Nucleophilic Substitutions of Nitroarenes and Pyridines

REVIEW 2111

Nucleophilic Substitutions of Nitroarenes and Pyridines: New Insight and New Applications NucleophilicManfred Substitutions of Nitroarenes and Pyridines Schlosser,*a Renzo Ruzziconi*b a Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale (EPFL – BCh), 1015 Lausanne, Switzerland E-mail: [email protected] b Chemistry Department, University of Perugia, Via Elce di Sotto 10, 06100 Perugia, Italy E-mail: [email protected] Received 29 March 2010

To a Teacher, Example and Friend

lyzed by the hydrogen bromide that was evolved. Decades Abstract: At the beginning of this article an in-depth comparison of electrophilic and nucleophilic aromatic and heterocyclic substitu- later, other researchers came across the electronic coun- tion processes examines their scopes of applicability in a new light. terpart, namely the base catalysis of the bromination or io- 2,3 In the subsequent parts, recent progress in the area of halide and hy- dination of acetone. About that time, mechanistic dride displacement from pyridines is highlighted. Particular atten- investigations began to depart in many different direction is paid to the leaving group aptitudes of fluoride and chloride, tions. They culminated in the systematization of reaction to the effect of ‘passive’ substituents on the reaction rates, and to the patterns by C. K. Ingold,4 the quantification of substituent control of the relative reactivity at halogen-bearing 4- versus 2-(or effects by L. P. Hammett 5 and H. C. Brown,6 the sophis- 6-)positions. ticated concept of non-classical resonance by S. 7,8 1 Introduction Winstein and R. Huisgen’s ground-breaking achieve- 2 Electrophilic as Opposed to Nucleophilic Substitutions ments featuring kinetics and selectivity.9 3 Nitroarenes as Substrates for Nucleophilic Substitutions The manifold contributions by the Huisgen school were 4 Nucleophilic Substitution at Resonance-Disabled Positions 5 Nucleofugality Contest between Fluorine and Chlorine unique in the sense that they invariably suggested practi- 6 Substituent Effects on the Reactivity of 2-Halopyridines cal applications and thus played a significant role in the 7 ‘Silyl Trick’: Discriminating between Two Potential revival experienced by organic synthesis since the 1970s. Exchange Sites Some highlights have since become textbook corner- 8 Hydride as the Nucleofugal Leaving Group stones, notably the 1,3-dipolar [3+2] cycloadditions 9 Summing Up (‘Huisgen reactions’), [2+2] cycloadditions, valence tau- Key words: fluorine, chlorine, lithium, nitroarenes, pyridines tomerizations, diazonium salt chemistry and 1,2-didehydroarene (‘aryne’) chemistry. The latter subject is closely related to the ‘additive’ nucleophilic (het)aromatic substitution. This highly important topic was covered by J. Sauer 1 Introduction and R. Huisgen in their seminal 1960 review.10 Physical Organic Chemistry or, in the continental Europe- The present article takes this previous experience for an vocabulary, Reaction Mechanisms, may be conceived granted. It intends to focus on more specific features, in as the life science equivalent of the mind-setting current particular on the regioselectivity of nucleophilic displace- known as Enlightenment (Aufklärung, Illuminismo, ments at the 2- and 4-positions and on leaving group (nu- Lumières) that shaped the thinking, feeling and literature cleofuge) effects exerted on the reaction rates.

of the 18th century. Cognition relieves man from his self- Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. imposed minority (I. Kant) and molds an emancipated, responsible and tolerant human being. This became a gen- 2 Electrophilic as Opposed to Nucleophilic eral belief. Substitutions In chemistry, the rational approach to cognition has well To bring the existing options into perspective, the electro- been triggered by the curiosity of a new generation of ex- philic and nucleophilic classes of aromatic substitutions perimenters. In 1904, A. Lapworth observed how identi- will be juxtaposed. Both categories of transformations can cal amounts of bromine consecutively added to acetone be accomplished in an addition/elimination or elimina- were decolorized, hence consumed, in progressively tion/addition mode (Scheme 1). Unlike carbocations, ‘na- shorter intervals.1 Endeavoring to understand this phe- ked’ carbanions hardly ever exist in the condensed phase. nomenon, he found the keto–enol equilibrium to be cata- Thus all negatively charged formulas shown below are an idealizing fiction. The real species are carbon–metal- SYNTHESIS 2010, No. 13, pp 2111–2123xx.xx.2010 bonded compounds as we shall see later. Advanced online publication: 02.06.2010 It crucially depends on its identity, whether or not an elec- DOI: 10.1055/s-0029-1218810; Art ID: C02410SS trophile can displace an arene-bound hydrogen atom. The © Georg Thieme Verlag Stuttgart · New York 2112 M. Schlosser, R. Ruzziconi REVIEW

H El X Nu

El – [H ] Nu –[X ]

– [El ] H – [ Nu ]

H El X Nu

– [Bs ] X Nu H-Bs

Bs El Bs Nu

H-Bs H-Bs – []X

Scheme 1 The principal modes available for executing electrophilic (left) and nucleophilic (right) aromatic substitutions: ‘electrophile or nu-

cleophile addition first’ (in the upper lanes) versus ‘deprotonation first’ (in the lower lanes) [EI+ = electrophile; Nu– = nucleophile; Bs– = base]

NMe NMe NMe

2 2 nitronium ion being a very powerful Lewis acid, it com- 2

– [HBr] bines with virtually all (het)aromatic substrates, be that 2

benzene, toluene, nitrobenzene or pyridine. Immediately Br 3

Br ensuing proton loss leads to the products, for example ni- H

Br trobenzene, a mixture of 2- and 4-nitrotoluene, 1,3-dini- 1 trobenzene or 3-nitropyridine. Weaker electrophiles such

as the bromonium ion require electron-rich substrates for Br

3 – [HBr]

11–13 Br 2 fast reaction. N,N-Dimethylaniline (1) or 2- H

N NH N NH NH aminopyridine (2) meet this condition. They form the N 2 2

corresponding ‘para isomers’ as the main, if not exclu- 2 sive, products (Scheme 2). 2 If the (het)aromatic substrate is electron-poor it is advis- Scheme 2 Reaction of an electron-rich arene and an electron-rich able to invert the sequence of the two individual steps. hetarene with bromine, a moderately strong electrophile Any electron-withdrawing substituent will acidify the ad-

Biographical Sketches

Manfred Schlosser, born in completed his Habilitation researcher (e.g., probing Ludwigshafen on Rhine, in 1966 before moving to metal effects in structure– was awarded a Ph.D. degree the newly founded German reactivity correlations), lec- (Dr. rer. nat.) under the su- Cancer Research Center (al- turer (e.g., at the University pervision of Georg Wittig at so in Heidelberg). In 1971 of Kyoto in 2009), author the University of Heidel- he was appointed to a chair and editor (e.g., Organome- berg in 1960. After one year for organic chemistry at the tallics in Synthesis, 2nd of freelance research with University of Lausanne. Manual, 2004, 3rd Manual the European Research As- Emeritus since 2004, he in preparation). Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. sociates in Brussels, he continues to be active as a

Born in Sassoferrato (Anco- Pharmacy and later at the Basilicata University in na, Italy), Renzo Ruzziconi Chemistry Department of 1994. Since 1998 he holds studied chemistry at the the University of Perugia. a chair in Perugia. His re- University of Perugia where From 1980 until 1982 he search interests cover polar he accomplished his thesis stayed at the University of organometallic reagents, work under the guidance of Lausanne as a postdoctoral metal-oxidant-promoted ra- Professor Enrico Baciocchi. fellow with Professor dical reactions, fluoro- After the ‘Laurea’ diploma Manfred Schlosser. Associ- organic compounds and (1973), he was a research ate Professor at the Perugia transition metal-catalyzed fellow of the ‘Accademia Chemistry Department stereoselective reactions. Nazionale dei Lincei’ since 1987, he was appoint- (1975) at the Faculty of ed as full professor to the

Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York

REVIEW Nucleophilic Substitutions of Nitroarenes and Pyridines 2113 jacent ortho site15–17 and in that way facilitate its deproto- Numerous aromatic and heterocyclic substrates have been nation by strong bases such as butyllithium, successfully subjected to regiochemically exhaustive phenyllithium, lithium diisopropylamide or lithium functionalizations. For example, 3-fluorophenol,19 3- 2,2,6,6-tetramethylpiperidide. The resulting organometal- fluoropyridine19 and 2-fluoropyridine20 (Scheme 5, acids lic intermediate 3 readily combines with virtually any 7–9) were ornamented with a carboxy group at each va- electrophile El-X and thus secures utmost product flexi- cant position. In addition, 2-, 3- and 4-(trifluorometh- bility (Scheme 3). yl)pyridines gave the corresponding ten carboxylic acids21

and several chloro- and bromo(trifluoromethyl)pyridines

Li 22–24 El were converted into a variety of new derivatives.

X X X

Li-R El -X

Cl SiMe 3

Cl Cl Cl

e.g ., F, Cl, Br; OMe, OCH OMe, SPh; NMe X =

2 2 N F

N F N F N F

R = alkyl or aryl

El e.g -X = ., FClO , FN(SO Ph) ; ClCF CFCl , Cl ; BrCH CH Br, Br ; I ; 3 2 2 2 2 2 2 2 2 2

1 1 1 1 1 2

B(OMe) /H O ; LiNHOMe, R OOC-N=N-COOR , R -N ; R -CH=O, R R C=O, CO 3 2 2 3 2

SiMe Li

Scheme 3 Structural elaboration of heterosubstituted arenes 3

Cl Cl

applying the ortho-metalation/electrophilic substitution sequence Li

F N N F N F F

The intermediacy of organometallic species in the electro- N philic substitution process offers several major advan- tages. The almost unrestricted choice of the electrophile has

been mentioned above. Another trump is the regiochemi- HOOC

cal reliability. Whereas the classic direct substitution gen- COOH

N F HOOC F N F erally gives rise to inseparable ortho/para mixtures, the N

organometallic route takes us just to the ortho product. More distant positions can nevertheless be selectively 78 9 metalated and subsequently derivatized (‘regiochemically Scheme 5 Regiochemically exhaustive functionalization of 2-fluo- exhaustive functionalization’) if protective groups such as ropyridine chloro or trialkylsilyl substituents are deployed.18 For example, it requires little effort to convert 1-fluoronaphtha- A final bonus associated with the organometallic ap- lene into 1- or 4-fluoro-2-naphthoic acid or even 4-fluoro- proach to electrophilic (het)aromatic substitution is the 1-naphthoic acid (Scheme 4, compounds 4, 5 or 6, respec- optional site-selectivity of metalation. The mechanism- tively).18 guided matching of the reagent with a substrate bearing

two or three different activating substituents offers the op-

F F

F portunity to direct the permutational hydrogen/metal in-

Li COOH

(1) CO

2 s -BuLi terconversion process, the ‘metalation’, exclusively to

(2) aq HCl

4 one of two or three potentially competing sites. Thus, 2-

2 and 4-fluoroanisole undergo lithiation only at the oxygen-

CF-CClF adjacent position when n-butyllithium is employed, but 2

Cl only at the halogen-adjacent position when sec-butyllithi-

F F F

(1) CO

2 um in the presence of PMDTA (N,N,N¢,N¢¢,N¢¢-pentameth- Cl Cl LITMP

(2) aq HCl yldiethylenetriamine) or n-butyllithium in the presence of 5

(3) H {Pd} 2

COOH Li potassium tert-butoxide (the superbasic LIC-KOR mix- Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material.

2 ture) serves as the base. n-Butyllithium in diethyl ether

CF-CClF 2 and in the presence of 1,8-diazabicyclo[2.2.2]octane

Cl (DABCO) deprotonates 3-fluoropyridine (10) at the nitro- F F F

(1) CO 26 2

Cl Cl gen-assisted 2-position whereas n-butyllithium in the

LIDA (2) aq HCl

6 presence of N,N,N¢,N¢-tetramethylethylenediamine

(3) H {Pd}

Cl (TMEDA) or lithium diisopropylamide in tetrahydrofuran Li

COOH accomplishes the metalation at the more acidic 4- 27–29 Scheme 4 Metalation of unprotected or protected 1-fluoronaphtha- position (Scheme 6). Both 2- and 4-(trifluorometh- lenes and subsequent carboxylation to afford the naphthoic acids 4–6 yl)pyridine (11 and 12) react with alkyllithiums at the alternatively [LITMP = lithium 2,2,6,6-tetramethylpiperidide; most acidic 3-position,30 but with Caubère’s base, n-bu- LIDA = lithium diisopropylamide] tyllithium in the presence of lithium 2-dimethylamino- ethoxide (LIDMAE), at the chelation-benefitting 2- position30 (Scheme 6).

Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York

2114 M. Schlosser, R. Ruzziconi REVIEW

Li when sodium methoxide is added to a solution of 2,4,6-

F F

n -BuLi or LIDA 42 n

-BuLi, DABCO trinitrophenetole (ethyl picryl ether) (Scheme 7, lower

THF O Et

2 line).

N N Li N

X 10

7 p

n -BuLi, LIDMAE LITMP

Nu X

THF Et O

N CF

N Li CF

CF N

3 3

–[ ] Nu X

CF CF 3 3 3

n -BuLi, LIDMAE

LITMP

Nu X

THF

Et O

N Li

N R

R R

[] – X

[] Nu –

NO 2 2 2 Scheme 6 Optionally site-selective lithiations of 3-fluoropyridine 14

and 2- or 4-(trifluoromethyl)pyridine

Nu X

X OMe

O N NO

O N NO O N NO if X = Cl 2 2 2 2 2 2

3 Nitroarenes as Substrates for Nucleophilic NaOMe

Substitutions if X = OEt

NO NO 2 2 2 15

If we turn now to nucleophilic (het)aromatic substitutions

R = H or O Nu N; X = nucleofuge; = nucleophile

we encounter the exact electronic counterpart of the elec- 2 trophilic substitution formalism. Deprotonation generates Scheme 7 Facile nucleophilic substitution of substrates activated by an ortho-haloarylmetal (in Scheme 1 oversimplified as an one or two nitro groups, yet ambiguities in the absence of any or in o-haloaryl anion) and, by ensuing halide ejection, a 1,2- the presence of three such substituents didehydroarene (‘aryne’) that subsequently undergoes addition of the nucleophile and reprotonation to give the fi- The nitrogen atom incorporated into a pyridine ring con- nal product. Alternatively to this elimination/addition 31 fers approximately the same activating effect as a nitro sequence, the nucleophile may get attached first, thus group attached to an arene ring does. Both 2- and 4-halo- giving rise to a cyclohexadienyl anion intermediate, be- 10 pyridines are indeed very prone to nucleophilic substitu- fore the departure of the nucleofuge restores aromaticity tion processes (see below). Halogenated diazines such as (Scheme 1). 2,4-dibromopyrimidine43 and triazines prove to be even In the following part we shall focus entirely on this addi- more reactive. 2,4,6-Trichloro-1,3,5-triazine (cyanuric tion/elimination sequence. There are three variables to be chloride)44,45 is manufactured in bulk and used to assem- examined in detail: the nucleofugal leaving group X, the ble, for example, a colorant and an optical brightener at entering nucleophile Nu and the electron-withdrawing ac- the heterocycle before linking this ‘reactive dye’, again by tivating substituent R. How critical is the latter? Accord- nucleophilic hetaromatic substitution, to the surface of a ing to literature reports, even fluorobenzene itself (with cellulose fiber. 32 sodium methoxide, at 0 °C), 1- or 2-bromonaphthalene The original synthesis of the gyrase inhibitor ofloxacin, a

33 Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. (with piperidine, at 230 °C) and, at least partly, 1-fluo- remarkably potent broad-spectrum antibacterial, sets off a ronaphthalene (with lithium piperidide, at approximately 46–48 34 firework of nucleophilic aromatic substitutions 40 °C) undergo direct substitution according to the addi- (Scheme 8). Starting from the industrially available 1,2- tion/elimination mechanism. However, the mechanism of dichloro-3-nitrobenzene the more mobile halogen at the such unactivated reactions remains obscure. In most cases, 2-position is replaced by fluorine. Subsequent chloro- single-electron-transfer (SET) initiated radical-chain 35–38 denitration and reintroduction of the nitro function affords processes (Scheme 7, upper line) have never been de- 1,3-dichloro-2-fluoro-4-nitrobenzene that enables one to finitively ruled out. In general, nucleophilic (het)aromatic carry out a double halogen/halogen exchange. Two of the substitutions proceed smoothly only if aided by one or three fluorine atoms in the resulting 1,2,3-trifluoro-4-ni- two activating groups (Scheme 7). The nitro group is the 39–41 trobenzene are sacrificed in the ensuing final stages of the most common auxiliary for that purpose (Table 1). sequence. Consecutive treatment with potassium hydrox- Three nitro groups may delocalize the negative charge so ide and chloroacetone followed by Raney nickel catalyzed effectively that the intermediate no longer collapses by hydrogenation gives 7,8-difluoro-3,4-dihydro-3-methyl- expulsion of the nucleofuge but rather stays intact as a sta- 2H-1,4-benzoxazine. Condensation with diethyl ble ‘Meisenheimer complex’. This happens, for example, (ethoxymethylene)malonate, acid-promoted cyclization

Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York REVIEW Nucleophilic Substitutions of Nitroarenes and Pyridines 2115

Table 1 Rates of Nucleophilic Aromatic Substitutions as a Function accompanied by ester hydrolysis and ultimate displace- of the Activating (or Deactivating) Substituent R ment of the fluorine atom at the 7-position by N-meth-

ylpiperazine eventually affords the antibiotic ofloxacin

R Cl R Cl

+ NaOMe +

R HN (Scheme 8). If (R)-propane-1,2-diol is used to attach the

(ref. 39)

(ref. 41) C -side chain, no racemate resolution is required to obtain NO NO 3 2 2 the therapeutically superior S-enantiomer (Levofloxa- N≡N+ 3.8 × 10+8 a – cin).47 O=N 5.2 × 10+6 a –

× +5 a O2N6.710 – 4 Nucleophilic Substitution at Resonance-

× +4 a Disabled Positions MeSO2 7.2 10 – N≡C3.8× 10+8 a – When a nucleophile binds to the ipso-carbon atom of a ha- loarene, electron excess builds up at the 2-, 4- and 6-posi- + × +4 a Me3N 2.2 10 – tions. Only when a pyridine nitrogen is located at one of O=CH 2.0 × 10+4 a – these three centers can it attenuate the negative charge by its electronegativity and only a nitro group that occupies +3 a MeCO 8.1 × 10 – one such site can ‘swallow’ electron density by delocaliz- PhN=N 1.1 × 10+3 a – ing it to its oxygen atoms. Consequently, solely 2-, 4- and 6-halogenated pyridines and nitroarenes are really fit to Br – 7.8 × 100 aa undergo facile nucleophilic (het)aromatic substitutions. Cl 5.0 × 10+1 a 5.6 × 100 aa On the whole this is correct, and highest reactivity is indeed associated with such substituent patterns.49,50 I – 5.4 × 100 aa Remarkably enough, however, azine nitrogens or nitro H 1.0 × 100 aa 1.0 × 100 aa groups at 3- and 5-positions, in other words at the electronic nodal points, still exert an activating effect. Thus, 1- × –1 a F–2.610 fluoro-3-nitrobenzene,51 3-fluorobenzotrifluoride,52 3- 53 54–56 Me – 1.7 × 10–1 b chlorobenzotrifluoride, 1,3-dinitrobenzene and 3- bromopyridine57 are known to react with sodium alkox- × –2 a MeO – 1.8 10 ides or piperidine, whereas chlorobenzene58 proves to be × –3 a fairly inert towards all nucleophiles. 2,3,5-Trichloropyri- Me2N– 1.210 dine (17) can be converted quite smoothly with potassium HO – 5.8 × 10–4 a fluoride into 5-chloro-2,3-difluoropyridine.59,60 The halo- × –4 a gen at the 3-position is displaced considerably faster than H2N– 1.210 that at the 5-position although, of course, much more a Estimated from the relative rate at +25 °C.40 slowly than its neighbor at the 2-position (Scheme 9). b × –4

If t-Bu instead of Me: krel 1.2 10 .

Cl F Cl Cl Cl Cl F F

KF KF Cl F F

(1) KOH KF

fast slow

N F N F

N Cl N F

CMe (2) HOCH

NO F NO F NO

F = 2 2 2

Cl F O 17

O Scheme 9 5-Chloro-2,3-difluoropyridine made from 2,3,5-trichlo-

HNO

H {Pd} 2 ropyridine

Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. Cl

F 5 Nucleofugality Contest between Fluorine and

F F

NH Chlorine

Cl O

(2) aq HCl 1-Fluoro-2,4-dinitrobenzene belongs to the most popular

(MeOOC) C 2

N =

KCl (3)

Me MeO-CH (1) fluorine-containing compounds. Owing to its ready cou-

NH pling with the N-terminal amino acid of peptides

O (Scheme 10) it became the key to a first reliable sequenc-

Cl Cl COOH

F ing method.61,62 Curiously enough, this so-called ‘Sanger

N F Cl N reagent’ was found to be far more reactive toward ‘free’

NO NO O

2 2 (i.e., non-amidic) amino functions than is 1-chloro-2,4- dinitrobenzene, the precursor from which it is made by Scheme 8 Synthesis of (S)-ofloxacin featuring six nucleophilic aro- halogen/halogen displacement. matic substitutions

Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York

2116 M. Schlosser, R. Ruzziconi REVIEW

NO 2

slow

O N Cl 2

NO 2

O O O O O

- H N-CH-C-NH-CH-C-NH-CH-C O N NH-CH-C-NH-CH-C-NH-CH-C-

2 2

2 R

1 R

2 3 R R R R

NO 2

O N F 2 fast

Scheme 10 Condensation of 1-fluoro-2,4-dinitrobenzene with the basic N-terminus of a peptide (to give derivative 18) thus enabling the iden-

tification of the correspondingly modified (and colored) a-amino acid after hydrolysis

X The superior performance of fluoroarenes as opposed to X

chloroarenes in nucleophilic substitutions is a general 19

phenomenon. It is encountered with mono-, di- and trinitro- 19

63–73

k k NO substituted substrates (Table 2). The / ratios fall NO F Cl 2

in the ranges of 300–1300 and 40–770 with, respectively, 2

HNR M-OR sodium alkoxides and aliphatic or aromatic amines as the 2

nucleophiles (Table 2). In a single case (Table 2, eighth

X NR X NR X NR X OR

2 2 column), the chloro compound reacts with N-methyl- 2

68 H

aniline even faster than the fluoro analogue (k /k 0.73). H

HNR F Cl intramolec.

2 H

The latter inversion of the halogen effect on the overall re- neutralization

NO NO NO NO

2 2 2 activity should remind us of the mechanistic complexity 2

of nucleophilic aromatic substitutions employing amines HNR 2

[] [] –– X X

–[ ] as the nucleophiles. Activated haloarenes such as 1-fluo- HX

ro- and 1-chloro-4-nitrobenzene (19, X = F or Cl) add am-

OR NR

monia and primary or secondary amines (HNR2, R = H, 2 alkyl, aryl) to form an inner salt, a 6-ammonio-6-halocy-

clohexa-2,4-dien-1-ide. This intermediate may revert to

its constituents or lose a proton to a base or transfer the NO NO 2 proton intramolecularly thus giving rise to a 5-amino-5- 2

halo-1,3-cyclohexadiene that can undergo amine-promot- X = e.g., F, Cl; R = H, alkyl, aryl; M = Li, Na, K ed b-elimination of H-X to afford the final substitution Scheme 11 The mechanistic pathways of amines (HNR2, on the product (Scheme 11). Compared to the reaction of a metal left) in nucleophilic aromatic substitutions are less unequivocal than alkoxide (Scheme 11) or a metal amide, this means sever- those of metal amides (M-NR2) and metal alkoxides (M-OR, on the al possible additional steps. right)

Table 2 Comparison between Nucleofuges in Nucleophilic Substitution Reactions; Rates Relative to the Chloro Compounds (X = Cl)

NO NO 2 2 NO

Nucleo- 2

O N X O N X

Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material.

O N fuge X 2

NO NO 2 2

X HN(CH2)5 HN(CH2)5 NaOMe H2NPh HN(CH2)5 H2NPh HN(Me)Ph NaOMe NaSPh H2NPh EtOH52 DMSO58 MeOH51,a EtOH57 MeOH54 EtOH49 EtOH53 MeOH50 MeOH55 EtOH56

F 430 410 310 44 770 62 0.73 1300 27 190

Clb 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0

Br 1.3 1.2 0.85 1.8 1.0 1.5 2.2 0.62 1.7 1.4

I 0.39 0.26 0.36 0.42 0.23 0.43 – 0.24 1.3 0.26

OMe – 0.002 – – – – – – – –

NO2 – 8.7 – 1600 210 – – – – 1900 a With NaOEt in EtOH at 91 °C: ref. 49. b The chloro compound has been chosen as the kinetic reference for each set of substrate/reagent combinations.

Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York REVIEW Nucleophilic Substitutions of Nitroarenes and Pyridines 2117

Data like those compiled of nitroarenes (Table 2) have stitution process, whereas it retards it if at the 5-position been widely lacking in the pyridine field. We have now, (Table 4).74 All other halogens, no matter where accom- for the first time, quantified the effect of the nucleofugal modated, increase the rate by one or up to almost two leaving group on the substitution rates of halopyridines. powers of ten (Table 4).74 Particularly noteworthy is the To this end, 2-halopyridines and a few 4-halopyridines effect exhibited by a trimethylsilyl group. As a moderate were treated with sodium ethoxide in a 1:2 mixture of eth- electron acceptor75 it slightly enhances the nucleophilic anol and diethyl ether at +25 °C. The relative reactivities attack as long as it stays remote from the combat zone. In were assessed by competition experiments.74 In all cases contrast, it effectively obstructs the nucleofuge/nucleo- examined, fluorine turned out to be a better leaving group phile exchange in its immediate vicinity (Table 4).74 than the heavier halogens. In particular, 2-fluoropyridine produced 2-ethoxypyridine 300 times faster than did 2- Table 4 4-Substituted (middle) and 3-Substituted 2,6-Difluoropy- chloropyridine (Scheme 12).74 ridines (left and right, depending on which site is undergoing substi-

tution) Reacting with Sodium Ethoxide

NaOEt

3 R R 3

EtOH–Et O

2 R N X N OEt

2 6 2 6 F N F F N F

62 F N F 20

> k : X = F >> X = Cl X = Br rel

~ F5× 10–1 4 × 10+1 b 5 × 10+1 Scheme 12 Substitution of 2-halopyridines by sodium ethoxide: ef- × 0 × +1 fect of the nucleofuge X on the reaction rates Cl 8 10 –710 Br 2 × 10+1 –1× 10+2 6 Substituent Effects on the Reactivity of 2-Ha- I3× 10+1 8 × 10+1 a 5 × 10+1 lopyridines × 0 × –2 Si(Me)3 3 10 –810 The next question to be addressed was to what extent typ- a Rates relative to the parent compound 2,6-difluoropyridine (R = H), ical substituents R would accelerate or retard the nucleo- statistically corrected in the case of 4-substituted substrates. b Not considering the substitution at the 4-position competing with philic substitution of 2-halopyridines. Competition that at the 2(6)-position in a ratio of 1:4. kinetics again provided the answer. Not surprisingly, electron-donor groups such as ethoxy were found to slow the reaction down and electron-withdrawing entities such as Data of 2-chloropyridines have been collected only spo- trifluoromethyl to speed it up (Table 3).74 The ambivalent radically. They reveal the same propensities as already fluorine substituent inductively assists the addition if lo- recognized with fluoropyridines. 2,6-Dichloropyridine cated at the 3-, 4- or 6-positions, but impedes it by its me- reacts with sodium ethoxide 60 times faster, or, after sta- someric electron-supplying effect (lone pair–lone pair tistical correction, 30 times faster than does 2-chloropyri- repulsion) if at the 5-position (Table 3). dine.74 An iodo substituent at the 4-position accelerates by a factor of 20. 2,6-Dichloro-3-(trifluoromethyl)pyridine a Table 3 Relative Rates of Nucleophilic Hetaromatic Substitutions outperforms 2-chloropyridine 1000-fold if the CF3-proxi- of Substituted 2-Fluoropyridines by Sodium Ethoxide mal and 6000-fold if the CF3-remote chlorine atom is dis-

R placed by sodium ethoxide.

R R

R N F N F N F

F N 7 ‘Silyl Trick’: Discriminating between Two EtO 8 × 10–2 a ––– Potential Exchange Sites Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. F3× 10+1 b 7 × 10–1 4 × 10+1 c 5 × 10+1 If two or three halogens occupy exchange-active sites in a Cl – – 7 × 10+1 a 8 × 10+1 pyridine it is difficult to tell a priori which one is going to act as the leaving group and which one stays on. As seen × +3 F3C–310 ––above, sodium ethoxide attacks the regioisomerically dif- a Rates relative to unsubstituted 2-fluoropyridine (R = H). ferent positions in 2,4-difluoropyridine (Table 3) and b Experimental rate divided by two for statistical correction. 2,4,6-trifluoropyridine (Table 4) concomitantly. Lack of c Relative rate of reaction at the 2-position (concomitant substitution selectivity was observed before. For example, 2,4- at the 4-position giving a 1:1 mixture of 2-ethoxy-4-fluoropyridine dichloropyridine76 and 2,4,6-tribromopyridine77 were and 4-ethoxy-2-fluoropyridine). found to give 2- and 4-amino substitution products in 1:3 and 1:1 ratios, respectively, when treated with aqueous An evaluation of the reactivity of substituted 2,6-difluoro- ammonia at 150–175 °C. pyridines toward sodium ethoxide confirms the trends ob- Regioselectivity in favor of the 4-position can, neverthe- served. A fluorine substituent at the 3- or 4-position (with less, be achieved with secondary amines (e.g., dimethyl- respect to the departing nucleofuge) accelerates the sub- amine) and, in particular, with hydrazine hydrate.78 The

Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York 2118 M. Schlosser, R. Ruzziconi REVIEW arylhydrazines thus obtained can be converted with mild 2,4-Dichloropyridine behaves analogously.78 When treat- oxidants (such as cupric sulfate) via the ephemeral aryl- ed with dimethylamine or hydrazine, it selectively under- diazenes into the corresponding arenes (Scheme 13).79 Al- goes substitution at the 4-position. In contrast, 2,4- ternatively, arylhydrazines may be reductively cleaved to dichloro-5-(triethylsilyl)pyridine reacts exclusively at the aminopyridines using zinc,80 sodium,81 Raney nickel82 or 2-position. 83 hydrogen (Scheme 13). The same scenario is encountered with 2,4,6-trifluoropyridine and 2,4,6-trichloropyridine (compounds 23,

N=NH Scheme 15). Direct substitution with dimethylamine, hy-

drazine and, this time even, sodium ethoxide occurs clean-

2 1

1 2 ly at the 4-position. After introduction of a trimethylsilyl X N X X X N

CuSO or triethylsilyl group into the 3-position the nucleophile is

1 78

X NHNH

2 rigorously diverted to the 6-position (Scheme 15). Pro-

H NNH

2 2 todesilylation of the thus accessible 2,4-dihalo-6-hydrazi-

no-3-(trialkylsilyl)pyridines (24) gives 2,4-dihalo-6-

2 1

2 1 X N X X X

N hydrazinopyridines and, upon oxidation/dediazotation, 78

H2 {Pd} the corresponding 2,4-dihalopyridines (Scheme 15). Nu NH 21 2

X Nu

2 1

X N X X N X

Nu M-

N X X X N X

1 2 1

Nu X = F, Cl; X = H or X ; = e.g., Br, I, OH 23

n -BuLi

Scheme 13 Regioselective substitution of 2,4-dihalo- or 2,4,6-tri- (1) SiCl (2) R halopyridines with hydrazine at the 4-position and subsequent trans- 3

formations

X X X

R Si

3 R Si 5

The regioselectivity in favor of the 4-position can be com- TBAF

Nu M- H O

X N Nu 6 2 Nu X N X X pletely reversed by exploiting the screening effect of tri- N alkylsilyl groups (Table 4). Whereas 2,4-difluoropyridine 24

reacts cleanly with dimethylamine or hydrazine at the 4-

Nu X = F, Cl; R = Me, Et; M- = NaOEt, HNMe , H NNH

2 2 position (Scheme 14), its 5-trimethylsilyl or 5-triethylsilyl 2 derivatives (22) undergo nucleophilic substitution exclu- 78 Scheme 15 Selective nucleophilic substitution of 2,4,6-trifluoropy- sively at the 2-position (Scheme 14). The controlling tri- ridine and 2,4,6-trichloropyridine at the 4-position or, by virtue of the alkylsilyl unit can be readily introduced by a sequence ‘silyl trick’, at the 2- (or 6-) position consisting of lithiation and iodination at the 3-position, lithium diisopropylamide triggered migration18 of the There have been numerous previous attempts to impose heavy halogen from the 3- to the 5-position, permutational regioselectivity on the nucleophilic substitution of 2,4-di- iodine/lithium interconversion and ultimate condensation halopyridines. The only approach that has so far been met with chlorotrimethyl- or chlorotriethylsilane. The trialkyl- with success, if only a modest one, was the palladium- silyl screen can eventually be removed and replaced by catalyzed condensation of 2,4-dichloropyridine with hydrogen, bromine or iodine using tetrabutylammonium phenylurea. 4-Chloro-2-(N¢-phenylureido)pyridine and 2- fluoride hydrate, molecular bromine or iodine chloride, chloro-4-(N¢-phenylureido)pyridine are formed in a 93:7 respectively.78,79 ratio and in a total yield of 86%.84

Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material.

1 2 F F NR R

1 2 n (1) -BuLi R HNR

(2) I

N F N F N F

(1) LIDA

(2) H O 2

F F F F

R Si 5 I R Si 3 3

(1) n El -BuLi -X

1 2

SiCl (2) R

HNR R

1 2 3

1 2 N NR R N F F N N NR R

3 1 2

R e.g. El = Me, Et; NR R = , NMe , NHNH ; = H, Br, I 2 2

Scheme 14 Selective nucleophilic substitution of 2,4-difluoropyridine at the 4-position or, by virtue of the ‘silyl trick’, at the 2-position

Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York REVIEW Nucleophilic Substitutions of Nitroarenes and Pyridines 2119

8 Hydride as the Nucleofugal Leaving Group

t -BuLi

(2.0 equiv)

85,86 N

26 –75 –75 °C The venerable Tchitchibabin reaction remains one of +100 °C

the most popular textbook examples of nucleophilic het-

OMe OMe

aromatic substitution. Sodium amide and pyridine are OMe

heated in an inert medium (e.g., xylene) to approximately

Q* 150 °C. Under such circumstances, smooth addition of the Q*

amide and elimination of sodium hydride take place si-

t -BuLi

multaneously. When the reaction is stopped by cautious Br

(2.0 equiv) N N

27 neutralization, 2-aminopyridine can be isolated in high –75 +100 °C yield. It is tempting to rationalize the initial addition step –75 °C

by attributing to pyridine, despite it p-sextet aromaticity,

Q* = Si(Me) i ( -Pr)

the electrophilic character of a cyclic azomethine. How- 2 ever, nucleophilic aminations of heteroatom-free naph- Scheme 17 Preparation of 2-[2-(methoxymethyl)phenyl]pyridine thalenes had already been reported by F. Sachs.87 and 2-o-tolyl-4-(isopropyldimethylsilyl)pyridine by aryl/hydride substitution K. Ziegler et al.88,89 were able to separate operationally the addition from the elimination step. As they demonstrated,

butyllithium and phenyllithium combine very readily with

pyridine, quinoline, isoquinoline or acridine at ambient H H Q* Q*

temperature to afford 2-substituted 1,2-dihydropyrid-1- Q*

H yllithiums (25) or, respectively, benzo derivatives thereof. H

R In the absence of oxidants, heating to approximately H 100 °C is required to provoke elimination of lithium hy-

dride and thus to restore the azine aromaticity 28

i R = MeO, Q* = H or R = H, Q* = Si(Me) ( -Pr)

(Scheme 16). 2

Scheme 18 Enantiomerization of 2-arylpyridine rotamers by pas-

+25 °C ≤ ≥ +90 °C sing through a coplanar transition state

Li-R – [LiH]

N R N N

H Li The rotational barriers of both 2-arylpyridine model compounds were found to be too small (<5.0 kcal/mol) to be

24 measured accurately. In fact, the activation energy re-

R = n

-Bu, Ph quired for the aryl/2-pyridyl rotation falls at least 4 kcal/ Scheme 16 Fast addition of alkyl- or aryllithiums to the 2-position mol below that for the aryl/aryl rotation of the carba-anal- of pyridine followed by slow elimination of lithium hydride ogous 2-methoxymethyl-3¢-(isopropyldimethylsilyl)biphenyl (B 8.8) and 3¢-(isopropyldimethylsilyl)-2-(o- 91 The practical potential of this method has so far been neg- tolyl)biphenyl (B 7.4). To the extent of that difference, lected. By taking advantage of the addition/elimination the nitrogen lone pair is ‘smaller’ (i.e., less repulsive or sequence, an entry to new 2-arylpyridines was opened. more compressible) than an ortho-C–H bond. According 92 Thus, 2-[(2-methoxymethyl)phenyl]pyridine (26; 56%) to computational data, the rotational barrier of 2-phe- was prepared by reaction of 2-(methoxymethyl)phenyl- nylpyridine, i.e. the energy difference between its twisted lithium with pyridine itself90 and 2-o-tolyl-4-(isopropyl- (by some 20°) ground state and its coplanar transition dimethylsilyl)pyridine (27; 67%) by reaction of o- state, approximates 1 kcal/mol whereas that of biphenyl 93 90 amounts to 2 kcal/mol. tolyllithium with 4-(isopropyldimethylsilyl)pyridine, Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. the latter made from 4-bromopyridine (Scheme 17). Both pyridines bear a diastereotopicity probe, the oxygen- 9 Summing Up adjacent methylene group in the first case and the silicon- bonded geminal methyls in the second. Line shape analy- This article started with a juxtaposition of electrophilic sis of variable temperature (‘dynamic’) NMR spectra can and nucleophilic (het)aromatic substitutions. These therefore provide the torsional barrier that has to be modes proved to be strictly complementary, one irreplace- crossed by passing through a coplanar transition state (28) able by the other. We nevertheless recognize synergistic when one enantiomeric conformer switches into its mirror effects. For example, halo-, alkoxy- and amino-bearing image (Scheme 18). Such B values (B standing for biaryl arenes, pyridines and other azines can be conveniently barriers) are more meaningful measures of steric bulk than subjected to electrophilic substitution through organome- other scales. tallic intermediates. A second stage of structural prolifer- ation may immediately follow if the new derivatives thus obtained are exploited as substrates for nucleophilic (het)aromatic substitution.

2120 M. Schlosser, R. Ruzziconi REVIEW

Whatever the type of reaction, selectivity is critical. The X

‘silyl trick’ represents a breakthrough after repeated vain 5 X

efforts to install regioselectivity in the competition be- 6

N N N

tween identical nucleofuges located at the 2- (or 6-) and 4- Nu

Li Nu

positions. If an appropriate nucleophile (secondary Li

29c 29a amines and, in particular, hydrazine) is chosen, the leav- 29b

ing group is preferentially or even exclusively displaced

2 1 2 1

R R R from the 4-position. Alternatively, a halide at the 4-posi- R

tion can be practically immobilized by the introduction of

Nu N X a 3-trialkylsilyl substituent that silences the surrounding N exchange sites. As a consequence, the nucleophile homes Scheme 19 Delocalization of the pyridine/nucleophile adduct: h3 in at the 6-position, the only unperturbed reaction center rather than h5? remaining. Substituents such as ethoxy, halogens or trimethylsilyl Cyclohexadienylpotassium97 and 1,4-dihydronaph-1- modulate the reactivity of 2-halopyridines toward nucleo- ylsodium98 do combine with carbon dioxide at the 3- and philes quite differently depending on whether they occupy 1-positions, respectively, i.e. at the most negatively the 3- or the 5-position. Fluorine, an electronic zwitter charged sites. On the other hand, pentadienylpotassium (see above), accelerates the reaction with sodium ethoxide again binds carbon dioxide and oxirane concomitantly or roughly 50-fold when neighboring (at the 5-position) the preferentially at the central 3-position (g/a ratios of 2:3 exchange site and retards it by about a factor of two when and 9:1, respectively), although this time the electron den- located across the ring at the 3-position (numbering as in sity is concentrated at the pentadienyl termini (as judged Scheme 19). This suggests that electron excess is accumu- by the 13C NMR chemical shifts95). The advantage of elec- lated at the latter position and there enters in conflict with trophilic attack at the internal position may merely have the electron-donating mesomeric effect of the fluorine at- an electrodynamic origin. Like water needs a fall to run, om. Thus the smallest halogen can serve as a sensitive electrons require a field imbalance to flow. The gradient probe monitoring the electronic outfit of an intermediate. gets steeper if a channel-shaped pool is tapped in its mid- As 1,2-dihydropyrid-1-ylmetals are aza analogues of 1,6- dle (at the 3-position of a pentadienylmetal or anion) rath- cyclohexa-2,4-dien-1-ylmetals, their charge density dis- er than at one end (at the 1- or 5-position). tribution can be inferred from that of the latter species if Incidentally, 1,2-dihydropyridyllithiums generated by the not straightaway from the dihydrocyclohexadienyl anion. addition of an organolithium onto pyridine react with bro- According to NMR spectroscopic94,95 and computational96 mine or iodomethane mainly at the 3-position99,100 but evidence, the electron density is higher in the center of the with acyl chlorides (e.g., ethyl chloroformate) cleanly at delocalized area (at the methylene-remote 3-position) the 1-position.101 The regioselectivity is thus critically de- rather than at the termini (the 1- and 5-positions flanking pendent on the nature of the electrophile and its interac- the tetragonal center). This may have to do with the prox- tion with the metal at the transition state. imity of the latter sites if constrained in a six-membered Fluoride is a better leaving group than chloride in nucleo- ring and the resulting menace of electrostatic repulsion. philic substitutions of halonitroarenes and, as we now The incorporation of an electronegative heteroatom into know, of halopyridines as well. This cannot be a conse- the ring inevitably causes a perturbation. The nitrogen quence of the (too) frequently evoked Pauling electroneg- atom will attract more electron density and thus deplete ativity. On the contrary, as the homolytic bond cleavage the 5-position even more. Fluorine, if located there, will of the C–Cl bond is at least 20 kcal/mol less expensive help to promote the attack of a nucleophile at the adjacent than that of the C–F bond and the electron affinity of the 6-position by its electron-withdrawing inductive effect.

chlorine atom is some 5 kcal/mol greater than that of the Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. A more refined analysis must also take into account the fluorine atom, the elimination step must favor the expul- trajectory of the entering nucleophile and the departing sion of a chloride as opposed to a fluoride ion. To gain its nucleofuge. Stereoelectronics of bond-making and bond- overall lead, the smaller halogen has to overcompensate breaking could be improved if the two particles approach for this handicap in the preceding addition step. Without or clear the ring in line with the C=N bond p-orbitals going into the details of this still-controversial issue, we (Scheme 19). Thus, the carbon at the 3-position should briefly outline once again our point of view.74 The polar bend out-of-plane first in one direction (structure 29a), C–F bond conserves little electron density in the vicinity then in the other direction (structure 29c) and both times of the carbon atom. Geminal substituents may conse- be imparted in resonance participation except at the copla- quently enlarge their bond angles without encountering nar transition state (29b). much resistance. Thus, fluoromethane and chloromethane At this point, a word of caution deems appropriate. widen their H–C–H bond angles from the tetrahedral Though seemingly plausible, the tacit assumption that 109.5° (in methane) to 110.1° and 110.3°, respectively, while their H–C–X angles are compressed to 108.8° and highest electron excess at a given site translates into high- 102 est local reactivity toward electrophiles is unfounded. 108.6°, respectively. The ‘altruistic’ behavior of fluorine and chlorine is spoiled to some extent if the halogens

Synthesis 2010, No. 13, 2111–2123 © Thieme Stuttgart · New York REVIEW Nucleophilic Substitutions of Nitroarenes and Pyridines 2121

are attached not to a tetragonal but rather to a trigonal or Me Me

digonal center. Double and triple bonds can be conceived δδ

as small rings (‘cycloethane’, ‘bicylo[1.1.1]ethane’). The Si R inherent strain prevents major angle changes. The result- M

ing lack of structural reorganization translates into a Me

30a X-SiMe + M-R X-M + Me Si-R 3

weakening of thermodynamic stability which is often 3 apostrophized as ‘destabilization of double and triple Me

bonds by fluorine’. Thus, the differential heats of forma- Me

X Si 0 R

tion (DDfH gph) of fluoroethane and chloroethane (relative to ethane) amount to –46 and –7 kcal/mol, respectively, M and diminish to –20 and –4 kcal/mol for fluoroethene and Me chloroethene (relative to ethene) and –14 and –3 kcal/mol 30b for fluoroethyne and chloroethyne (relative to ethyne).103–109 Scheme 20 Halide-displacing substitution of a halotrimethylsilane 0 and a nucleophile (e.g., an allyl-metal M-R): concerted mechanism The differential heats of formation (DDfH gph) of fluorobenzene and chlorobenzene (relative to benzene) are, versus an SN2-like process passing through a silicate complex having a finite life span with –47 and –7 kcal/mol, also somewhat smaller than those of fluorocyclohexane and chlorocyclohexane (relative to cyclohexane) with –51 and –10 kcal/mol, respectively.109–113 Conversely, the transformation of a trigonal Acknowledgment center into a tetragonal one by addition of a nucleophile The authors are indebted for financial support provided by the Mi- must benefit from an extra driving force if the carbon at nistero dell’Università e Ricerca (MUR PRIN 2004 contract the reaction center bears a chlorine atom and still consid- 033322) and the Schweizerische Nationalfonds zur Förderung der erably more if it bears a fluorine atom. wissenschaftlichen Forschung, Bern (grant 20-100'336-02). Major experimental results presented in the framework of this article have The attempt to extend such a thermochemical analysis of been accomplished by Carla Bobbio, Fabrice Cottet, Elena Marzi, the fluoride/chloride leaving group contest into the silicon Thierry Rausis and Sara Spizzichino. The Lausanne author is grate- area means entering uncharted waters. Fluorotrialkylsi- ful to his colleagues Alain Borel and Luc Patiny for precious help lanes have been found to undergo nucleophilic substitu- in various respects. tion by polar allylmetals more slowly than the 114 corresponding chloro, bromo and iodo analogues. At References first glance this seems to rule out the intermediacy of a pentacovalent silicon-based ate complex and to suggest an (1) Lapworth, A. J. Chem. Soc. 1904, 85, 30. (2) Dawson, H. M.; Spivey, E. J. Chem. Soc. 1930, 2180. SN2-like direct displacement process, implying simulta- (3) Bartlett, P. D. J. Am. Chem. Soc. 1934, 56, 967. neous bond making and bond breaking with Walden in- (4) Ingold, C. K. Structure and Mechanism in Organic version. This may be an unwarranted conclusion. Chemistry; Cornell University Press: Ithaca NY, 1953. Arguments developed in the case of the nucleophilic sub- (5) Hammett, L. P. Physical Organic Chemistry: Reaction stitution of halonitroarenes and halopyridines may not be Rates, Equilibria and Mechanisms; McGraw-Hill: New applicable to halosilanes. The formation of a hypervalent York, 1970. silicate complex 30b (Scheme 20) inevitably causes all (6) Stock, L. M.; Brown, H. C. Adv. Phys. Org. Chem. 1963, 1, 35. bonds of the halosilane precursor to stretch and hence to (7) Winstein, S.; Lewin, A. H.; Pande, K. C. J. Am. Chem. Soc. lose strength. This may compromise the fluorosilane more 1963, 85, 2324. than the other halosilanes because of its exceptionally (8) Sargent, G. D. Quart. Rev. 1966, 20, 301. strong Si–F bond (the homolytic dissociation energies of (9) Huisgen, R. The Adventure Playground of Mechanisms and Si–F, Si–Cl, Si–Br and Si–I bonds averaging 135, 113, 96 Novel Reactions; American Chemical Society: Washington and 77 kcal/mol115,116). This impairment may be accentu- DC, 1994. Downloaded by: Universiteitsbibliotheek Antwerpen, Wilrijk. Copyrighted material. ated by repulsive forces acting between the halogen lone (10) Sauer, J.; Huisgen, R. Angew. Chem. 1960, 72, 294. (11) Olah, G. A.; Ohanessian, L.; Arvanaghi, M. Synthesis 1986, pairs and the equatorial (basal) silicon–methyl bonds at 868. the hypothetical transition state 30a (Scheme 20). There- (12) Cerichelli, G.; Luchetti, L.; Mancini, G. Tetrahedron 1996, fore, no valid mechanistic conclusion can be drawn before 52, 2465. new facts become available. (13) Le, Z.-G.; Chen, Z.-C.; Hu, Y.; Zheng, Q.-G. Synthesis 2004, 2809. Exploring nucleophilic (het)aromatic substitutions has al- (14) Cañibano, V.; Rodríguez, J. F.; Santos, M.; Sanz-Tejedor, ways been and will continue to be rewarding. The variety M. A.; Careño, M. C.; Gonzáles, G.; García-Ruano, J. L. of inherent facets as yet uncovered will be both mechanis- Synthesis 2001, 2175. tically intriguing and promising for further practical, syn- (15) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1. thesis-oriented applications. In this respect, the topic fits (16) Schlosser, M. In Organometallics in Synthesis: A Manual, perfectly well Rolf Huisgen’s label of an ‘adventure play- 2nd ed.; Schlosser, M., Ed.; Wiley: Chichester, 2002. ground’.9 (17) Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: Amsterdam, 2002. (18) Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376; Angew. Chem. 2005, 117, 380.

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