Low yields and the heterogeneous nature of the reac- All nitrations were carried out in tetramethylene sulfone solutions tions due to the limited solubility of metal nitrates in common at temperatures between 00C and 50C. organic solvents rendered the reaction of limited use. No stud- pyridinium fluoride, giving vicinal fluoronitroalklanes: ies of mechanism were reported either, probably for the same reasons. Because of the excellent solubility of AgNO13 in NO-LBF- HF CH3CN, we have developed the AgNO3/BF3 system (18) for RCH=CH2 NO7B RCH - CHN2 --HF -HF both preparative nitrations and for investigation ofthe reaction mechanism. The reactions are homogeneous and, if necessary, F RCH=CHNO2. silver is easily recovered from the tetrafluoroborate salt:

These 1,2-fluoronitroalkanes then can be dehydrofluorinated AgNO3/BF3 to the corresponding nitroolefins. ArH ArNO2. Nitration with Alkyl Nitrates. In our studies of electrophilic nitrations, we also found alkyl nitrates (particularly CH11NO3) AgNO3 is a highly efficient nitrating agent under these re- to be very effective nitrating agents in the presence of BF3 as action conditions. We have been able to carry out selective a catalyst (13, 14). The reaction was found to be particularly mononitrations of polymethylbenzenes to obtain the corre- useful as a selective and mild nitration method-for example, sponding nitroalkylbenzenes in excellent yields (Table 5). allowing mononitration of durene and other highly alkylated Nitration with Solid Catalysts. Electrophilic ar- which, when with mixed acid, usually undergo dini- omatic nitration is generally carried out with HNO or its metal tration (Table 5). CH3NOJBF3 also can be used to achieve salts, mixed anhydrides, or nitrate esters catalyzed by H2S04 dinitration oftetramethylbenzenes by using a 2-3 molar excess (1-5). Lewis acid catalysts have also been used in nitration (O1-). of CH3NO3. Other Friedel-Crafts type catalysts can also be All of these methods require subsequent aqueous basic work- used, but BF3 was found to be the most suitable. AIC13 and up. The use of solid acid catalysts in nitration is limited to a Ti(IV)C14 in the nitration of pentamethylbenzene caused for- recent report by Kameo et al. (19) on the use of polystyrene- mation of significant amounts of chlorinated derivatives, sulfonic acid in the nitration of aromatics with HNO3. whereas use of H2SO4 led to nitrodemethylation products. The method is of limited use because the catalyst is degraded Acetone cyanohydrin nitrate has enhanced reactivity com- by the strong acid. Table 2. Nitration of nitroarenes and nitrohaloarenes with NO2 BF7 Reaction Yield of nitro Substrate Product Temp., TC Time, min product, % Nitrobenzene m-Dinitrobenzene 25 20 81 a-Nitronaphthalene Dinitronaphthalenes 25 20 85 p-Pluoronitrobenzene 2,4-Dinitrofluorobenzene 30 30 78 o-Fluoronitrobenzene 2,4-Dinitrofluorobenzene 30 30 84 2,4-Dinitrofluorobenzene Picryl fluoride 120 720 40 p-Nitrochlorobenzene 2,4-Dinitrochlorobenzene 30 1,800 75 o-Nitrochlorobenzene 2,4-Dinitrochlorobenzene 30 1,200 77 2,4-Dinitrochlorobenzene Picryl chloride 100 600 80 Tetramethylene sulfone was used as the solvent in all cases except that for 2,4-dinitrofluoro. and 2,4- dinitrochlorobenzene 100% H2SO4 was used. Downloaded by guest on September 28, 2021 .nt;view: Olah et aL Proc. Natl. Acad. Sci. USA 79 (1982) 4489

Table 3. Nitration of arylcarboxylic acid esters and halides with NOSBF4 Yield of Reaction mononitro Substrate Product Temp., OC Time, min product, % Methyl benzoate m-Nitromethyl benzoate 30 20 88 Ethyl benzoate m-Nitroethyl benzoate 30 20 79 Propyl benzoate m-Nitropropyl benzoate 30 20 82 m-Nitroethyl benzoate 3,5-Dinitroethyl benzoate 85-90 120 60 Benzoyl fluoride m-Nitrobenzoyl fluoride 50 30 69 Benzoyl chloride m-Nitrobenzoyl chloride* 50 30 70 All nitrations were carried out in tetramethylene sulfone solutions. * exchange to acid fluoride takes place with byproduct HF. Our studies showed that preparative nitrations with n-butyl When the Nafion-H catalyst is modified by impregnation nitrate and acetone cyanohydrin nitrate catalyzed by a perfluo- with Hg(N03)2, the isomer ratios ofproduct nitroalkylbenzenes rinated resin-sulfonic acid (Nafion-H) provide the cleanest show significant differences from conventional acid-catalyzed method yet known for nitrations ofaromatics (20). All ofthe by- nitrations, yielding larger amounts ofthe less-hindered isomer products are volatile organic materials. Nitro compounds there- (21) (Table 7). The nitroarenes are formed under the reaction fore can be isolated simply by removal of the catalyst by filtra- conditions both by direct nitration (catalyzed by Nafion-H) and tion, without the need of any aqueous basic washing or by nitrodemercuration (or nitrosodemercuration-oxidation) of work-up. initially formed arylmercuric nitrates (or surface arylmercuric When nitrations ofaromatics are performed with mixed acid, Nafionates). Nitrodemercuration regenerates the Hg(N03)2 (or the rate of reaction slows with time. This is due to swater pro- Nafionate), which reenters the catalytic cycle. duced in the reaction mixture, which dilutes the acid. In pre- Because the water is removed azeotropically from the reac- parative nitrations, consequently, a large excess of acid is lion vessel, the catalyst (mercury-impregnated Nafion-H) can needed, with much of the acid being wasted because of its di- be recovered without loss of activity and reused. lution. Disposal of spent acid also represents increasing envi- Transfer Nitrations. Electrophilic aromatic nitrations are ronmental problems. It was therefore of interest to studv the usually carried out with acid systems, and an equivalent amount Nafion-H catalyzed nitration ofaromatics with fuming and con- of acid is also produced as a by-product due to proton elimi- centrated HNO3 under conditions of azeotropic removal of nation from the aromatic, even in nitronium salt nitrations. water. Fuming and concentrated HNO3 were found to be equally effective. The yields ofnitro compounds, however, var- NO2 ied depending upon the nature of the aromatic substrate (20).

+ NO+A-. { +A- R

NO+ It was therefore of interest to carry out nitrations under es- NO sentially neutral conditions, by tying up the acid product with a suitable base. This has led to work on transfer nitrations with N-nitropyridinium and N-nitroquinolinium salts (22, 23).

Hg(NO2 xO+ or Hg Nafionate KSX2 ArH + PFJ(BF-) -+ ANO2 + PF4(BFy) Hg(NO3) (or Hg Nafionate) NO2

NO+ NO2 H

Table 4. Nitration of aryl and aralkyl nitriles with NOWhBF? Reaction Yield of nitro Substrate Product Temp.,0C Time, min product, % Benzonitrile 3-Nitrobenzonitrile 20-35 30 85 o-Toluonitrile 2-Methyl-5-nitrobenzonitrile 20-35 30 90 m-Toluonitrile Nitrotoluonitriles 20-35 30 85 p-Toluonitrile 4-lMethyl-3-nitrotoluonitrile 20-35 30 92 Nitro-o-toluonitrile 3,5-Dinitro-o-toluonitrile 100 60 93 Nitro-m-toluonitrile Dinitro-m-toluonitriles 100 60 84 Nitro-p-toluonitrile 3,5-Dinitro-o-toluonitrile 100 60 89 p-Fluorobenzonitrile 4-Fluoro-3-nitrobenzonitrile 40-50 30 90 p-Chlorobenronitrile 4-Chloro-3-nitrobenzonitrile 50-55 40 92 1-Naphthonitrile Nitronaphthonitrile 20-35 30 91 Benzyl Nitrobenzyl 0-15 15 84 All nitrations were carried out in tetramethylene sulfone solutions with a ratio of ArCN/NO2BF4 of 1:1.25 in mononitrations and a ratio of ArNO2CN/NO2BF4 of 1:2 in dinitrations. Downloaded by guest on September 28, 2021 19 Review: Olah et aL Proc. NatL Acad. Sci. USA 79 (1982)

Table 5. BF3-catalyzed mononitration of polymethylbenzenes Table 7. Nitration over Nafion-H catalyst with and without Yield of mononitro mercury promotion product, % Isomer distribution, % CH03NO3 in AgNO3 in Substrate Products Nafion-H Nafion-H/Hg(No3)2 Polymethylbenzene CH3N02 CH3CN Toluene 2-Nitro 56 33 3-Nitro 4 7 4-Nitro 40 60 Ethylbenzene 2-Nitro 44.7* 43 HXC 99 92 3-Nitro 2.0 6 4-Nitro 53.3 51 CH3 o-Xylene 3-Nitro 45 33 H3C 4-Nitro 55 67 H30 C,3 Chlorobenzene 2-Nitro 38 37 3-Nitro 1 2 H3C = CH3 95.4 86 4-Nitro 61 61 Bromobenzene 2-Nitro 45 44 4-Nitro 55 56 H3 CH3 Naphthalene 1-Nitro 98 97 2-Nitro 2 3 H3C 97.5 83 tert-Butylbenzene 2-Nitro 18 11 3-Nitro 11 17 OH3 4-Nitro 71 72 * Results of HN03/H2S04 nitration (18).

97.0 87 +

Nitrations with these salts can be carried out under essen- tially neutral conditions because the only acid present, due to proton elimination from the nitration of aromatics, will bind Steric factors, however, were shown to play a minor role in of nitration. Positional with the liberated heterocyclic base. At the same time, the reac- determining the positional selectivity were to be of one tivity ofthe nitrating agent can be varied byaltering the electron and substrate selectivities found independent are to be determined in tvo separate demand as well as the steric crowding of the pyridine ring with another and suggested steps (see the discussion of mechanism below). suitable substituents. with N-ni- N-Nitropyridinium and N-nitroquinolinium salts were pre- Transfer Nitrations N-Nitropyrazole. Although salts used in transfer nitrations are quite stable, pared by the method of Olah et aL (24). Addition of the corre- tropyridinium in a because oftheir sen- sponding pyridine derivative to an equivalent amount of the they require handling dry atmosphere to one the N-ni- nitronium salt in CH3CN, CH3NO2, or sulfolane solution gives sitivity moisture. In principle, could generate trammonium in situ of a nitramine. the corresponding N-nitropyridinium in practically quan- salt by protonation titative yield. The reverse addition should be avoided because R R H it can lead to ring-opening reactions. can isolated as stable The N-nitropyridinium salts be (al- N-NO2 + H+ Nl NO2 though hygroscopic), crystalline salts or generally can be used A-N° in situ in solution. Except for N-nitropyridinium hexafluoro- R R phosphate, other substituted salts are readily soluble in or is in CH3NO2 sulfolane, whereas the former soluble only This approach was developed successfully by using N-nitropyr- Nitrations were studied in and CH3NO2. CH3NO2, CH3CN, azole as a transfer nitrating agent (25). sulfolane solution. The nitrations were found to take place via a nucleophilic displacement pathway involving the N-nitropyr- idinium ions themselves and not by the free nitronium ion. H- + Ar-H + N ArNO2 ¢,fl\N N Table 6. Nitration by acetone cyanohydrin nitrate/BF3 etherate N I Yield, Relative yield, % NO2 Compound % 2-Nitro 3-Nitro 4-Nitro Toluene 77.6 59.8 4.5 35.7 N-Nitropyrazole is a stable, crystalline compound. o-Xylene 75.2 0 60.3 39.7 Transfer nitrations with N-nitropyrazole can be carried out m-Xylene 78.0 15.3 0 84.7 with Lewis acids (BF3 etherate) or protic acids (CH3SO3H1 p-Xylene 90.0 - - - CF3SO3H, etc.). N-Nitropyrazolonium ion or a related Lewis Mesitylene 74.1 - - acid complexed species is the actual nitrating agent displaced Anisole 73.1 72.4 0 27.6 by the aromatics. Downloaded by guest on September 28, 2021 .'Dnu-View: Olah et aL Proc. Nati Acad. Sci. USA 79 (1982) 4491 02N H nitrate, or form a covalent intermediate. + N RX R N - --+ v R 7\ NO+ Y- + R-X-R - LR NQ RXNO2 + RF + PF5(BF3)Rj Y = PFJ, BF7; X = O. S; R = alkyl, H. In the course of our studies, we have also prepared N- and + 8 N S-nitrito onium salts and found them to be electrophilic nitrat- H N ing agents in their own right (27). The dimethylnitritosulfonium R ion and N-nitrito4-nitropyridinium ion were prepared from H and dimethyl sulfoxide or 4- Protonation ofN-nitropyrazole on the unsubstituted nitropyridine N-oxide, respectively. was demonstrated by 13 NMR studies. The substrate selectiv- ities in nitration with IN'-nitropyrazole/BF3 etherate are lower 0- thaninnitrationwithHNNOjH2SO4acidinsulfolane, CH3CONO3, I CH3NOJBF3, or N-nitropyridinium salts but higher than in S+ + NO+ nitration with nitronium salts, thereby suggesting that the de- veloping nitronium ion is still loosely bound to the pyrazole OH3 OH3 ring. Transfer Nitrations with Nitro and Nitrito Onium Salts. + Zollinger and co-workers (26) showed that addition of2 equiv- NO2 NO2 alents of water changes the substrate reactivities observed in nitronium salt nitrations to those conventionally observed in A HNO3 solutions. A more detailed study of the competitive ni- + NO+ tration of toluene and benzene in the presence of a series of N nucleophileswas undertaken. The results, summarized inTable I 8, show that the ktoluenekbenzene rate constant ratios are in the 0 0I range 2-5 when 1 equivalent ofalcohol, , or thioether is added but are 25-66 when 2 equivalents ofthe are _ N=0_. used. The relative reactivity of the nitrating agent in the pres- ence of added is in the decreasing order ROH The isomeric nitro onium ions were alsoprepared by treating > ROR > RSR. The isomer distributions, however, are similar. nitronium hexafluorophosphate with and 4- The data are best interpreted in terms of the nitronium ion re- nitropyridine, respectively. acting with the n-donor nucleophile forming an 0- or S-nitro onium ion intermediate, which can either reverse, or transfer - N02 -+ S + NO+2 Table 8. Competitive nitration of benzene and toluene with OH3 OH3 LOH S N0WPF? and NO4PF- in the presence of , , CH3 CH3/\ thioethers, sulfoxides, and N-oxides in CH3NO0 at 250C LCH3 CH3J Isomer distribution, % Ratio: Nitrating agent kr/kB ortho mfeta para O/p NO2 NO2 NO;PF;/ (1:1) 3.3 63 3 34 1.85 NO+PF-/methanol (1:2) 26.1 62 3 35 1.77 NO PF/neopentyl

(1:1) 2.8 62 3 35 1.77 + N0O - NO'PFi/neopentyl alcohol (1:2) 25.4 62 3 35 1.77 N N NO PF;/methyl ether (1:1) 4.0 62 4 34 1.82 NO PFj/methyl ether (1:2) 31.3 62 4 34 1.82 N2;PFg/ethyl ether (1:1) 3.8 62 4 34 1.82 LN02 - NO2PFJ/ethyl ether (1:2) 32.8 62 4 34 1.82 NO2PF/tetrahydro- furan (1:1) 3.6 62 3 35 1.77 The nitrito onium ions werefound topossess significantlyless NO2PFj/tetrahydr- furan (1:2) 28.9 62 4 34 1.82 nitrating ability than the corresponding nitro onium ions. The N02PFg/dimethyl electrophilic nitrating ability of the nitrito compounds is some- sulfide (1:1)* 4.6 62 3 35 1.77 what surprising in view ofthe fact that nitrites are known to act NO4PF;/dimethyi mainly as nitrosation agents. To our knowledge, the above-men- sulfide (1:2) 65.7 62 3 35 1.77 onium salts the only known examples of nitrito de- NO+PF-/dimethyl tioned are sulfoxide (1:1)t 27.3 59 4 37 1.60 rivatives acting directly as nitrating agents in electrophilic ar- N0 PF/4-nitropyridine- omatic nitrations (excluding nitrosative nitrations of highly N-oxide (1:1)t 33.4 51 8 41 1.24 activated aromatics, such as phenols and ). kri/kB, ratio of rate constaw nit in toluene to that in benzene. According to Ingold (5), the reactivity of a nitrating agent, * In nitroethane at -780C. X-NO2, is proportional to the electron affinity of X. As a con- t At 6000. sequence, it is obvious that differences in species such as Downloaded by guest on September 28, 2021 ,92 Review: Olah et aL Proc. Natl. Acad. Sci. USA 79 (1982)

R4XN02, RtXONO, and R-X-NO2 play an important role in /CH3 + these reactions. Furthermore, these studies indicated the am- [ArCH3 + NO2 bident reactivity of the nitronium ion. Ambident Reactivity of the Nitronium Ion. Nitronium hex- \CH3 afluorophosphate (tetrafluoroborate) was found to react rapidly at - 780C with diaryl, arylalkyl, and dialkyl sulfides, affording In the course of acid-catalyzed nitration ofaromatics, the re- sulfoxides as the major products (28). Selenides, , versibility of nitration was not directly established until re- , and react equally readily, giving the corre- centl.v Gore (33) reported in 1957 that heating of 9-nitroan sponding oxygenated products. In the case ofdiphenyl sulfide, thracene with 6 M1 in trichloroacetic acid solution less than 5% ofcompeting ring C nitro products were obtained. for 15 min at 9500 gave a dark solution in which, after dilution These observations suggest that the intermediate nitrito oniumn with water, an 81% yield offree was estimated. An- ion (X'-ONO) is in equilibrium with the related nitro onium thracene itselfcould not be isolated, but a 20% yield of anthra ion (X+-NO2). The ambident reactivity of NO2 and NOq is well quinone and appreciable amounts of polymer and soluble sul- known from the literature. The suggested equilibrium was con- fonic acids were obtained. Experiments conducted in the firmed bycarryingout trans-nitrosation ofN,N-dimethylaniline presence ofadded nitrobenzene to detect cross-nitration prod- in the presence of these onium salts. 13C, 15N, and 3 P NMR ucts failed. studies ofthe onium salts showed that nitro onium salts are ir- A strong indication for the possible reversibility of aromatic nitrito onium salts either upon rais- reversibly transformed into was by Cerfontain and Telder (34) who found ing the temperature or during prolonged reaction times. The nitration obtained ambident nature of the nitronium ion has far-reaching impli- a primary kinetic hydrogen isotope effect in the nitration of an- cations in the industrial nitration ofaromatics, in which phenolic thracene-9-d (compared to light anthracene), indicative of the products could be arising by attack through the of the relative slowness ofthe proton transfer from the intermediate nitronium ion. of the reaction. Reversibility ofElectrophilic Aromatic Nitrations. Acid-cat- We have recently obtained unequivocal evidence for the re- alyzed nitration is a typical electrophilic aromatic substitution versibility of electrophilic aromatic nitration by observing su- reaction. Nitration is generally considered to be an irreversible peracid-catalyzed transfer nitration of mesitylene and toluene reaction, and nitroaromatics, in general, do not undergo rear- by 9-nitroanthracene and pentamethylnitrobenzene, respec- rangement or isomerization under the reaction conditions; how- tively, and isolating the product nitromesitylene and nitrotolu- ever, some isomerization ofthe nitroarenium ion intermediates enes (35). The following mechanism was proposed for the trans- has been observed (29). Relative reactivities and substituent fer nitration with 9-nitroanthracene.

NOo An~~~~+ NO2 NO2 L H + . H H ArH ArNO2

effects have been extensively studied in nitration of aromatics, Tfhe primary kinetic hydrogen isotope effect, kH/kD 2.25 on the assumption that the nitro compounds formed do not re- + 0.05, in the nitration of anthracene-d10 with nitronium hex- vert to starting materials. Otherwise, relative reactivities cal- afluorophosphate in CH3NO2 solution is thus in good accord culated on the basis ofproduct ratios would be affected and re- with the reversibility of the nitration of anthracene. quire a more rigorous treatment taking into account the reverse reaction. MECHANISMS Examples of acid-catalyzed migration of nitro groups have Electrophilic aromatic nitration has been shown by Ingold's been reported (29). The mechanisms of these migrations, how- classical studies (5) to proceed via the formation ofthe nitronium ever, are not always fully established and, at least in some in- ion (NO+). Reaction ofthe with aromatic substrates stances, may involve radical cations [as in the case ofnitramine results in the formation ofnitroarenium ions (a complex; Whe- rearrangements (30)]. In the case of hexamethylnitrobenzen- land intermediate) which, upon proton abstraction, yield the ium ion, the intramolecular nitro group migration was directly nitro products. There are spectroscopic indications for the af studied by us using NMR spectroscopy, and the complex was complex and significant isotope effects in the nitration (with also found capable oftransfer nitration ofadded aromatics (31). nitronium salts) of anthracene (34). A consequence of the two- CH3 CH3 step/one-intermediate mechanism is that substrate and posi- tional (inter- and intramolecular) selectivity are determined in H3C CH3 H3C OH3 one and the same step-i.e., the formation of the arcomplex. This is expressed in the Brown-Stock reactivity/selectivity re- t~~~~~~~~~~etc. lationship (36) which is based on the empirical Hammett equa- H30 0H3 H3C CH3 tion. Indeed, a large body ofdata correlate well with the rela- CH3 NO2 tionship. The implication of the Brown-Stock reactivity/ OH3 selectivity rule is that, if substrate selectivity is lost, positional This degenerate rearrangement was subsequently also studied (regio-) selectivity also should be lost. by Koptyug and co-workers (32). They showed that the rear- Olah et al (27, 37-41) found that nitration with highly re- rangement takes place through successive intramolecular 1,2- active nitronium salts under homogeneous conditions results migrations of the nitro group and ruled out the possibility of an in loss of substrate selectivity (kT/kBn 1.7 vs. t20 under nor- alternative pathway proceeding through the formation of a rad- mal acidic conditions) with maintenance ofpositional selectivity ical cation. (meta substitution, < 4%). It is instructive to note that free-rad- Downloaded by guest on September 28, 2021 Review: Olah et aL Proc. Nadti Acad. Sci. USA 79 (1982) 4493 ical nitrations with N204, C(NO2)4, and chloropicrin result in Table 9. Nitration of naphthalene with various nitrating agents low substrate and regio-selectivity, with close to statisticalprod- a/0 uct distributions (27, 42). Temp., isomer Accordingly, Olah proposed (43, 44) a three-step mechanism Reagent Solvent 0C ratio in which the first step determines the substrate selectivity (if NO2BF4 Sulfolane 25 10 rate controlling) and the second step, the positional selectivity. N02BF4 Nitromethane 25 12 Thus, for a given substrate the reactivity of the nitrating agent HN03 Nitromethane 25 29 determines which of the two transition states is of highest en- HNT03 25 21 ergy. The same applies to variations of the basicity of aromatic 1103 Acetic acid 50 16 substrates in a given nitrating system. Schofield and co-workers HN03 Sulfuric acid 70 22 (45) similarly found that, in nitric acid nitration in strong acids, HN03 25 9 substrate selectivity only may be lost, and they also formulated CH30NO2/CHC3OSO2F Acetonitrile 25 13 the formation ofan intermediate prior to the ar complex. AgNO3/CH3COCI Acetonitrile 25 12 by AgNO/C,5H6COCI Acetonitrile 25 12 The nature of the first intermediate has been discussed N204 Acetonitrile 25 24 Olah (43, 44) in terms of t-complex character. The fast nitric N204/Ce(NO3)t2NH4NO3 Acetonitrile 65 16 acid nitrations were interpreted by Schofield and co-workers HNTO:JH.SO^/urea Acetonitrile - 11 (45) to be a result ofmicroscopic diffusion control with formation Electrochemical oxi- of the first intermediate at the encounter rate-accordingly dation + N204 Acetonitrile - 9 named "encounter pair"-in which there is no significant in- C(NO2)4 Gas phase 300 1 teraction between the reactants. Nitronium salt nitrations have AgNOJBF3 Acetonitrile 25 19 been discussed in terms ofmacroscopic diffusion control (mixing NO2 control) (46). However, we consider this inadequate to explain many of the experimental observations. Although mixing con- Acetonitrile 25 10 trol for very reactive species (mesitylene, durene) has been sug- gested (47, 48), there is no evidence for the fundamental cases ofbenzene and toluene. On the contrary, the fact that a reverse N+ isotope effect was found for nitration of heavy and light benzene O -N 0 and toluene (49, 50) (kH/kD = 0.81) renders mixing control, if present at all, of minor importance. From ref 57. Isomer ratios are accurate to ± 1. Formulation of the first intermediate in terms of v-complex of a ni- /3 ratio of 40, whereas a ratio of 10-12 was found for the naph- nature is strongly supported by the recent observation thalene NO' reaction under similar conditions. From repetition tronium ion charge transfercomplex, reported by Fukujumi and of Perrin's experiments, Eberson et aL (59, 60) concluded that Kochi (51) between m-tolunitrile and nitronium tetrafluoro- the electrochemical nitration of naphthalene is predominantly, borate. In their elegant study they also suggested, for various ifnot exclusively, due to the homogeneous nitration ofnaphtha- slow electrophilic aromatic substitutions, the occurrence of a lene by dinitrogen tetroxide catalyzed by anodically generated CT complex prior to a-complex formation on the reaction path- acid. way. It is noteworthy that the calculated diffusion barrier for The above addresses, in fact, the question to what extent the encounter pair formation (t6 kcal/mol) (4) is similar in mag- isomer distribution (as determined in the a-complex forming nitude to that of CT complex formation in general (s4 kcal/ step) varies on changing the rate-determining step. Although, mol) (52). Also, the correlation ofcalculated encounter rate with as discussed, positional selectivity is maintained when substrate solvent viscosity has only been shown for HN03 nitration in selectivity is lost, careful scrutiny ofthe isomer distributions for strong H2S04 and 13P04 (4). various toluene nitrations shows (4, 27) that there are varying The proposal ofinitial one-electron transfer between the ni- substitution patterns with tespect to the ortholpara ratios but, tronium ion and the aromatic substrate, recently reemphasized significantly, the amount of the nwta isomer is always 3%. by Perrin (53), resulting in a radical-radical cation pair prior to Extreme ortho/para ratios are 2.19 and 0.50, but the main body the formation of the a complex is in fact only an extreme of the of ratios ranges from 2.1 to 1.6 (4). Steric factors, such as the ir-complex formulation. A full one-electron transfer can occur bulkiness of the effective nitrating agent, can affect the orthol if the ionization potential and electron affinity for the reactants para isomer ratio (increasing the pars) but are not considered are compatible prior to electronic interactions, and it is named to be the only reason for the obsenred variations. ipso attack "outer sphere mechanism" in molecular complex terminology oftoluene by NO+, ifleading to product formation, would result (54, 55). Although nitrations with very reactive aromatic sub- in ortho substitution and also affect the orthol/para isomer ratio, strates are likely to be subject to one-electron transfer, this is but only to a small extent (<4% ipso) (4). It is anticipated that not the case for benzene and toluene and it seems not even for the reactivity ofthe nitrating agent is reflected in the energetics naphthalene. For an argument against the electron-transfer ofthe first intermediate, affecting the nature and position ofthe mechanism in the nitration of mesitylene, see ref. 56. Perrin transition state on the reaction coordinate for a-complex (53) found in the 'electrochemical nitration" ofnaphthalene, by fonration. generation of the naphthalene radical cation in the presence of Despite the debate on the nature of the first intermediate, NO,', the a/f3 isomer distribution of 9, similar to that of the all recent studies agree on the necessity of two separate steps HNOJH2SO4 nitration, 11. Our results (57) on nitration of na- in the mechanism leading to the a complexes. The first step phthalene with various nitrating agents in different solvents, as determines the substrate selectivity (ifrate controlling) and the well as other literature data (53. 58) (Table 9) show that the a/ second step determines the positional (regio) selectivity. Proton $ ratio may vary between 9 and 29. Eberson et al. (59) examined elimination does not result in a primary hydrogen isotope effect in detail the diffusion-controlled radical cation coupling, by re- and thus is not rate controlling. Consequently, the original In- action ofsolid [naphthalene] +PFJ with N204, and found an al gold scheme must be amended. Downloaded by guest on September 28, 2021 "Cu Review: Olah et aL Proc. Natl. Acad. Sci. USA 79 (1982)

NO + ArH - "first intermediate" 19. Kameo, T., Nishimura, S. & Manabe, 0. (1974) Nippon Kagaku Kaishi 1, 122-126. 20. 01, C. A., Malhotra, R. & Narang, S. C. (1978)]. Org. Cheme "first intermediate"' Ar ArNO2 + H+ 43, 4628-4630. \NO2 21. Olah, G. A., Krishnamurthy, V. V. & Narang, S. C. (1982) J. Org. C/em. 47, 596-598. The nitronium ion can be obtained under protic conditions from 22. Cupas, C. A. & Pearson, R. L. (1968) J. Am. Chem. Soc. go, nitric acid 4742-4743. 23. Olah, G. A., Narang, S. C., Glah, J. A., Pearson, R. L. & Cupas HI + HNO3 =± HONOt C. A. (1980)J. Am. Chern. Soc. 102, 3507-3510. 24. Olah, C. A., 01ah, J. A. & Overchuck, N. A. (1965) J. Org. Chem. 30, 3373-3376. H20NO -* 1H20 + NO+ 25. Olah, G. A., Narang, S. C. & Funng, A. P. (1981)J. Org. Cheyn. or nitronium salts can be directly used under aprotic conditions 46, 2706-2709. or bound to a conjugate base (transfer nitration). 26. Hanna, S. B., Hunziker, E., Saito, T. & Zollinger, H. (1969) Helv. Chim. Acta 52, 1537-1548. 27. Olah, 0. A., Lin, H. C., Olah, J. A. & Narang, S. C.(1978) Proc. CONCLUSIONS AND OUTLOOK Ntt. Acad. Sci. USA 75, 1045-1049. Thirty years after Ingold's fundamental studies on the mecha- 28. Olah, G. A., Gupta, B. G. B. & Narang, S. C. (1979)J. Am. Chern. Soc. 101, 5317-5322. nism ofelectrophilic aromatic substitution were published, the 29. Myhre, P. C. (1972)J. Am. Chemr. Soc. 94, 7921-7923. field is undergoing a renaissance of interest and activity. The 30. White, W. N. & Klink, J. R. (1970)J. Org. Chem. 35, 965-969. preparation and preparative use ofstable nitronium salts as ni- 31. Olah, C. A., Lin, H. C. & Mo, Y. K. (1972)J. Am. Chem. Soc. trating agents opened up new possibilities in anhydrous nitra- 94, 3667-3669. tions. A series ofother more selective new nitrating agents and 32. Mamatyuk, V. 1., Derendyaev, B. G., Destina, A. N. & Koptyug, systems were also developed. A recent trend is the use ofhighly V. A. (1974) Zh. Org. Khim. 10, 2506-2511. 33. Gore, P. H. (1957)j. Chem. Soc., 1437-1439. acidic solid catalysts to replace acids such as H2S04. 34. Cerfontain, H. & Telder, A. (1967) Rect Trav. Chim. Pays-Bas Mechanistic studies resulted in realization of the necessity of 86, 371-380. an additional step in the classical Ingold mechanism between 35. Ola, G. A., Narang, S. C., Malhotra, R. & Olah, J. A. (1979) J. the reactive nitrating agent and aromatics, determining overall Am. Chem. Soc. 101, 1805-1807. substrate reactivity (if rate controlling), prior to regioselective 36. Stock, L. M. & Brown, H. C. (1963) Adv. Phys. Org. Chem. 1, arenium ion (ar complex) formation. Because substrate and po- 35-154. 37. 014h, G. A., Kuhn, S. J. & Flood, S. H. (1961) ]. Am. Chem. Soc. sitional (regio) selectivities may be determined in separate 83, 4571-4580. steps, no simple relationship between reactivity and selectivity 38. Olah, G. A. & Kuhn, S. J. (1962) J. Am. Chem. Soc. 84, exists. 3684-3687. The ambident nature of the nitronium ion was also demon- 39. 01ah, G. A., Kuhn, S. J., Flood, S. H. & Evans, J. S. (1962)J. strated and utilized in explaining nitration and oxidation Am. C/em. Soc. 84, 3687-3693. reactions. 40. Olah, G. A. & Kuhn, S. J. (1964) J. Am. Chern. Soc. 86, 1067-1070. Support ofour work by the U.S. Army Office of Research is gratefully 41. Oah, G. A., Lin, H. C., Olah, J. A. & Narang, S. C. (1978) Proc. acknowledged. Ned. Aced. Sci. USA 75, 545-548. 42. 01a, G. A. &a Overchuck, N. A. (1965) Can. J. Chem. 43, 1. de la Mare, P. B. D. & Ridd, J. H. (1959) Aromatic Substitution, 3279-3293. Nitration and Halogenation (Butterworth, London). 43. O14, G. A. (1976) Industrial and Laboratory Nitrations, eds. 2. Olah, G. A. & Kuhn, S. J. (1964) in Friedel-Crafts and Related Alibright, L. F. & Hanson, C. (ACS, Washington, DC), Ser. 22, Reactions, ed. Olah, C. A. (Wiley-Interscience, New York), Vol. pp. 1-47. 3, pp. 1393-1491. 44. Olab, G. A. (1971) Acc. Chem. Res. 4, 240-248. & 3. Hoggett, J. 0., Moodie, R. B., Penton, J. R. Schofield, K. 45. Coombes, R. C., Moodie, R. B. & Schofield, K. (1968)J. C/em. (1971) Nitration and Aromatic Reactivity (Cambridge Univ. Soc. B., 800-804. Press, New York). 46. Ridd, J. H. (1971) Acc. C/em. Res. 4, 248-253. 4. Schofield, K. (1980) Aromatic Nitration (Cambridge Univ. Press, 4 Pfister, F., Rys, R. & Zollinger, H. (1975) Helv. C/tim. Acta 58, New York). 2093-2105. 5. Ingold, C. K. (1969) Structure and Mechanism in Organic Chem- 48. Nabholz, F. & Rys, P. (1977) Helv. Chim. Acta 60, 2937s-2943. istry (Cornell Univ. Press, Ithaca, NY), 2nd ed. 49. 01a, G. A., Kuhn, S. J. & Flood, S. H. (1961)J. Am. Ctmer. Soc. 6. Hantsch, A. (1925) C/em. Ber. 58, 941-961. 83, 4571-4580. 7. Hantsch, A. (1930) Z. Phys. Chem. (A) 149, 161-178. 50. 01ah, G. A., Kuhn, S. J. & Flood, S. H. (1961)J. Am. Chem. Soc. 8. Olah, C. A. & Kuhn, S. J. (1956) Chem. Ind., 98. 83, 4581-4585. 9. Olah, G. A., Kuhn, S. J. & Mlinko, A. (1956)] Chem. Soc., 51. Fukujumi, S. & Kochi, J. K. (1981) J. Am. Chem. Soc. 103, 4257-4258. 7240-7252. 10. Kuhn, S. J. & Olah, G. A. (1961) J. Am. Chem. Soc. 83, 52. Foster, B. (1969) Organic Change Transfer Complexes (Aca- 4564-4571. demic, New York). 11. Desvergnes, L. (1931) Chim. Ind. 25, 291-306. 53. Perrin, C. L. (1977)J. Am. Chem. Soc. 99, 5516-5518. 12. Clarke, H. T. & Hartman, W. W. (1943) Organic Syntheses 54. Mulliken, R. S. & Person, WV. B. (1969) Molecular Complexes (Wiley, New York), Collected Vol. , pDp. 541-542. (Wiley-Interscience, New York). 13. Olah, C. A. & Lin, H. C. (1973) Synthesis, 488-490. 55. Marcus, R. A. (1956)]. Chern. P/ys. 24, 966-978. 14. 01ah, C. A. & Lin, H. C. (1974) J. Am. Chem. Soc. 96, 56. Draper, M. R. & Ridd, J. H. (1978)J. Chem. Soc. Chem. Com- 2892-2898. mun., 445-446. 15. Emmons, W. D. & Freeman, J. P. (1 955)J Am. Chemr. Soc. 77, 57. Olah, . A., Narang, S. C. & Oah, J. A. (1981) Proc. Nad. Acad. 4391-4393. Sci. USA 78, 3298-3300.

16. Narang, S. C. & Thompson, M. J. (1978) Aust. ]. Ch/en. 31, 58. Alcorn, P. G. E. & Wkells, P. R. (1965) Aust]. /Chemr. 18, 1839-1840. 1377-1389. 17. Topchiev, A. V. (1959) Nitration of Hydrocarbons and Other 59. Eberson, L., Jonsson, L. & Radner, F. (1978) Acte Chern. Scand. Organic Compounds (Pergamon, New York). Ser. B 32, 749-753. 18. Olah, G. A., Fung, A. P., Narang, S. C. & Olah, J. A. (1981)J. 60. Eberson, L. & Radner, F. (1980) Acta Chem. Scand. B. 34, Org. Chem. 46, 3533-3537. 739-745. Downloaded by guest on September 28, 2021