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Unformatted text preview: Chapter 18 Aromatic Substitution Reaction 18.2 Electrophilic aromatic substitution reactions
+ +E H + Y E A comparison with the electrophilic addition of HBr to olefins:
R2C=CH2 + HBr R2C-CH3 Br
1 General mechanism of electrophilic aromatic substitution:
+ step 1 slow H
+ E E
step 2 :B HB fast arenium ion ( A α− complex
+ ) HE H
+ E H E + arenium ion: a hybrid of 3 resonance structures
2 The curve of reaction energy: E2
HE + E1 + E+
Since △ Ε1 >> △ Ε2 , the first step of the reaction is a slow step—rate determining step.
3 E 18.3 Effect of substituents on reactivity and orientation of electrophilic aromatic substitution reactions a. Electronic effect of substituents
induction effect (IE) resonance effect (RE) e-releasing IE e-withdrawing IE e-donating RE e-accepting RE Electronic effect 4 ◆ 7 different cases of IE and RE of substituents: i. Only with e-releasing IE on a benzene ring
e-r IE R alkyl groups have weak e-r IE ii. Only with e-withdrawing IE on a benzene ring
e-w IE CX3 X = F,Cl
+ e-w IE NH3 or NH2R, NHR2, NR3
+ + + The CX3 and the groups with positive charges have strong e-w IE.
5 iii. Only with e-releasing RE on a benzene ring
e-r RE C=C
+ e-r RE Phenyl and vinyl groups have weak e-r RE on a benzene ring.
C=C E H C=C E + H C-C
+ C=C E H + + E H iv. With both e-releasing IE and e-releasing RE on a benzene ring
e-r IE O e-r RE e-r IE S e-r RE
6 The groups with negative charges have a strong e-r effect on the benzene ring. v. With both e-withdrawing IE and e-withdrawing RE on a benzene ring
e-w IE O CR e-w RE
This kind of substituents, including -CHO, -CO2R, -CONH2, -CO2H, -SO3H, -CN and -NO2, have strong e-w effect on a benzene ring. vi. With strong e-withdrawing IE and weak e-releasing RE on a benzene ring
e-w IE .. X: .. e-r RE X = F, Cl, Br, I Since e-w IE is larger than e-r RE, the general electronic effect of a halogen atom is weakly e-withdrawing.
7 vii. With weak e-withdrawing IE and strong e-releasing RE on benzene ring
e-w IE NH2 .. e-r RE
Since e-w IE is weaker than e-r RE, the general electronic effect is e-releasing. This kind of substituents includes: -NHR, -NR2, -NHCHO, -NHCOR, -OH, -OR, -OCR, -OCH O O b. Effect of substituents on reactivity of electrophilic aromatic substitutions The order of Eact (∆ E1): Eact(Ye-w) > Eact(H) > Eact(Ye-r) Reaction rate: C6H5Ye-w < C6H6 < C6H5Ye-r e-releasing groups—activating groups e-withdrawing groups—deactivating groups
8 c. Effect of substituents on orientation of electrophilic
Based on the effect of substituents on orientation, substituents can be divided into 2 types: • para-ortho directive groups—including all ereleasing substituents and the weak e-withdrawing groups which have at least one nonbonding e-pair on the atom attached to the benzene ring. • meta directive groups—including all e-withdrawing groups without non-bonding e-pair on the atom attached to the benzene ring. aromatic substitutions Y 9 d. General classification of substituents based on their effect on reactivity and orientation
i. Activating, para-ortho directive substituents including following groups:
strongly activating: -O , -S , -NR2, -NHR, NH2, -OH O O O O moderately activating: -OR,-SR,-OCH,-OCR,-NHCH,-NHCR weakly activating: -CH3, -R, -C6H5, -C=CR2, -C=CH2
The new coming group will be bonded to para or ortho-position towards the original substituent.
OH + Cl2 FeCl3 OH + Cl para OH Cl ortho 10 For ortho-attack:
.. : OH +E
+ .. : OH + E H
+ .. : OH E H .. : OH
+ E H + OH .. E H Among 4 resonace structures, the 4th structure is relatively stable, since every atom has 8 es in the valence shell. For para-attack:
.. :OH +E
+ + .. : OH HE .. : OH
+ + .. OH .. :OH
+ HE HE HE Among 4 resonance structures, the 3rd structure is relatively stable.
11 For meta-attack:
.. :OH +E
+ .. :OH
+ .. : OH H E
+ .. : OH H E
+ H E 3 resonance structures ii. Deactivating, meta directive substituents including following groups:
strongly deactivating: -NH3, -NR3, -NO2, -CF3, -CCl3, -CN, -SO3H moderately deactivating: -COOH, -COOR, -CONH2, -COR, -CHO, -CHCl2
12 + + This kind of e-w groups will direct an incoming group bonded to the meta-position towards the original substituent.
NO2 + HNO3 H2SO4 NO2
meta NO2 93% For ortho-attack: NO2 +E
+ NO2 E H
+ NO2 E H
+ NO2 E + H The 3rd strucutre is relatively unstable since the carbon atom bearing a positive charge directly attached to the e-withdrawing group.
13 For para-attack:
+ + NO2 HE NO2
+ NO2 HE
+ HE The 2nd structure is relatively unstable. For meta-attack:
+ + NO2 E H NO2
+ E H E H 14 iii. Deactivating, para-ortho directive subtituents (includes all halogen atoms)
Cl + HNO3 H2SO4 NO2 70% 30% Cl + Cl NO2 For ortho-attack:
.. :Cl: +E
+ .. :Cl: E H
+ + .. : Cl: E H .. : Cl:
+ E H + Cl : .. E H Among 4 resonance structures, the 4th is relatively stable, since every atom has 8 es in the valence shell. 15 For para-attack:
.. :Cl: +E
+ + .. :Cl: .. : Cl:
+ .. + Cl : .. : Cl:
+ HE HE HE H E Among 4 resonance structures, the 3rd is relatively stable. For meta-attack:
.. :Cl: +E
+ .. :Cl:
+ .. : Cl: E H
+ .. : Cl: E H E H + 3 resonance structures p 846 Table 18.1
16 18.4 Orientation in multiple substituted benzenes 3 empirical rules: i. When the groups on a benzene ring direct the incoming group to the same position, their directive effect can be reinforced. OH NO2
CH3 NO2 NO2 17 ii. When two groups on a benzene ring direct the incoming group to different positions, the orientation of the incoming group will be determined according to the following order: strongly activating groups > moderately activating groups >w CH3 NH2 NHCOReakly activating groups > deactivating groups major
COOH Cl iii. The incoming group does not go to the position between meta substituents if another position is open, this causes by hindrance.
Cl Br CH3 CH3 OCH3 NO2
18 18.5~18.7 Halogenation, nitration and sulfonation of benzene of benzene a. Halogenation ( A )
X + X2 Lewis acid + HX X2 = Cl2, Br2 Lewis acid: FeCl3, FeBr3, Fe/X2, AlCl3, ZnCl2
19 Mechanism of halogenation:
Step 1: polarization of X2 (X = Cl2, Br2)
X X + FeX3 fast XX
+ δ FeX3 X + [XFeX3] + Step 2: formation of an arenium ion +X
+ slow HX + arenium ion X2 = F2, I2 Step 3: loss of a proton
H + X + [XFeX3] fast X + HX + FeX3
20 b. Nitration ( A
General equation: ) of benzene
NO2 + H3O + HSO4
+ only HNO3, slow + HNO3 H2SO4 (conc.) Mechanism of nitration:
slow + nitronium ion
+ NO2 H + NO2 Step 2 H + NO2 + HSO4 base fast NO2 + H2SO4
21 c. Sulfonation ( A
General equation: ) and desulfonation
SO3H r.t. + H2SO4 + H2O fuming dil. H2SO4 or conc. benzene sulfonic acid ( A ) Mechanism of sulfonation and desulfonation:
H SO3 + SO3 step 1 slow + HSO4 - H2SO4 step 2 fast SO3
+ H3O SO3H H2O step 3 fast
22 Desulfontation reaction is useful in organic synthesis. e.g.
CH3 Cl2/Fe Cl major CH3 + CH3 Cl minor CH3 H2SO4 conc. CH3 Cl2/Fe SO3H CH3 Cl dil. H SO 2 4 CH3 Cl SO3H o-chlorotoluene 23 18.8~18.9 Friedel-Crafts reactions ( A
Friedel-Crafts reactions include: Alkylation( A Acylation( A ): introduce an R group to a benzene ring ): introduce an acyl group (–COR) to a benzene ring. ) a. Friedel-Crafts alkylation
R + RX X = Cl, Br AlCl3 + HX X , C=C-X RX = AlCl3 is used in a catalytic amount.
24 The mechanism of Friedel-Crafts reaction:
Step 1 Step 2
RCl + AlCl3 R + AlCl4
+ +R + slow HR + Step 3 H + R R AlCl4 + HCl + AlCl3 e.g. +
+ HF 25 Notice: In the reaction, the initially formed carbocation can rearrange to the more stable one. C C-C-C-C + minor major C C-C-C-C + CH3 H + H3C-CH-C-CH3 or BF3 H OH H + C C-C-C-C + OH 2 - H2O C C-C-C-C H 2
+ C C-C-C-C
26 b. Friedel-Crafts acylation
O + RCCl O C-R + HCl AlCl3 benzene, acyl chloride OO AlCl3 + R-C-O-C-R benzene, acid anhydride O C-R O + R-C-OH AlCl3 is used in a stoichiometric amount.
27 Mechanism of acylation
Step 1: to form an acylium ion
O R-C-Cl + AlCl3 O R-C + + AlCl4 acylium ion Step 2: to form an arenium ion
O slow + R-C + step 2 O H CR + Step 3 and Step 4: to form a complex and to break O Al bond
O H CR + + AlCl4 R-C O AlCl3 H2O step 4
+ δ O R-C
28 - HCl step 3 e.g. to form a ring by acylation:
O C-OH O H2SO4 29 c. Synthetic application of Friedel-Crafts reactions Limits for synthetic application of Friedel-Crafts reactions: i. When there is a substituent more electron withdrawing than a halogen on the benzene ring, the Friedel-Crafts reaction cannot occur.
Y R-X O AlCl3 Friedel Crafts reaction + R-C-Cl (RCO)2O Y = NO2, NH2, NHR, NR2 e.g. .. H2 N + AlCl3 fast H2N AlCl3 δ + δ By this fast coordination reaction, the e-r group turns to be a strong e-w group which causes the aromatic ring somewhat e-dificient. 30 ii. Possible rearrangement of a carbocation (R+) may results in another product rather than the target product.
C-C-C + C-C-C-Br AlCl3 major + minor but target C-C-C A very useful method is the Clemmensen reduction.
O C-C-C O + C-C-C-Cl AlCl3 - HCl H2O Zn(Hg) HCl CH2-CH2CH3 amalgamated zinc Clemmensen reduction 31 iii. It is difficult to control mono-alkylation, since
R reaction rate: < Because of this, some di-substituted by-product will be formed. In order to obtain mono-substituted product, benzene is normally used in a great excess or even as solvent.
C-C-C + C-C-C OH BF3 + C-C-C C-C-C 32 18.10 Electrophilic substitutions of polycyclic aromatic compounds a. The reactions of naphthalene( A )
8 7 6 5 1 4 2 3 Two kinds of Hs on the naphthalene: Hs on the position 1, 4, 5, 8—α position Hs on the position 2, 3, 6, 7—β position Reactivity for electrophilic attack: Hs on α positions > Hs on β positions For irreversible electrophilic substitutions, such as halogenation, nitration, the reactions mainly occur on α position of naphthalene.
33 e.g. NO2 HNO3 H2SO4 Br Br2 For reversible electrophilic substitutions, such as sulfonation, at low temp. the reaction mainly occur on α− position, while at relatively high temp. the α-substituent can transfer to β -position. e.g.
+ H2SO4 60 C 160 C SO3H 160 C SO3H Thermodynamically controlled: β -position Kinetically controlled: α-position
34 General orientation rules for electrophilc multisubstitution of naphthalene:
i. With an e-releasing group or a halogen atom on α-position of naphthalene, the reaction occurs on para or orthoposition towards the original group.
OCH3 OCH3 + NO2 OCH3 NO2 HNO3 H2SO4 35 ii. With an e-releasing group on β position, the reaction mainly occurs on the α-position adjacent to the original group.
Br OCH3 Br2 FeBr3 major OCH3 + Br minor OCH3 iii. With an e-withdrawing group on α- or β -position, the reaction occurs on the α -position of the unsubstituted ring. The reaction will not occur on the deactivated ring.
NO2 HNO3 H2SO4 NO2 NO2 + NO2
36 NO2 b. The reactions of anthracene( A ) and phenanthrene( A ) 7 6 8 9 1 4 2 3 5 10 3 kinds of Hs for anthracene α position: 1, 4, 5, 8 β position: 2, 3, 6, 7 γ position: 9, 10 8 7 9 10 1 2 3 65 4 5 kinds of Hs for phenanthrene 1, 8; 2, 7; 3, 6; 4, 5; 9,10 37 In general, the reactions easily occur at position 9 and 10 of anthracene and phenanthrene. e.g.
Br Br2 CCl4 h.t. O2/V2O5 O O oxidation 9,10 anthraquinone 9,10- A Na/EtOH or H2/cat hydrogenation 9,10 dihydroanthracene electrophilc substitution 38 e.g. The reactions of phenanthrene
Br2 CCl4 CrO3 H2SO4 O O 9,10-dihydrophenanthrane Na/ROH or H2/cat Br 9,10-phenanthraquinone 9,10- A 39 18.11 Nucleophilic aromatic substitution(I) via diazonium ions ( A )
Y 5C Ar-N NX ArY Ar-NH2 + NaNO2 + 2HX -NaX, -2H2O -X, -N2 sodium nitrite arenediazonium saltY = F, Cl, Br, I, CN, HONO OH, H, NO2, ·ª •/ Z nitrous acid ( A )
+ General reaction: SO3, SCN, Ar NH2 NaNO2/HCl H2O , 5 °C N2Cl + CuX(or Cu/HX) - CuCl, - N2
+ X X = Cl, Br, CN Sandmeyer reaction
HBF4 N2BF4 - N2,- BF3
40 Schiemann reaction F MI - N2, - MX
+ H3O I M = Na, K OH H NO2 SO3Na SCN thiocyanato A - N2
+ NH2 NaNO2/HCl H2O 5 C N2Cl H3PO2 or NaBH4 H2O Cu, NaNO2 - N2, - NaCl Cu, NaSO3 - N2, - NaCl Cu, KSCN - N2, - KCl /NaOH - N2,- NaCl Bachmann reaction41 e.g.1 To prepare 1,3,5tribromobenzene
Br2/Fe HNO3 H2SO4 NO2 Fe/HCl NH2 3Br2 Br 2Br2/Fe Br Br Br 1,2,4-tribromobenzene NH2 N2Cl EtOH or Br Br Br Br NaNO2 Br Br H3PO2 H2O HCl, H2O Br Br Br 5C e.g.2 To prepare multicyclic compounds
Z NH2 NaNO2 HCl, H2O 5C Z
+ N2 X NaOH - N2, - NaX Z Z = CH=CH, CH2CH2, NH, CO, CH2
42 18.12~18.13 Nucleophilic aromatic substitution (II) H2O CH CH OH + NaCl
CH3CH2Cl + NaOH
3 2 H2O CH2=CHCl + NaOH reflux X + NaOH H2O a. Nucleophilic substitution by addition-elimination mechanism
◆ Aryl halides with at least one strong e-withdrawing group (NO2) on the ortho- or para-position towards the halogen atom General equation:
Cl NO2 B +B NO2 B = OH (Na2CO3/H2O), SH (NaSH/H2O), NH3, NH2R, OR (NaOR/ROH)3 4 e.g. Nucleophilic aromatic substitution of halogen atom:
H2 O Na2CO3 NaSH H2 O OH NO2 NO2 SH NO2 Cl NO2 NO2 NHCH3 NO2 NO2 OCH3 NO2 NO2
44 NO2 CH3NH2 NaOCH3 CH3OH Mechanism of nucleophilic substitution by addition-elimination:
X +B NO2 addtion step 1 slow XB NO2 B elimination step 2 fast +X NO2 reaction rate: I-Ar, Br-Ar, Cl-Ar, F-Ar
OC2H5 O2N NO2 CH3OK NO2
◆ H5C2O OCH3 O2N NO2 NO2 red crystals K + meta-nitroaryl halides doesn’t undergo nucleophilic substitution reaction by addition-elimination
45 b. Nucleophilic aromatic substitution by eliminationaddition mechanism
◆ Simple aryl halides without NO2 group on the ortho- or paraposition of a benzene ring
Cl + NaOH H2O 350 C OH nucleophile OH- Br + KNH2 or NaNH2 LiNR2
Br + LiR NH3 - KBr NH2 NH2-,NR2- R - LiBr R- (carbanion)
46 Mechanism of nucleophilic substitution by elimination-addition Step 1: elimination
Br H + NH2 Br - NH3 - Br benzyne Step 2: addition
NH2 NH2 NH3 - NH2 NH2 The molecular orbital of benzyne ( A
H H H H ) Y
sp2-sp2 orbitals overlap with each other Y group has only IE, no RE on benzyne 47 The benzyne mechanism is proved by the following experimental facts A
i. If two ortho-hydrogens are replaced by other groups, no nucleophilic substitution reaction takes place.
CH3 Br CH3 KNH2 NH3 ii. When benzyne is formed in the presence of furan, the product is a Diels-Alder adduct.
O +O formed in situ Diels-Alder adduct
48 iii. The incoming group will be attached to either the position of the leaving group or the ortho-position to the leaving group.
Br NaNH2 NH3 CH3 CH3 NH2 + CH3 NH2
" CH3 " iv. If 14C-labeled bromobenzene is used as the starting compound, 2 kinds of labeled anilines are formed in an equal amount.
* Br NaNH2 NH3 * NH2 * NH2 + * NH2
49 The orientation of nucleophilic substitution for substituted aryl halides:
orthosubstituted : metasubstituted: parasubstituted:
Y X H Y H X H Y H X H 4-Y-benzyne
50 Y 3-Y-benzyne Y: e-w IE Y: e-r IE Y Further reaction of the intermediate—benzyne:
Y Y a + NH2 b 3-Y-benzyne a b I Y II NH3 NH2 - NH2 NH2 NH3 - NH2 Y NH2 Y meta product
Path b: Y—e-w IE NH2 ortho product
Path a: Y—e-r IE Y Y a + NH2 b 4-Y-benzyne a b NH2 III Y Y NH3 - NH2 para product NH2 Y
Path b: Y—e-w IE NH3 NH2 - NH2 meta product NH2 Path a: Y—e-r IE
51 IV e.g.1 OCH3 X NaNH2 NH3 " OCH3 " NH2 OCH3 + NH2 OCH3 + NH2 OCH3 NH2 OCH3 NH2 e.g.2
CF3 Cl NaNH NH3 CF3 a + NH2 b a major
major b NH3 NH2 - NH2 NH3 NH2 - NH2 NH2 CF3 NH2 minor CF3 52 e.g.3
CH3 CH3 Cl KNH2 NH3 CH3 a + NH2 a b b NH2 CH3 NH3 - NH2 CH3 38% NH2 CH3 NH2 62% NH3 NH2 - NH2 18.14 Some Additional useful reactions a. Reduction of nitro group
Reduce NO2 to NH2 by the following reductants: Fe/HCl, Zn/HCl, Sn/HCl, SnCl2/HCl, H2S/NH3, Ni/H2 or Pt/H2
53 Compare the following reactions:
NO2 Fe/HCl NH2 NH2 Fe/HCl CH2OH NH2 Fe/HCl NH2 NO2 CHO NO2 NO2 NH2 SnCl2/HCl CHO NH2 NO2
O NHCCH3 H2S/NH3 or SnCl2/HCl H2N NH2 Fe/HCl O2N - CH3COOH O NHCCH3 Pt/H2 EtOH H 2N 54 b. Reduction of carbonyl groups
Carbonyl groups of aldehydes and ketones can be reduced to methylene groups (CH2) by the following three methods: i. By Clemmensen reduction For the compounds which are stable towards HCl acid
O R'CR Zn-Hg/HCl R'CH2R e.g.
O CH=CHCH2CR Zn-Hg/HCl Cl CHCH2CH2R + CH=CHCH2CH2R 55 ii. By Wolff-Kishner reduction For the compounds which are stable towards bases
O CH=CHCH2CR (hydrazine A ) NH2NH2 , NaOH (HOCH2CH2)2O CH=CHCH2CH2R (diethylene glycol A ) iii. By Pd/H2 For the aromatic ketones in which the carbonyl group bonds to benzene ring directly A comparison:
O CCH2CH3 H2/Pd CH2CH2CH3
O CH2CH2CCH3 H2/Pd
56 OH CH2CH2CHCH3 c. Oxidation of the side-chain of benzene ring
alkyl alkenyl C-C-C-R' C=C-C-R' COOH alkynyl C C-R' 1) KMnO4,OH, 2) H3O
+ acyl O C-R' R R = CH2Cl, CHCl2, CH2OH, CHO, CH2NO2 ... having at least one α-H on the benzylic C atom
57 3°alkyl on the benzene ring cannot be oxidized under the same condition aforementioned, since there is no H on the C atom directly attached to the benzene ring.
◆ C very h.t. C-C-COOH KMnO4 C C C-C-C KMnO4, OH d. Halogenation of the side-chain of benzene ring A comparison:
CH3 X2 or hν CH3 X2/FeX3 X CH2X X = Cl, Br
58 + CH3 X e.g.
CH2CH2CH3 + O NBr Br CHCH2CH3 ROOR O N-bromo-succinimide NBS 18.15 Synthesis of aromatic compounds
a. Direct nitration of aniline or phenol is not a good method for organic synthesis 59 e.g.1
NH2 CH3COCl or (CH3CO)2O O NHCCH3 O NHCCH3 + NO2 90%
+ H3O HNO3 H2SO4 O NHCCH3 NO2 minor NH2 + NO2 major NH2 NO2 - CH3COOH minor e.g.2
NR2 HNO3 H2SO4 HNR2
+ HNR2 HNO3 H2SO4 NO2 + - H+ NR2 NO2
60 b. If there is more than one benzene ring in a molecule, the electrophilic substitution will occur on the one which is more electron-rich H3 C O C C O HNO3 H2SO4 HNO3 H2SO4 O2N H3 C CH3O N O2 N CH3O N O C C O c. If there is no other electrophiles, the carbocation formed in the side-chain can form a 6- or 5-membered stable compounds with the benzene ring.
C C-C-C-C H2SO4 OH - H2O C C +C C C C C CC C
61 d. An important skill in designing a synthetic route is the arrangement of the order in which the reactions should be carried out. Compare 2 synthetic routes for preparation of o-nitrobenzoic acid:
CH3 1) KMnO4, OH, 2) H3O
CH3 CH3 HNO3 H2SO4 + NO2
+ COOH COOH HNO3 H2SO4
COOH + NO2 NO2
COOH NO2 CH3 NO2 1) KMnO4, OH, 2)
+ H3O separated by steam-distillation 62 Homework for Chapter 18 Page : 891~897 Problems : 18-41, 18-43, 18-44, 18-46, 18-59
O C-O O AlCl3 + CH3C-Cl
O + O O AlCl3 63 ...
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