Why does chlorobenzene not react with NaOH?

Substitution reactions on aromatics

Author: Priv.-Doz. Dr. B. Kirste
  1. Aromatic character and aromaticity
    1. Aromatic character of benzene
    2. Criteria for aromaticity
    3. Polycyclic aromatic hydrocarbons, aromatic heterocycles
    4. Non-benzoic aromatics
  2. Electrophilic substitution on aromatic systems
    1. pi- and sigma complexes, mechanism of substitution
    2. Electrophilic substitution on unsubstituted benzene
    3. Orientation and reactivity in the second substitution
      1. General rules
      2. The ortho-para ratio
      3. Targeted orientation
    4. Orientation in the case of multiply substituted benzene
    5. Orientation with polycyclic hydrocarbons
    6. Orientation for heterocyclic compounds
    7. Reactions
  3. Nucleophilic substitution on aromatic systems
    1. Nucleophilic A-E mechanism
      1. mechanism
      2. Evidence for the reaction mechanism
      3. Reactivity and orientation
    2. SN1 mechanism on aromatics
    3. Arin mechanism
    4. Reactions

1. Aromatic character and aromaticity

1.1. Aromatic character of benzene

Discovery of benzene by 1825 Michael Faraday, Insulation from luminous gas condensate. 1865 List of Kekulé-Formula. Benzene does not show the high reactivity expected for a "polyene" (1,3,5-cyclohexatriene); chemical tests proved the equivalence of all six carbon atoms and all six bonds. X-ray structure analysis: benzene is planar, C-C-C bond angle 120 °, C-C bond length 139.8 pm (1.398 Å; compare 1.54 Å for C-C single bonds and 1.34 Å for C = C double bonds).

Notable chemical properties:
a) substitution reactions instead of addition reactions (e.g. no reaction with bromine water), b) oxidative resistance (e.g. against KMnO4), c) thermal resistance, d) special properties of functional groups (e.g. relatively stable diazonium salts, Ph-NH2 -> Ph-N2 (+ )).

Resonance or delocalization energy:
The amount of combustion and hydrogenation enthalpies of benzene is smaller (i.e. less exothermic) than expected for hypothetical "cyclohexatriene",

Cyclohexene + H2 -> Cyclohexane (Delta H ° = -119 kJ / mol) benzene + 3 H2 -> cyclohexane (Delta H ° = -207 kJ / mol) => delocalization energy = 150 kJ / mol (36 kcal / mol).

Theoretical description of aromaticity:

a) Resonance theory (mesomerism, valence bond (VB) method):
"Resonance" of two Kekulé boundary structures (contribution 39% each) and three Dewar boundary structures (contribution 7.3% each) explains an energetic stabilization of benzene.

b) HÜCKEL's molecular orbital method (HMO):
The HMO theory gives a total energy of the six pi-Electrons of 6 *alpha + 8*beta (alpha: Coulomb integral, beta: Resonance integral), corresponding to a stabilization of 2 *beta versus a system with localized double bonds. (Comparison with the experimental value of the enthalpy of hydrogenation provides beta = -75 kJ / mol.) In general, the Hückel theory predicts stabilization for planar monocyclic conjugated systems which (4n + 2) pi-Contain electrons.

1.2. Criteria for aromaticity

a) Structure:
planar cyclic conjugated hydrocarbons with approximately equal bond distances of approx. 140 pm.
b) Reaction behavior:
Substitution reactions preferred over addition reactions (does not apply to higher annulenes).
c) resonance energy:
Determinations of the enthalpies of combustion or hydrogenation indicate an energetic stabilization.
d) Hückel theory:
planar cyclic conjugated hydrocarbons with (4n + 2) pi-Electrons (in this form only applies to monocycles).
e) NMR criterion:
an external magnetic field induced in the cyclic conjugated pi-Electron clouds one diamagnetic ring current. This ring current has an induced magnetic field which is opposite to the generating field inside (LENZ's rule), while it intensifies this outside (at the location of the benzene protons). Consequently, one finds the resonance of aromatic protons at a particularly deep field, the chemical shift delta is approx. 2 ppm larger than with olefinic protons (range: delta = 6.5 - 9.0 ppm, benzene: delta = 7.26 ppm).

Note: there is no ideal criterion for aromaticity; the criterion of the diamagnetic ring current is probably the best.

1.3. Polycyclic aromatic hydrocarbons, aromatic heterocycles

Fused hydrocarbons: naphthalene, anthracene, phenanthrene. Six-membered heterocycles (pi-Electron deficiency compounds): pyridine, sym-Triazine, quinoline. Five-membered heterocycles (pi-Electron excess compounds): pyrrole, furan.

1.4. Non-benzoic aromatics

Annulene ions (triphenylcyclopropenylium cation, cyclopentadienyl anion and ferrocene, cycloheptatrienylium cation, cyclooctatetraene dianion), calicene, annulenes (1,6-methano-, 1,6-oxido- and 1,6-imino- [10] annulene, [18] annulene); Porphyrins as diaza- [18] annulenes (heme, chlorophyll); Azulene.

2. Electrophilic substitution on aromatic systems

2.1. pi- and sigma complexes, mechanism of substitution

substitution instead of addition for energetic reasons (loss of mesomeric stabilization in the latter case): CH2 = CH2 + Br2 -> BrCH2-CH2Br (Delta H ° = -122 kJ / mol) benzene + Br2 -> 5,6-dibromocyclohexa-1,3-diene (Delta H ° = 8 kJ / mol) benzene + Br2 -> bromobenzene + HBr (Delta H ° = -45 kJ / mol)

Electrophilic Attack occurs because of the high electron density (pi-Electron clouds) on both sides of the aromatic ring. Mechanism of Electrophilic Aromatic Substitution (sigmaComplex mechanism, arenium ion mechanism): The attacking electrophile forms through interaction with the pi-Electrons first one pi complex. Then becomes a sigmaBond to one of the aromatic carbon atoms, whereby this changes into the tetrahedral sp3 hybridization state; the positive charge in this sigma complex is delocalized to form a mesomeric stabilized cyclohexadienyl cation. Finally, with regression of the aromatic system, the proton is split off from the sp3 carbon atom; as an intermediate stage there is again a pi-Go through complex.

HAr + E (+) -> [HAr-> E (+)] -> [Ar (H, E)] (+) -> [H (+) <- ArE] -> pi-complex sigmacomplex pi-Complex ArE + H (+)

Reaction profile: In general, the formation of the sigmaComplex the rate-limiting step. The importance of the pi-The complex is controversial; in the case of nitration with NO2 (+) BF4 (-) or bromination with Br2 and FeCl3 in nitromethane, a correlation between the reaction rate and the stability of the pi-Complex found.

pi complex: Special case of an electron donor-acceptor complex, detectable using the electron spectrum (UV / VIS), in some cases stable solutions (e.g. with HCl at -78 ° C, Br2, I2, Ag (+) or picric acid). The pi-The complex of benzene and HCl is colorless and does not conduct electricity; there is no H / D exchange with DCl.

sigma complex: Forms particularly in the presence of a Lewis acid (e.g. AlCl3), in some cases stable solutions at low temperatures. Example: A solution of HCl and AlCl3 in benzene is colored and conducts electricity (dissociation into ions), with DCl there is H / D exchange. Benzenonium ion and pentamethylbenzenonium ion can be detected by NMR spectroscopy at -134 ° C in super acidic solution (HF-SbF5-SO2ClF-SO2F2). The sigmaThe complex of mesitylene (1,3,5-trimethylbenzene) and C2H5F / BF3 can even be isolated in crystalline form at -80 ° C.

Isotope Effects: In the case of electrophilic aromatic substitution, as a rule, no kinetic isotope effect (reaction with ArD instead of ArH) is observed (this applies in particular to nitration); at most one finds a small effect
k_H/k_D = 1 - 3. Consequently, the C-H bond is not broken in the rate-limiting step.

2.2. Electrophilic substitution on unsubstituted benzene

a) nitration:

the attacking agent is the nitronium ion (NO2 (+)), e.g. in nitrating acid (conc. HNO3 / H2SO4)

HNO3 + 2H2SO4 = NO2 (+) + H3O (+) + 2HSO4 (-) ArH + NO2 (+) -> ArNO2 + H (+)

b) halogenation:

usually with halogen (Cl2, Br2) in the presence of a Lewis acid

Cl-Cl + FeCl3 = Cl (+) [FeCl4] (-) ArH + Cl (+) - Cl (-) - [FeCl3] -> ArCl + HCl

c) sulfonation:

usually with conc. H2SO4, attacking agent is SO3 (possibly bound as H3SO4 (+) or H2S2O7)

2H2SO4 = SO3 + H3O (+) + HSO4 (-) ArH + SO3 - [H2SO4] -> ArSO3H

The sulfonation is reversible, when heated with dilute H2SO4 (to approx. 150 ° C) the sulfonic acid group is split off.

d) Friedel-Crafts alkylation:

with alkyl halides in the presence of a Lewis acid; a rearrangement of the reagent is often observed (carbenium ion)

PhH + (CH3) 3CCH2Cl - [FeBr3] -> PhCH2C (CH3) 3 PhH + (CH3) 3CCH2Cl - [AlCl3] -> PhC (CH3) 2CH2CH3

2.3. Orientation and reactivity in the second substitution

If an electrophilic aromatic substitution is carried out on a monosubstituted benzene, the group present influences both the entry position (ortho, meta or para) of the second substituent and the reaction rate compared to unsubstituted benzene. Some groups mainly conduct in the meta position; these are without exception deactivating. Other groups direct predominantly in the ortho and para positions; these are mostly activating.

Example: nitration (NO2 (+)) of nitrobenzene (PhNO2) yields 93% m-Dinitrobenzene, 6% ortho and 1% para isomer; Nitration of toluene (PhCH3) yields 56% O-Nitrotoluene, 40% para and 4% meta isomer.

2.3.1. General rules

The electrophilic aromatic substitution is usually under kinetic Product control carried out. According to the Hammond postulate, the sigmaServe complex as a model for the relevant transition state. Orientation and reactivity can therefore be based on inductive, mesomeric and steric effects in the sigmaUnderstand complex.

(1)+ I-Effect: stabilization of the sigma-Complex, all positions are activated, especially strong ortho and para; ortho / para-directing.
(2)-I-Effect: deactivation of all positions, especially ortho and para, meta-directing.
(3)+ M-Effect: activating, ortho / para-directing; In the ortho and para positions, particularly favorable quinoid resonance structures can be formulated in which the + M-Group contributes a pair of electrons (filling of the octets).
(4)-M-Effect: deactivating, meta-directing.

There are three types of substituents:
(a) activating and ortho / para-directing,
(b) weakly deactivating and ortho / para-directing,
(c) deactivating and meta-directing.

Substituent effects on the benzene ring with a second substitution

Substituent type effect dirig. Effect on the reactivity O (-) (a) + I, + M o, p very strongly activating NH2, NR2, OH, OR (a) -I, + M o, p strongly activating NHCOR, OCOR (a) - I, + M o, p activating Ar (aryl) (a) -I, + M o, p moderately activating R (alkyl) (a) + I o, p moderately activating H (-) - - - (reference standard) F. -I, + M o, p very low Cl, Br, I, CH = CH-COOH (b) -I, + M o, p weakly deactivating COOR, COOH, CHO, COR, CN, NO2, SO3H (c) -I, -M m strongly deactivating NH3 (+), NR3 (+), SR2 (+), CF3 (c) -I m strongly deactivating

Partial speed factors: For quantitative comparisons of the reaction rates, it is advisable to look at individual positions and to use them one Compare benzene position. (Partial speed factor f_i = (k_i / n) / (k_Benzol / 6), n = 1 for para, n = 2 for ortho and meta.)
Chlorination of toluene: f_o = 620, f_m = 5, f_p = 820.
Nitration of toluene: f_o = 42, f_m = 2.5, f_p = 58.

Hammett relationship: The rate of electrophilic substitution on substituted benzenes can be described quantitatively using the Hammett relationship (lg = decadic logarithm):

lg f_i = lg (k / k_0) = rho * sigma (+)

in which rho the reaction constant is (here negative) and sigma (+) the (modified) substituent constant (in each case for the meta and para position; negative: activating, positive: deactivating). The Hammett relationship does not apply to the ortho position.

2.3.2. The ortho-para ratio

Purely statistical expectation: 67:33 for ortho / para.
Electronic substituent effect: + M favors para-substitution (p-chinoid system more stable than O-chinoides).
Steric effects: voluminous substituents or electrophiles increase the para proportion.
- of the substituent:
Nitration of toluene: f_o = 42, f_m = 2.5, f_p = 58;
Nitration of tert-Butylbenzene: f_o = 5.5, f_m= 4.0, f_p= 75.
- of the electrophile:
Chlorination of chlorobenzene: 39% ortho, 55% para;
Bromination of chlorobenzene: 11% ortho, 70% para.

Note: the ortho / para ratio varies greatly with the reaction conditions.

2.3.3. Targeted orientation

Tricks for targeted orientation: a) sequence of the substitution reactions, b) choice of reaction conditions, c) use of an auxiliary group that is later split off.

Examples:
a) Chloronitrobenzene: Nitration of chlorobenzene mainly gives a mixture of ortho- and para-isomer, while chlorination of nitrobenzene mainly leads to the meta-product.
b) Aniline (benzolamine, PhNH2): the NH2 group acts in neutral solution (+ M) activating and ortho / para-directing, in (strongly) acidic solution there is the deactivating NH3 (+) group, which directs in the meta positions. Note: it may be advisable to introduce an acetyl protective group.
c) 1,3,5-tribromobenzene: bromination of aniline (with Br2 / FeBr3) yields 2,4,6-tribromaniline; the amino group is then removed by diazotization and reductive cleavage (using hypophosphorous acid, cf. nucleophilic substitution reactions).

2.4. Orientation in the case of multiply substituted benzene

(1) Substituents direct in the same direction. Examples: m-Xylene (1,3-dimethylbenzene), p-Chlorobenzoic acid (4-chlorobenzenecarboxylic acid).
(2) With different orientations, the dominates more activating Group. Example: in p-Methylacetanilide (N-(4-methylphenyl) ethanamide) dominates the acetamido group.
(3) Steric Influence: Because of steric hindrance, it is unlikely that a substituent will occur between two groups that are meta to one another. Example 1-chloro-3-nitrobenzene: no attack in the 2-position.
(4) ortho effect: when a meta-directing group is meta-to an ortho / para-directing group, the electrophile occurs mainly in ortho-position to the meta-directing group. Example: preferential attack on 3-chlorobenzoic acid in the 6-position.

6.2.5. Orientation with polycyclic hydrocarbons

Condensed aromatic systems are more reactive than benzene itself, since it forms the sigmaComplex less delocalization energy is lost. The positions are not equivalent in the unsubstituted hydrocarbons either.

Naphthalene: preferred substitution in 1-position (with kinetic control), since the resonance stabilization of the sigmaComplex (or the transition state) is more effective than with an alternative attack in 2-position. Chlorination of naphthalene (Cl2 / FeCl3) yields 95% 1-chloronaphthalene, sulfonation with conc. H2SO4 at 80 ° C 96% 1-naphthalenesulfonic acid (kinetic control), at 165 ° C 85% 2-naphthalenesulfonic acid (thermodynamic control).
Substituted naphthalene: An activating substituent (+ M) in ring A also directs the second substituent into ring A, a deactivating (-M) on the other hand in ring B.
Phenanthrene: preferential attack in positions 9 and 10 (substitution or addition).

2.6. Orientation for heterocyclic compounds

pi-Excess heterocycles: The five-membered heterocycles furan, thiophene and pyrrole are more reactive than benzene, substitution takes place mainly in the 2-position.

pi-Undershoot heterocycles are very slow to react with regard to electrophilic substitution; nucleophilic substitution is preferred here. Example pyridine: is protonated to the pyridinium ion, electrophilic attack takes place mainly in the 3-position (all positions are deactivated).

2.7. Reactions

2.7.1. Hydrogen (proton) as a leaving group

2.7.1.1. Proton as an electrophile

a) H / D exchange: ArH + D (+) = ArD + H (+)

2.7.1.2. N as an electrophile

a) Nitration (nitro-de-hydrogenation): ArH + HNO3 - [H2SO4] -> ArNO2

active agent: nitronium ion NO2 (+)
Design variants: in H2SO4 / HNO3, in conc.HNO3, in N2O5 or with nitronium salts

b) Nitrosation (nitroso-de-hydrogenation): ArH + HONO -> ArNO

Only with active substrates (e.g. tertiary amines), but not with primary and secondary amines (diazotization or N-nitrosation)

c) Diazo coupling (arylazo de-hydrogenation): ArH + ArN2 (+) -> Ar-N = N-Ar

with active substrates (amines, phenols).

d) direct amination (amino-de-hydrogenation):

ArH + NH2-O-SO2-OH - [AlCl3] -> ArNH2

2.7.1.3. S as an electrophile

a) Sulfonation (sulfo-de-hydrogenation): ArH + H2SO4 -> ArSO2OH

b) Halosulfonation (Halosulfo-de-hydrogenation):

ArH + ClSO2OH -> ArSO2Cl

c) Sulfurization: ArH + SCl2 - [AlCl3] -> ArSAr

2.7.1.4. Halogens as an electrophile

a) Halogenation with chlorine and bromine (halo-de-hydrogenation):

ArH + Br2 - [AlCl3] -> ArBr

with Lewis acid as a catalyst; with active substrates (e.g. phenol) even without a catalyst.

b) halogenation with iodine
least reactive halogen, substitution reaction reversible.

c) halogenation with fluorine
too reactive; Introduction of fluorine into phenols indirectly by means of ClO3F possible (via gem-Difluoroproducts and subsequent reduction).

2.7.1.5. C as an electrophile

a) Friedel-Crafts alkylation (alkyl de-hydrogenation):

ArH + RCl - [AlCl3] -> ArR

Reactivity of the alkyl halides: F> Cl> Br> I
Possible rearrangements of the electrophile (carbenium ion) must be taken into account.

b) Friedel-Crafts arylation (Scholl reaction):

2ArH - [AlCl3 / H (+)] -> Ar-Ar + H2

c) Friedel-Crafts acylation (acyl de-hydrogenation):

ArH + RCOCl - [AlCl3] -> ArCOR

Reactivity of the acid halides: I> Br> Cl> F
Note: because of complex formation, you need a little more than the stoichiometric amount of the "catalyst" AlCl3.

d) amidation with isocyanates (N-Alkylcarbamoyl de-hydrogenation):

ArH + RNCO - [AlCl3] -> ArCONHR

e) Formylation with CO and HCl (Gattermann-Koch reaction):

ArH + CO + HCl - [AlCl3 / CuCl] -> ArCHO

with benzene and alkylbenzenes.

f) Formylation with HCN and HCl (Gattermann reaction):

ArH + HCN + HCl - [ZnCl2] -> ArCH = NH2 (+) Cl (-) - [H2O] -> ArCHO

g) Formylation with N, N-disubstituted formamides (Vilsmeier reaction. Formyl de-hydrogenation):

ArH + PhN (CH3) CHO - [POCl3] -> ArCHO + PhNHCH3

with active substrates (amines, phenols).

h) Formylation with formyl fluoride: ArH + FCHO - [BF3] -> ArCHO

i) Formylation with chloroform + base (Reimer-Tiemann reaction):

(-) O-Ph + CHCl3 - [OH (-)] -> O-(-) O-Ph-CHO

only works with very strongly activated substrates (phenolate)

j) Carboxylation with phosgene (carboxy-de-hydrogenation):

ArH + COCl2 - [AlCl3] -> ArCOOH

k) Carboxylation with CO2 (Kolbe-Schmitt reaction):

(-) O-Ph + CO2 -> O-(-) O-Ph-COO (-)

only works with very strongly activated substrates (phenolate)

l) Hydroxyalkylation (hydroxyalkyl de-hydrogenation):

ArH + RR'C = O - [H2SO4] -> Ar-C (RR ') - OH or Ar-C (RR') - Ar

Special cases are the Bischler-Napieralski reaction (cyclization of amides with POCl3), the ring closure in the Skraupbetween quinoline synthesis and the Pechmann reaction (formation of coumarin with ring closure).

m) Haloalkylation (haloalkyl de-hydrogenation):

ArH + HCHO + HCl - [ZnCl2] -> ArCH2Cl

n) Acylation with nitriles (Hoesch reaction. Acyl de-hydrogenation):

ArH + RCN - [ZnCl2 / HCl] -> ArCOR

2.7.1.6. O as an electrophile

Direct hydroxylation (hydroxy de-hydrogenation):

ArH + F3CC (= O) OOH - [ZnCl2] -> ArOH

2.7.1.7. Metals as an electrophile

a) ArH + RM -> ArM + RH

b) ArH + M -> ArM + 1/2 H2

Reaction at activated sites of the aromatic; typical reagent for (a) is BuLi.

2.7.2. Hydrogen as a leaving group in intramolecular rearrangements

2.7.2.1. Rearrangement at the O

a) Fries rearrangement: RC (= O) O-Ph - [AlCl3] -> p, o-HO-Ph-C (= O) R

b) Rearrangement of phenol ethers: RO-Ph - [AlCl3] -> p, o-HO-Ph-R

2.7.2.2. Rearrangement on the N

a) Rearrangement of the nitro group:

O2N-N (R) -Ph - [H2SO4] -> o, p-HN (R) -Ph-NO2

b) Rearrangement of halogen (Orton rearrangement):

H3CC (= O) N (Cl) -Ph - [HCl] -> p-H3CC (= O) NH-Ph-Cl

2.7.3. Leaving groups other than hydrogen

2.7.3.1. C as a leaving group

a) Reversal of Friedel-Crafts alkylation (hydro-de-alkylation, dealkylation):

ArR + H (+) - [AlCl3] -> ArH

b) Decarboxylation of aromatic carboxylic acids:

ArCOOH - [Cu / quinoline] -> ArH + CO2

2.7.3.2. O as a leaving group

Reduction of aromatic ethers:

ArOR - [Raney Ni] -> ArH + RH

2.7.3.3. Desulfonation

ArSO3H - [150 ° C, dil. H2SO4] -> ArH + H2SO4

2.7.3.4. Halogen as a leaving group

Dehalogenation: ArX - [AlCl3] -> ArH

3. Nucleophilic substitution on aromatic systems

The nucleophilic substitution on aromatics is in principle more difficult than on the saturated carbon atom; e.g. the hydrolysis of chlorobenzene to phenol requires very drastic conditions (8% NaOH, 300 ° C, 150 atm).

There are three main mechanisms of nucleophilic aromatic substitution: 1) nucleophilic addition-elimination mechanism (nucleophilic aromatic ipso-Substitution, SNAr), 2) SN1 mechanism, and 3) aryne mechanism. In contrast, the SN2 mechanism is not possible on aromatics for steric reasons, since it requires attack from the rear. (A fourth mechanism, SRN1, occurs via radical ions.)

3.1. Nucleophilic A-E mechanism

The nucleophilic addition-elimination mechanism (SNAr) requires at least one strongly electron withdrawing group (-M). A typical activating substituent in this sense is a nitro group in the ortho or para position. The hydrolysis of 2,4,6-trinitro-1-chlorobenzene (picryl chloride) proceeds under similarly mild conditions as that of acyl chlorides (Na2CO3).

3.1.1. mechanism

Z-C6H4-X + Y (-) -> [Z-C6H4 (X, Y)] (-) -> Z-C6H4-Y + X (-)

The two-stage reaction takes place via an intermediate complex, which has the opposite sign to that sigmaComplex (arenium ion) is analogous to electrophilic aromatic substitution: a tetrahedral sp3 hybridization state is formed at the substitution site, the negative charge is delocalized via the ortho and para positions (formation of a mesomerism-stabilized cyclohexadienyl anion). A -M-Substituent in ortho or para position stabilizes this intermediate complex.

3.1.2. Evidence for the reaction mechanism

1) The reaction is second order, bimolecular.
2) Most convincing evidence: isolation of the intermediate complex (J. Meisenheimer, 1902).

2,4,6- (O2N) 3Ph-OCH2CH3 + (-) OCH3 = [2,4,6- (O2N) 3Ph (OCH2CH3, OCH3)] = 2,4,6- (O2N) 3PhOCH3 + (-) OCH2CH3

The action of potassium ethoxide on 2,4,6-trinitroanisole or of potassium methylate on 2,4,6-trinitrophenetol gives the same red salt, the Meisenheimer complex. The structure of this and similar complexes was later proven by IR, 13C-NMR and X-ray structure analysis.
3) When converting 2,4-dinitro-1-X-benzene (X = Cl, Br, I, SOPh, SO2Ph, p-Nitrophenoxy) the reaction rates only vary by a factor of about 5. The bond to the leaving group is therefore not split in the rate-determining step. The reaction takes place particularly quickly with X = F (3300 times faster than with X = I), so the high electronegativity of the leaving group increases the reactivity. (In the SN1 or SN2 reaction on aliphatics, however, F is the worst leaving group among the halogens.)

3.1.3. Reactivity and orientation

1) Influence of the substrate: As a rule, activating groups (with -MEffect) required; typical and particularly effective are nitro groups. Heterocyclic sp2-N (pyridine) is similarly effective. The -M-Substituent acts ortho / para-directing. Approximate order of activating effect of substituents:

N2 (+)> NO> NO2> N (+) Me3> SO2Me> CN> COR> CF3

2) Influence of the leaving group:

F >> Cl> Br> I

This order is reversed to that of solvolysis reactions (SN1) and SN2 reactions on aliphatic substrates. Good leaving groups for SNAr are also NO2 (-) and SOPh (-), in contrast to aliphatics. The observation that -I- Effects strongly accelerate the reaction, suggests that the first step of the SNAr reaction is rate-determining.

3) Influence of the nucleophile: a nucleophile is generally the more reactive, the more basic it is; In addition, the reactivity within a group of the periodic table increases towards heavier atoms (higher polarizability, e.g. S better than O). CN (-) is usually not suitable here. Approximate order of reactivity:

NH2 (-)> Ph3C (-)> ArS (-)> RO (-)> OH (-)> I (-)> Br (-)> Cl (-)> H2O> ROH

3.2. SN1 mechanism on aromatics

In aromatics, the SN1 mechanism is only important in reactions of diazonium salts:

ArNH2 - [HNO2] -> Ar-N (+) N -> Ar (+) + N2 - [Y (-)] -> ArY

Proofs:
1) Elimination of N2 (low energy).
2) The reaction is first order (only dependent on the diazonium salt concentration).
3) The first step (the elimination of N2) is reversible, it takes place in the solvent cage; Evidence by N-15 labeling:

Ar- (15) N (+) N = [Ar (+) + (15) NN] (cage) = Ar-N (+) (15) N

3.3. Arin mechanism

When reacting non-activated aryl halides with very strong bases, one often finds a substitution combined with a rearrangement. E.g. 2-chlorotoluene with KNH2 in liquid ammonia provides a mixture of 2-aminotoluene and 3-aminotoluene. cine substitution). If both ortho positions are blocked, as in 2-chloro-1,3-dimethylbenzene, no reaction takes place at all. These findings indicate an elimination-addition mechanism in which a triple bond is initially formed through the elimination of HCl (aryne, dehydrobenzene, benzyne):

PhCl + NH2 (-) -> C6H4 (dehydrobenzene) + NH3 + Cl (-)

C6H4 + NH3 -> PhNH2

Proofs:
1) Isotope labeling (C-14, J. D. Roberts, 1956):

[1- (14) C] PhCl - [NH2 (-)] -> [1- (14) C] PhNH2 + [2- (14) C] PhNH2 (50:50)

2) no reaction if both ortho positions are occupied,
3) Trapping reaction of the dehydrobenzene by Diels-Alder reaction (e.g. with furan),
4) Leaving group effect, order of reactivity:

Br> I> Cl >> F

(Bond cleavage in the rate-limiting step).

3.4. Reactions

3.4.1. Leaving groups other than hydrogen and N2 (+)

3.4.1.1. O as a nucleophile

a) Replacement of halogen by OH (hydroxy-de-halogenation):

ArBr + OH (-) -> ArOH (A-E mechanism)

b) Exchange of NH2 for OH (Bucherer reaction. Hydroxy-de-amination):

ArNH2 - [H2O, NaHSO3] -> ArOH

Ar = 1- or 2-naphthyl; not possible with aniline; special A-E mechanism

c) Alkaline Melting of the Sulphonates (Oxido-de-Sulphonato-Substitution):

ArSO3 (-) - [NaOH, 300 ° C] -> ArO (-) (A-E mechanism)

d) Exchange of halogen for OR (alkoxy-de-halogenation):

ArBr + OR (-) -> ArOR (A-E mechanism)

3.4.1.2. S as a nucleophile

a) Exchange of halogen for SH or SR (mercapto-de-halogenation, alkylthio-de-halogenation):

ArBr + SH (-) -> ArSH (A-E mechanism)

3.4.1.3. N as a nucleophile

a) Exchange of halogen for NH2, NHR, NR2 (amino-de-halogenation):

ArBr + NH3 -> ArNH2 (A-E mechanism)

b) Exchange of OH for NH2 (Bucherer reaction. Amino-de-hydroxylation):

ArOH - [NH3, NaHSO3] -> ArNH2

Ar = 1- or 2-naphthyl; not possible with phenol; special A-E mechanism

3.4.1.4. Halogen as a nucleophile

Halogen exchange (halo de-halogenation):

ArX + X '(-) -> ArX' + X (-) (A-E mechanism)

3.4.1.5. H as a nucleophile

a) Reduction of phenols, phenol ethers, phenol esters (Hydro-de-Hydroxylation, Dehydroxylation):

ArOH - [Zn] -> ArH (A-E mechanism)

b) Reduction of halogen and nitro compounds:

ArNO2 - [NaBH4] -> ArH (A-E mechanism)

3.4.1.6. C as a nucleophile

a) Exchange of halogens for CN (Rosenmund-von Braun reaction. Cyano-de-halogenation):

ArBr + CuCN - [200 ° C] -> ArCN

b) Exchange of sulfonate for cyanide in the melt (cyano-de-sulfonato substitution):

ArSO3 (-) - [NaCN] -> ArCN

(A-E mechanism)

c) Arylation on a carbon atom with active H (bis (ethoxycarbonyl) methyl-de-halogenation etc.):

ArBr + Z-C (-) H-Z '-> Z-CH (Ar) -Z' (Arine mechanism)

d) direct coupling (Ullmann reaction):

2ArI - [Cu] -> Ar-Ar

3.4.2. H as a leaving group

a) Alkylation and arylation (Ziegler alkylation, alkyl de-hydrogenation):

ArH + BuLi -> ArBu

Ar = 2-pyridinyl or the like; A-E mechanism

b) Amination of heterocyclic N-compounds (Tschitschibabin reaction. Amino-de-hydrogenation):

ArH + NH2 (-) - [100-200 ° C] -> ArNH (-) + H2

Ar = 2-pyridinyl or the like; A-E mechanism

c) Amination by hydroxylamine:

ArH + NH2OH - [OEt (-)] -> ArNH2

Ar = activated aromatic (e.g. 1-nitronaphthalene provides 4-amino-1-nitronaphthalene); A-E mechanism

d) Hydroxylation of aromatic acids (hydroxy-de-hydrogenation):

Ph-COO (-) Cu (2+) OH (-) - [210-220 ° C] -> O-HO-Ph-COOH (A-E mechanism)

3.4.3. N2 (+) (diazonium) as a leaving group

a) Exchange for OH (hydroxy-de-diazonation):

ArN2 (+) + H2O -> ArOH + N2 + H (+) (SN1 mechanism)

b) Exchange for S-containing groups (mercapto-de-diazonation etc.):

ArN2 (+) + HS (-) -> ArSH + N2

2ArN2 (+) + S (2-) -> ArSAr + 2N2

ArN2 (+) + RS (-) -> ArSR + N2

ArN2 (+) + SCN (-) -> ArSCN + ArNCS + N2

SN1 mechanism

c) Exchange for iodine (iodine de-diazonation):

ArN2 (+) + I (-) -> ArI + N2 (SN1 mechanism)

d) Exchange for fluorine (Schiemann reaction. Fluorine de-diazonation):

ArN2 (+) + BF4 (-) -> ArF + N2 + BF3 (SN1 mechanism)

*) Note: The best way to exchange for chlorine or bromine (and cyanide) is through the Sandmeyer reaction, which, however, occurs after a radical Mechanism expires:

ArN2 (+) + CuCl -> ArCl

Mechanism:

ArN2 (+) X (-) + CuX -> Ar (.) + N2 + CuX2

Ar (.) + CuX2 -> ArX + CuX

e) Exchange for H (Hydro-de-Diazonation):

ArN2 (+) + H3PO2 -> ArH

Hypophosphorous acid is used in excess as reducing agent. The reaction can serve as a second step in the deamination. Mechanism: probably radical.

3.4.4. Rearrangements

a) von Richter rearrangement:

p-Z-Ph-NO2 - [CN (-)] -> m-Z-Ph-COOH

b) Sommelet-Hauser rearrangement:

Ph-CH2N (+) (CH3) 3 X (-) - [NaNH2] -> O-H3C-Ph-CH2N (CH3) 2N (CH3) 2

c) Rearrangement of aryl hydroxylamines into aminophenols:

Ph-NHOH - [H (+)] -> p-HO-Ph-NH2

d) Smiles rearrangement:

O-Y (-) - CR2CR2-X-Ph-Z -> O-X (-) - CR2CR2-Y-Ph-Z

Mechanism: intramolecular nucleophilic substitution


Burkhard Kirste, 1994/09/12