1 nucleophilic substitution and elimination

31
How to Solve Organic Reaction Mechanisms: A Stepwise Approach, First Edition. Mark G. Moloney. © 2015 John Wiley & Sons, Ltd. Published 2015 by John Wiley & Sons, Ltd. Companion website: www.wiley.com/go/moloney/mechanisms 1 Nucleophilic substitution and elimination 1 Nucleophilic substitution: S N 1 and S N 2 reactions + X S N 1 S N 2 X R 3 R 3 R 3 R 3 R 3 R 3 R 3 R 1 R 1 R 1 R 1 R 1 R 2 R 2 R 2 R 2 R 2 R 2 sp 2 Planar Nu Nu Nu Nu Nu + + X + X Equal amounts (racemate) S N 1 is stepwise and unimolecular, proceeding through an intermediate carbocation, with a rate equation of Rate α [R 3 R 2 R 1 CX], that is, proportional only to the concentration of alkyl halide starting material. The order of stability of the carbocation depends on structure, R 3 C + >R 2 CH + > RCH 2 + > CH 3 C + >H 3 C + , and rearrangements, by either hydrogen or carbon migrations, are possible. S N 2 is bimolecular with simultaneous bond-making and bond-breaking steps, but does not proceed through an intermediate, with a rate equation of Rate α [R 3 R 2 R 1 CX][Nu ], that is, the rate is reaction is proportional to both the concentration of alkyl halide starting material and the nucleophile. The nature of the substrate structure, nucleophile, leaving group, and solvent polarity can all alter the mechanistic course of the substitution. There are important stereochemical consequences of the S N 1 and S N 2 mechanisms (the former proceeds with racemisation and the latter with inversion). Steric effects are particularly important in the S N 2 reaction (neopentyl halides are unreactive). Neighbouring group participation in S N 1 reactions can be important. Special cases: (i) Allylic nucleophilic displacement: S N 1and S N 2; (ii) Aryl (PhX) and vinylic (R 2 C = CRX) halides: these are generally unreactive towards nucleophilic displacement, although benzylic (PhCH 2 X) and allylic (RCH = CHCH 2 X) are more reactive. Elimination: E 1 and E 2 eliminations H X X H H + HB + X + HB + X + B B E 2 E 1 E 1 is stepwise and unimolecular, proceeding through an intermediate carbocation; E 2 is bimolecular with simultaneous bond-making and bond-breaking steps but does not proceed through an intermediate. The Saytzev’s Rule and Hofmann’s Rule can be used to predict the orientation of elimination, and the stereochemistry is preferentially antiperiplanar. Elimination and substitution are often competing reactions. COPYRIGHTED MATERIAL

Upload: others

Post on 30-Dec-2021

24 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: 1 Nucleophilic substitution and elimination

How to Solve Organic Reaction Mechanisms: A Stepwise Approach, First Edition. Mark G. Moloney. © 2015 John Wiley & Sons, Ltd. Published 2015 by John Wiley & Sons, Ltd. Companion website: www.wiley.com/go/moloney/mechanisms

1

Nucleophilic substitution and elimination1

Nucleophilic substitution: SN1 and SN2 reactions

+

– X

SN1

SN2

XR3

R3

R3

R3 R3

R3

R3 R1

R1

R1 R1

R1

R2 R2

R2

R2

R2

R2

sp2

Planar

Nu

–Nu Nu Nu

Nu

+ + X–

+ X–

Equal amounts (racemate)

• SN1isstepwiseandunimolecular,proceedingthroughanintermediatecarbocation,witharateequationof  Rateα [R3R2R1CX], that is, proportional only to the concentration of alkyl halide startingmaterial.The orderofstabilityof thecarbocationdependsonstructure,R3C

+>R2CH+>RCH2+>CH3C

+>H3C+, and

rearrangements,byeitherhydrogenorcarbonmigrations,arepossible.• SN2 is bimolecular with simultaneous bond-making and bond-breaking steps, but does not proceed

throughanintermediate,witharateequationofRateα[R3R2R1CX][Nu−], that is, therate isreactionis proportionaltoboththeconcentrationofalkylhalidestartingmaterialandthenucleophile.

• Thenatureof thesubstratestructure,nucleophile, leavinggroup,andsolventpolaritycanallalter themechanisticcourseofthesubstitution.

• ThereareimportantstereochemicalconsequencesoftheSN1andSN2mechanisms(theformerproceedswithracemisationandthelatterwithinversion).

• StericeffectsareparticularlyimportantintheSN2reaction(neopentylhalidesareunreactive).• NeighbouringgroupparticipationinSN1reactionscanbeimportant.• Specialcases:(i)Allylicnucleophilicdisplacement:SN1′andSN2′;(ii)Aryl(PhX)andvinylic(R2C=CRX)

halides: thesearegenerallyunreactive towardsnucleophilicdisplacement, althoughbenzylic (PhCH2X)andallylic(RCH=CHCH2X)aremorereactive.

Elimination: E1 and E2 eliminations

H

X

X

HH

+ HB + X–

+ HB + X–

+

B

–B

E2

E1

• E1isstepwiseandunimolecular,proceedingthroughanintermediatecarbocation;E2isbimolecularwithsimultaneousbond-makingandbond-breakingstepsbutdoesnotproceedthroughanintermediate.

• TheSaytzev’sRuleandHofmann’sRulecanbeused topredict theorientationof elimination, and thestereochemistryispreferentiallyantiperiplanar.

• Eliminationandsubstitutionareoftencompetingreactions.

0002195062.indd 1 12/20/2014 9:55:19 AM

COPYRIG

HTED M

ATERIAL

Page 2: 1 Nucleophilic substitution and elimination

2

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

NH(i)

(ii) Et3N, H2N

(iii) H2SO4, Me2C = CH2

HCI

CH2OH

Alcohols are nucleophiles and bases, sincethe oxygen possesses lone pairs. HCl is astrong acid and fully ionised (pKa = –7).Triethylamine is a weak base and sulfuric acidis also a very strong acid.

Aromatic rings can be protonated, but thealcohol is the most basic and nucleophilic siteof Ph3COH.

Alcohols are easily protonated by strongacids, which converts the hydroxyl into a goodleaving group, an oxonium ion, which is ableto depart as water, leaving a carbocationintermediate.

The leaving group departs to give a tertiarycarbocation, which is also resonancestabilised, called the triphenylmethyl cation,which is then intercepted by chloride.

* Triphenylmethyl chloride readily undergoesSN1 reactions; departure of the goodleaving group (chloride) regenerates thetriphenylmethyl carbocation, which isintercepted by the most nucleophilic functionalgroup of the aniline reagent, that is, the aminegroup. A series of proton transfers then givesthe product.

* Under stongly acidic conditions (H2SO4),isobutene is protonated (Markovnikov addition)to give a t-butyl cation; this is intercepted togive the ether product in its protonated form.

Deprotonation of this oxonium cation givesthe ether product.

Me3CO

Ph3COHPh3C

1.1

0002195062.indd 2 12/20/2014 9:55:20 AM

Page 3: 1 Nucleophilic substitution and elimination

3

H

O H

O

H

Ph

Ph

Ph

O

H

Ph

Ph

Ph O

H

H

Ph

Ph

Ph

Ph

Ph PhCl

Ph

Ph

Ph

HOH2C

NH2

HO

N

Ph

Ph

Ph H

H

NH

NPh3C H

a

O

N

Ph

Ph

PhH

Me3C

Ph

Ph Ph

a

aHO

NH

HO

H

H

HO

N

Ph

Ph

Ph H

H

b

a

a

a

a

b

a

b

OMe3C

OMe3C

a

HOH

NHPh3C Ph3C Ph3C

NH2

HO1

1

2 2

2

–Cl

–H3O

Cl

NEt3

H

–H2O

+Me3C

– Et3NH

+Et3N

+H2O

+Cl

+

+

+

+

+ +

+

+

+

++

+

+

Now try questions 1.8 and 1.9

Summary: There are several examples of nucleophilic substitution (SN1) reactions in this question:

Nu R-Nu+ +R-X X– –

0002195062.indd 3 12/20/2014 9:55:20 AM

Page 4: 1 Nucleophilic substitution and elimination

4

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Alkyl chlorides are good electrophiles (chloride isa good leaving group and its electronegativitypolarises the C-Cl bond). Alcohols are nucleophilesand weak acids. Calcium hydroxide is aweak base.

Under the basic conditions of the reaction, the alcohol function is deprotonated to give an alkoxide anion which is very nucleophilic. The alkyl chloride is the most electrophilic site.

Alkyl halides readily undergo nucleophilicsubstitution reactions with alkoxides to giveethers (the Williamson ether synthesis). In thiscase, the reaction would be an intramolecularone.

The alkoxide undergoes an intramolecularnucleophilic substitution reaction with the alkylchloride to give an epoxide.

* Methanethiolate is a good nucleophile, and attacks both the C-Cl bond and the epoxide function (which has two electrophilic sites) at the less hindered end, to give the alkoxide product; this is protonated on work-up.

* Sodium hydride is a good base, anddeprotonates the alcohol; alkylation with MeI,via a nucleophilic substitution mechanism,gives the ­nal ether product (Williamson ethersynthesis).

Not needed here.

1.2

MeS SMe

OMe(i) Ca(OH)2, H2O

(ii) 2 MeSNa(iii) NaH, THF then MeI, THF

Cl Cl

OH

12

3

0002195062.indd 4 12/20/2014 9:55:20 AM

Page 5: 1 Nucleophilic substitution and elimination

5

––

+

Now try questions 1.10 and 1.16

Nu R-Nu+ +R-X X– –

MeS SMe

OMe

Cl Cl

OH

12

31

23

b

ClO

MeSO

MeS SMe

OH

MeS SMe

OCH3 I

MeS SMe

OMe

ClO

δ+δ+

ClCl

OH

a

b

HO

b

bb

a

MeS SMe

O HO

H

H

b

MeS SMe

O

aa

a

a

MeS SMe

OH δ−

a

Cl Cl

O

b

H

–H2O

–H2O

– H2

δ+ δ+

δ+

+MeI

+H3O+

ClO

+OH

+MeS

+MeS

SMe

SMe

–Cl

–Cl

–I

Ca2+ (OH–)2

Summary: This question involves several examples of nucleophilic substitution (SN2) reactions:

+NaH

0002195062.indd 5 12/20/2014 9:55:21 AM

Page 6: 1 Nucleophilic substitution and elimination

6

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Alkyl chlorides are good electrophiles (chlorideis a good leaving group) and alcohols are goodnucleophiles (the oxygen has two lone pairs).Methanethiolate is an excellent nucleophile(the sulfur is very polarisable and carries anegative charge).

Since the reaction is with the highly nucleophilicreagent, MeS–, the most reactive site is the alkylchloride. An alcohol is not reactive with anucleophilic reagent.

Alkyl chlorides readily undergo nucleophilicsubstitution reactions, since they possess aleaving group, and are electrophilic by virtueof the electronegative halogen substituent.

Since the reaction here is between a 1° alkylchloride and a highly nucleophilic thiolate anion,an SN2 mechanism is most likely.

* Thionyl chloride is highly electrophilic, andconverts the alcohol to the corresponding alkylchloride via an addition-elimination process (withneighbouring group or anchimeric assistance ofthe SMe group).

* The nucleophilic hydroxyl oxygen of thecarboxylic anion, generated by deprotonationof the carboxylic acid, undergoes a nucleophilicsubstitution reaction with the alkyl chlorideformed in the previous step (with anchimericassistance of the SMe group) to give theester product.

Not needed here.

1.3Cl

OH

(i) MeSNa

(ii) SOCl2, py(iii) PhCH2NHCH2CO2H, Et3N

PhNH

O

O

MeS1

2

0002195062.indd 6 12/20/2014 9:55:21 AM

Page 7: 1 Nucleophilic substitution and elimination

7

Cl MeSCl

ClOH

MeSOH

ClS

Cl

O

ClS

Cl

O

MeSO

SCl

O

H

MeSO

SCl

O

PhNH

O

δ+

O

b

δ+1

Now try questions 1.11 and 1.17

2

a

c

b

PhNH

2

O

O

1

MeS

δ+

b

b

b–SO2, –Cl

c

a

a

b

MeSCl

d

MeS

a

b

a

a

Cl

a

δ−

δ−δ−

δ+

N

δ−

+ +

–Cl

Cl

MeS

MeS

MeSOH

δ−

OH

δ−Na

– C5H5NH

PhCH2NHCH2CO2H Et3N Et3NHPhCH2NHCH2CO2

+S(O)Cl2

+py

SMe

MeS

–Cl

Summary: This is an example of anchimeric assistance (also called neighbouring group participation) in nucleophilic substitution reactions

YX+ +

YNu

YNu

–X

+

+

+

–Cl–

– –

– +

+

+

+

MeS

0002195062.indd 7 12/20/2014 9:55:22 AM

Page 8: 1 Nucleophilic substitution and elimination

8

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Amines are good nucleophiles (the nitrogen has alone pair). Alkyl bromides are good electrophiles,since bromine is electronegative and bromide is agood leaving group.

Although an aromatic ring is a possiblenucleophile, the most nucleophilic site ofthis molecule is the dimethylamino group. The most reactive electrophile is ethyl bromide.

Alkyl halides readily undergo nucleophilicsubstitution reaction, and in this case; thenucleophile is the dimethylamino function.

Since bromoethane is a 1° alkyl halide, andamines are good nucleophiles, the reactionwill proceed by an SN2 process, to givea quaternary ammonium salt.

* Quaternary ammonium groups are good(neutral) leaving groups, and are easily displaced by the nucleophile acetate, givingin this case an acetate ester.

* Esters are easily hydrolysed under alkalineconditions (addition-elimination mechanism)to give the alcohol product upon acidic work-up.

* Reaction with butyllithium (a strong base)�rstly deprotonates the more acidic alcohol,and only then deprotonates the benzylic methylgroup to give a resonance stabilised carbanion;this nucleophilic carbanion is quenched withbromoethane (SN2 reaction), but only the mostreactive benzylic carbon centre reacts with theone equivalent of EtBr.The alkoxide is protonated on acidic work-up togive the alcohol product.

1.4

NMe2

Me

OH(i) EtBr, EtOH, Δ′(ii) NaOAc, AcOH, Δ′

(iii) NaOH, Δ′, then acidic work-up(iv) 2 BuLi, then EtBr (1 equiv.), then acidic work-up

12

3

4

0002195062.indd 8 12/20/2014 9:55:22 AM

Page 9: 1 Nucleophilic substitution and elimination

9

NMe2

Me

OH

HO

H

H

NMe2

Me

Br

NMe2

Me

EtNMe2

Me

Et

O

O

O

Me

O

O

Me

O

O

Me

O

Me

Br

a

H

a

b

δ+

O

CH

HH

δ−

b

a

1

O

CH2

O

a

OH

Br

c

b

b

HO

H

H

Bu

a

1

d

a

b

a

b

b

2

3

4

2

34

5

6

65

δ−

δ+

δ+

δ−

–2 C4H10

–Br

H

a

b

Br

OH

–EtNMe2

–CH3CO2H

–H2O

O

O

Na+

NaHO

+AcO

+NaOH

2 BuLi

+H3O

Now try questions 1.12 and 1.18

Summary: This question includes an example of nucleophilic attack at a benzylic position:

Ph X Nu+ +Ph Nu X– –

+

+

+

––Br–

+

Bu–

–O

+

Br–

+

0002195062.indd 9 12/20/2014 9:55:22 AM

Page 10: 1 Nucleophilic substitution and elimination

10

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Alkyl chlorides are electrophiles, sincechlorine is electronegative and chloride is agood leaving group. Sodium carbonate is aweak base; in aqueous solutions, hydroxide isgenerated which is a good base as well as agood nucleophile.

The allylic chloride is the most electrophilicsite (vinylic chlorides have a much strongerC-Cl bond and are not electrophilic). Hydroxideis the only available nucleophile.

Allylic chlorides are very susceptible tonucleophilic substitution reactions, whichcan be either by an SN1 or SN2 mechanism,depending on the substrate and solvent.

Allylic chlorides easily undergo SN1 reactionsin polar solvents, proceeding via the highlyresonance stabilised allyl cation; this isintercepted by hydroxide, which, afterdeprotonation, gives the allyl alcohol product.

* Sodamide is a strong base; the �rstequivalent �rst deprotonates the alcoholfunction; the second then induces eliminationof the vinylic chloride to give the alkyneproduct.

* Nucleophilic substitution by the sodiumsalt of PhC(O)NHPh (N more nucleophilicthan O) gives the product directly.

* Thionyl chloride is highly electrophilic, andconverts the alcohol to the correspondingpropargyl chloride via an addition-elimination process.

Not needed here.

1.5

Cl Cl

Me

1Ph N

Ph

O

Me

2

(i) Na2CO3, H2O

(ii) 2 NaNH2, NH3, then acidic work-up

(iii) SOCl2 , py

(iv) PhC(O)N–Ph Na+

4

3

0002195062.indd 10 12/20/2014 9:55:23 AM

Page 11: 1 Nucleophilic substitution and elimination

11

Cl Cl

Me

HO

H

H

Cl Cl

Me

Cl O

Me

H

MeO

Cl O

Me

H

H

MeOH

MeCl

Ph NPh

O

Ph NPh

O

ClS

Cl

O

MeMe

OS

Cl

H

O

Ph NPh

O

Me

MeO

MeCl

a

a

δ+1

ClS

Cl

O

Ph NPh Na

O

2

c

–Cl

a

a b

b

a

1

2

4

4

3

b

a

Cl OH

Me

δ−

c

b

b

OH

MeO

SCl

O

d

δ+

b

δ−

δ−

a

bc d

Me

N

3

Cl

Me

e

a

δ+

a

–NH3, –Cl

–SO2,–Cl

+ +

NH2

Na

OH

–NH3

–H2O

–C5H5NH

H2O Na2CO3 HO NaHCO3

H2N

+S(O)Cl2

+NH3

+NH3

Now try questions 1.13 and 1.19

Summary: This question gives more examples of nucleophilic substitution and elimination reactions:

+

– Cl–

–Cl–

+

– +

+

Cl–

+

0002195062.indd 11 12/20/2014 9:55:23 AM

Page 12: 1 Nucleophilic substitution and elimination

12

OH

Me

(i) HI(ii) Me3N

(iii) Ag2O, H2O then 160°C(iv) H2, Pd-C

12

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Alcohols are nucleophiles and bases, since theoxygen possesses lone pairs. HI is a strongacid, and fully ionised (pKa = –10).

The alcohol is the only basic and nucleophilicsite in this molecule, and HI the mostelectrophilic reagent.

Alcohols are readily protonated by acids,thereby converting the hydroxyl group intoan oxonium ion, which is able to depart aswater; they therefore readily undergonucleophilic substitution reactions underacidic conditions with suitable nucleophiles.

The oxonium ion is a good leaving group,and is easily displaced by the goodnucleophile, iodide, in an SN2 process(1° substrate, good nucleophile).

* Trimethylamine is a good base andnucleophile. Alkyl iodides are also reactiveto SN2 reactions, and the iodide is easilydisplaced to give a quaternary ammoniumiodide.

* Hydrogenation of the alkene using Pdsupported on charcoal as catalyst givesthe alkane (syn- addition of H2).

* Treatment with silver oxide converts theiodide salt to the hydroxide salt (driven bythe precipitation of AgI); heating of thissalt causes an elimination reaction (Hofmannelimination) to give the corresponding alkene.

Not needed here.

1.6

0002195062.indd 12 12/20/2014 9:55:23 AM

Page 13: 1 Nucleophilic substitution and elimination

13

a

OH

Me2

OHH

O H

H

I

a

NMe3

δ−

1

NMe3

2

NMe3

H

Me

H H

b

b

b

1

a

a

c

I–AgI(s)

a

b

δ−

δ+

δ+

δ−

– I

–H2O, –NMe3

OH

I

HO

Me3N

H I

– H2O

+Me3N

+AgI

+H2

– I

Now try questions 1.14 and 1.20

Summary: This is an example of the Hofmann elimination reaction of quaternary ammonium iodides:

N+

I–

+

– I–

+

+

+

++

0002195062.indd 13 12/20/2014 9:55:24 AM

Page 14: 1 Nucleophilic substitution and elimination

14

SO

O

HN

O

Ph

O

H2NO

Ph

O

H(i) MeI(ii) 0.01 N NaOH/H2O, then acidic work-up

(iii) CF3CO2H, then aqueous work-up1 3

2

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Sulfur, oxygen and nitrogen are allnucleophilic, since all possess lone pairs.Methyl iodide is a good electrophile, sinceiodine is electronegative and iodide is agood leaving group.

Sulfur is the most nucleophilic heteroatom,since it is the least electronegative of O, Nand S. Methyl iodide is the most reactiveelectrophile.

Alkyl halides readily undergo nucleophilicsubstitution reactions, the nucleophile inthis case being the sulfur atom.

The nucleophilic sulfur undergoes anucleophilic substitution reaction withmethyl iodide (SN2) to generate asulfonium cation.

* The α-protons of the sulfonium cationare very acidic (highly stabilised conjugatebase), and only weak base is required fordeprotonation; this induces an elimination(E1CB) reaction.

* Esters can be protonated on the carbonyloxygen by strong acids (e.g. CF3CO2H); theester alkyl group departs in an E1 process, togive the amino acid product and a t-butylcation. The cation is intercepted by water,to give an oxonium cation.

Deprotonation of the oxonium cation onwork-up gives the product, t-butyl alcohol.

1.7

0002195062.indd 14 12/20/2014 9:55:24 AM

Page 15: 1 Nucleophilic substitution and elimination

15

SO

O

HN

HN

O

Ph

O

H

O

H

H2NO

Ph

O

H

SO

O

O

Ph

O

SO

O

HN

Ph

OH H

HNO

Ph

OH2N

O

Ph

O

H2NO

Ph

OH

δ−

H2NO

Ph

OH

O

H3C I

H3C Iδ+

1

δ−1 3

a

2

a

c

d

H

b

H

3

H

O

H

2

a

OH

b

b

c

H2NO

Ph

O

a

a

ab

δ−

δ+

δ− HO CF3

O

HO

–CF3CO2

SO

O

HN

O

Ph

O

+NaOH

HNOtBu

OtBu

OtBu

Ph

O

a

HO

H

+H3O

Hb

+MeI

++H2O

+H2O

OH H

SO

O

HN

Ph

O

S

b

c

a

–H2O

+CF3CO2H

–H3O+

Now try questions 1.15, 1.21 and 1.9

Summary: This is an example of a base catalysed β-elimination and acid-catalysed ester hydrolysis.

+

+

+

++

+ +

+

+

++

+

–I–

0002195062.indd 15 12/20/2014 9:55:25 AM

Page 16: 1 Nucleophilic substitution and elimination

16

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Amines and alcohols are both basic, sincethey both possess non-bonded electronpairs. HBr is a strong acid, and fully ionised(pKa = –8).

Although amines and alcohols are bothbasic, amines are more so (nitrogen is lesselectronegative than oxygen). HBr is thestrongest acid present.

Amines are easily protonated by hydrogenbromide, but so too are alcohols.

The amine function is initially protonatedby the hydrogen bromide. Protonation ofthe amine generates bromide anion.

* HBr is a strong acid, easily capable ofprotonating the remaining alcohol. Thisconverts the alcohol into an excellenthydroxonium leaving group, which candepart as water, if a suitable nucleophileattacks, which in this case would bebromide anion. Deprotonation on basicwork-up generates the amine product.

* Reaction with a cysteine derivative occursby attack of the most nucleophilic sulfuratom on the bromide (with anchimericassistance of the NH2 group) to give theprotonated form of the thioether product.

Deprotonation on work-up generatesthe thioether product.

1.8

HONH2 Br

NH2(i) HBr, Δ′1

2

3

(ii) dil. NaOH(iii)

Me(O)CHN CH C

CH2SH

NHMe, pH 7.5

O

0002195062.indd 16 12/20/2014 9:55:25 AM

Page 17: 1 Nucleophilic substitution and elimination

17

–H2O

BrH

BrH3N

O H

H

OH

ab

a

HONH2

12

3

12

3δ−

1 2 3H2N

OH

a

1 2 3

H3N

OH

1 2 3

H3N

Br

Br

Br

+HBr

δ−

H–Br

+HBr

O H

ab

N

Br

H

H

H

–H2O

N

Br

H

H

+NaOH

Me(O)CHN CH C

CH2

NHMe

O

SH

pH 7.5N

H H

Me(O)CHN CH C

CH2

NHMe

O

SH

NH H

a b

CH C

CH2

NHMe

O

SH NH2

CH C

CH2

NHMe

O

SNH2

Me(O)CHN CH C

CH2

NHMe

O

SNH2

ba

HO

Me(O)CHN Me(O)CHN Me(O)CHNCH C

CH2

NHMe

O

SNH2

H

– H2O

H

Now try question 1.9

Summary: This is an example of the nucleophilic substitution (SN2) reaction:

Nu R–Nu+ +R–X X– –

––Br

–Br–

+

+ –

++

+

+

+

+ –

+

–+

+ –

H3N+

+

0002195062.indd 17 12/20/2014 9:55:25 AM

Page 18: 1 Nucleophilic substitution and elimination

18

O

ClCl

(i) HCl, Δ′

(ii) NaOPh1

2

3

5

4

Ethers have oxygen nucleophiles, since theoxygen possesses lone pairs, and HCl is a strong acid and fully ionised (pKa = –7).

The ether function is the only reactive group in this molecule, and HCl is the strongest acid.

Ethers are generally unreactive to most reagents, but may be cleaved by strong acids like HCl, to generate alkyl halides.

The ether function can be protonated by the HCl, to generate an oxonium cation. This cation provides an excellent leaving group (water), which may be displaced by the weak nucleophile, chloride anion. This generates an alkyl halide product.

* The alchoholic group simultaneously generated may react as before; protonation by the strong acid HCl gives the corresponding oxonium ion. This oxonium cation provides an excellent leaving group, which may be displaced by the weak nucleophile, chloride anion. This generates an alkyl halide product, and the dichloro product is thus formed.

Not needed here.

* Reaction of the dichloride with sodium phenoxide gives the product from double displacement of halogen by nucleophilic substitution.

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

1.9

0002195062.indd 18 12/20/2014 9:55:26 AM

Page 19: 1 Nucleophilic substitution and elimination

19

ClH

Cl

H

ab

a

O

1

2

3

5

4

ClCl1

2

35

4

O2

3

5

4

–Cl

+HCl

O

H

ClOH

+ HCl

– Cl

ClO

HClO

H

H H

a

Cla

b

ClCl

– H2O

ClCl

O a

b

ClOPh

PhOOPh

ClOPh

O

a

b

–Cl

+PhO +PhO

Summary: This question involves several examples of nucleophilic substitution (SN2) reactions:

Nu R-Nu+ +R-X X– –

+

+–

– –

++ –

–+

0002195062.indd 19 12/20/2014 9:55:26 AM

Page 20: 1 Nucleophilic substitution and elimination

20

Me OMe

OMe

O

ClO

Me

OMe

OMe(i) , ZnCl2

(ii) KOtBu(iii) HCl, H2O

12

3

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Alkenes are good nucleophiles. Alkylchlorides are electrophiles, since chlorine iselectronegative and chloride is a good leavinggroup. Epoxides are also electrophiles, sinceoxygen is electronegative and can be a goodleaving group. Zinc chloride is an excellentLewis acid. Potassium t-butoxide is astrong base.

Once activated by the Lewis acid, the epoxideis the most electrophilic site.

Epoxides are very susceptible to nucleophilicsubstitution reactions, especially whenactivated by Lewis acids. Under thesecircumstances, the alkyl chloride is the lessreactive group. Alkenes are weak nucleophiles.

The zinc cation co-ordinates to the epoxide,and this group is then attacked by the alkene.This attack is promoted by the presence twomethoxy groups which activate the alkene,leading to the formation of an oxonium cation.Ring closure of the released alkoxide onto thisoxonium cation generates the ring closed product.

* Potassium t-butoxide is a strong base;this induces elimination of the alkyl chlorideto give the alkene product. This is mostlikely to proceed by an E2 mechanism.* Under aqueous acidic conditions, theacetal is readily hydrolysed, by the usualprotonation–elimination–addition of water-elimination sequence for acetal hydrolysis.

Not needed here.

1.10

0002195062.indd 20 12/20/2014 9:55:26 AM

Page 21: 1 Nucleophilic substitution and elimination

21

OtBu

OtBu

Zn2+

a

a

b

b

a

c

Me OMe

OMe

O

Cl

O

Me

OMe

OMe

12

3

K tBuO

ZnCl21

2

3

δ+δ+

O

Cl δ+δ+

O

Cl δ+δ+

Zn2+

Me OMe

OMeO

Cl

Zn2+

δ+δ+ Me OMe

OMe123

Cl O

OMe

MeO

MeO

Me

OMe

OMeCl

O

Me

OMe

OMeCl

H

O

Me

OMe

OMe

δ+

O

Me

HO

H

H

H

OH

a

a

a

b

b

b

δ−

–MeOH

O

Me

OMe

OMe

O

Me

OMe

OMe

H

–MeOH

O

Me

OMe

a

b

O

Me

O

OMe

O

Me

OH2

OMe+H2O

+H3O

H

H

O

+Zn2+

– HOtBu

–Cl

–H+ + H+

Now try question 1.16

Summary: This question involves nucleophilic substitution and elimination reactions:

Nu R-Nu+ +R-X X– –

+

+

+

+

+

+

+

+

+

+ –

0002195062.indd 21 12/20/2014 9:55:27 AM

Page 22: 1 Nucleophilic substitution and elimination

22

Me

PhCH2 HOH

Me

PhCH2 OHH

Me SO2Cl, py

(ii) KOAc(iii) KOH, H2O

(i)

1

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Alcohols are good nucleophiles (oxygen possesses lone pairs). p-TsCl is an acid chloride derived from a sulfonic acid, and is electrophilic due to the electronegative oxygen atoms with a chloride being a good leaving group. Potassium acetate is a weak base and good nucleophile.

The alcohol is the only nucleophilic site, tosyl chloride is the only electrophile. Pyridine is a base.

Alcohols are easily converted to esters by acid chlorides, in this case a sulfonyl chloride.

The alcohol undergoes a nucleophilic addition-elimination reaction at the sulfonic acid group,with loss of chloride; this generates aprotonated sulfonate ester. Deprotonation bypyridine generates the product.

* The tosylate group is an excellent leaving group, and this system is especially activated towards SN2 reactions by attack from the weak nucleophile, acetate. Such reaction leads to displacement of the tosylate giving an ester product but with stereochemical inversion.

* Hydroxide is highly nucleophilic, and hydrolyses the ester; this converts the esterto the alcoholate anion via an addition-elimination process.

The basic conditions of this reaction gives an alcoholate product, which is reprotonated on acidic work-up.

1.11

0002195062.indd 22 12/20/2014 9:55:27 AM

Page 23: 1 Nucleophilic substitution and elimination

23

a b

δ−

δ+

Me

PhCH2

PhCH2

PhCH2

H

OH

Me

PhCH2 OHH

Me S1 1

K AcO

N

HO

O

O

Clδ+

Me

H

OH1S

Cl

OO

ab

cd

a

Me

PhCH2 H

OS

O

OMe

H

OH1

Me

PhCH2 H

OTsAcO

Me

OH

CH2Ph

O

HO

H

H

a

a

a

bb

b

OH

Me

OH

CH2Ph

OMe

OH

CH2Ph

O

–H2O

OH

Me

OH

CH2Ph

CH2Ph

–HOAc

+H3O+

Me

OHMe

HOH

CH2Ph

+KOH

+AcO–

–OTs

δ+Me

PhCH2 H

OS

O

O

H

Me

PhCH2 H

OS

O

O

H

Na

b

+TsCl

–Cl

+py

Now try question 1.17

Summary: This question involves several examples of nucleophilic substitution (SN2) reactions:

Nu R-Nu+ +R-X X– –

+–

+K

+– –

+

+

0002195062.indd 23 12/20/2014 9:55:28 AM

Page 24: 1 Nucleophilic substitution and elimination

24

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Phthalimide is acidic, and potassium hydride is a strong base. The epoxide has two electrophilic sites, at the less hindered endof the epoxide, and at the chloride-bearing carbon.

The chloride is the most electrophilic site, and the N–H is the only acidic bond present.

Alkyl chlorides are electrophiles and arevery susceptible to nucleophilic substitution reactions, which can be either by an SN1 orSN2 mechanism, depending on the substrateand solvent.

Phthalimide is easily deprotonated by potassium hydride, to give the corresponding anion. Alkyl chlorides easily undergo SN2reactions with good nucleophiles, such as the phthalimide anion, and give the amine product.

Phthalimide anion is a strong nucleophile, and reacts further to open the epoxide at the least hindered end, to give an alkoxide product.

The alkoxide product is protonated on acidic work-up to give the �nal product.

1.12

NH

O

O

Cl

O

N N

O

O

O

O

(i) KH

(ii) 0.5

then acidic work-up

OH1

0002195062.indd 24 12/20/2014 9:55:28 AM

Page 25: 1 Nucleophilic substitution and elimination

25

–H2a

b

a

b

N

O

O

Cl

O

N N

O

O

O

O

OH1

14 2

3

4 2

3δ+ δ+

N

O

O

1

H

Cl

O

N

O

O

H N

O

O

H

H

N

O

O

1

–Cl

K H

N

O

O

O

N

O

O

1

N

O

O

O

a

b

N N

O

O

O

O

O

–H2O

N N

O

O

O

O

OH

N N

O

O

O

O

O

HO

H

Hb

a

+H3O+

Now try questions 1.18

Summary: This question involves several examples of nucleophilic substitution (SN2) reactions:

Nu R-Nu+ +R-X X– –

+

–+

K H–+

0002195062.indd 25 12/20/2014 9:55:28 AM

Page 26: 1 Nucleophilic substitution and elimination

26

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

Allyl bromides are excellent electrophiles, since bromine is electronegative and bromide is a good leaving group. Amines are weak bases and good nucleophiles. Sodamide is an excellent base.

The allylic bromide is the most electrophilic site (vinylic bromides have a much strongerC-Br bond) and the amine is the onlynucleophile present.

Allylic bromides are very susceptible to nucleophilic substitution reactions, which can be either by an SN1 or SN2 mechanism, depending on the solvent.

Allylic bromides easily undergo nucleophilic substitution reactions, even with weak amine nucleophiles; the initially formed product is depronated on work-up, to give the allylic amine product.

Sodamide is a strong base; it induces elimination of the vinylic chloride to give the alkyne product.

Not needed here.

1.13HN

N

(i) CH2=C(Br)CH2Br then basic work-up

(ii) NaNH2, NH3

1

0002195062.indd 26 12/20/2014 9:55:29 AM

Page 27: 1 Nucleophilic substitution and elimination

27

b

a

a

b

N N1

Na H2N NH3

14

23

4 23

Br

Br

δ+

a

N

H

H

NH2

N

Br

Brc

N

–Br

H Br

OHa

bNH Br

Br

N

Br

H

H

N

N

1

H

+OH

+NaNH2

–NH3

–H2O

Now try questions 1.19

Summary: This question involves examples of nucleophilic substitution (SN2) and elimination (E2) reactions:

Nu R-Nu+ +R-X X– –

+

+

–+

0002195062.indd 27 12/20/2014 9:55:29 AM

Page 28: 1 Nucleophilic substitution and elimination

28

* This methylamine product is a weak base and good nucleophile, better in fact thanthe starting material as a result of inductive electron release of the N substituents; the alkylation reaction therefore repeats to give the dimethylamine.* This dimethylamine product is an even better nucleophile; the alkylation reaction therefore repeats to give the trimethylammonium product. This is called exhaustive methylation.* Sodium ethoxide then induces eliminationof the trimethylammonium groups to givethe alkene product, in a reaction which is controlled kinetically, to give the less substituted alkene (Hofmann elimination).

Label electrophilic/nucleophilicand acidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it. Not needed here.

NH2

(i) Excess MeI

(ii) NaOEt12

3

4

Alkyl iodides are electrophiles, since iodine is electronegative and iodide is a good leaving group. Amines are good nucleophiles, since the nitrogen possesses a lone pair. Sodium ethoxide is an excellent base.

The alkyl iodide is the only electrophilic site and the amine the only nucleophilic site.

Alkyl iodides are very susceptible to nucleophilic substitution reactions, which can be either by an SN1 or SN2 mechanism, depending on the substrate.

Methyl iodide easily undergoes SN2 reactionssince it is very unhindered; amines are weak nucleophiles, and reaction gives the ammonium intermediate which is deprotonated to give the methylamine product.

1.14

0002195062.indd 28 12/20/2014 9:55:29 AM

Page 29: 1 Nucleophilic substitution and elimination

29

OEt

Me I

a

b

a

c

b

–EtOH,–NMe3

NH2

12

3

4

12

3

4

Me I

δ−

δ+

Na EtO

NH2

12

3

4NH H

Me

NHMe

Me I

a b

NHMeNH Me

MeNMe2

Me I

a b

NMe2 NMe3

–I

NMe3

H

H

H

+NaOEt

Now try question 1.20

Summary: This is an example of the quarternisation of an amine followed by Hofmann elimination reaction:

BaseI–

N+

+

+

++

+ –

–I–

–I–

–H+

–H+

0002195062.indd 29 12/20/2014 9:55:30 AM

Page 30: 1 Nucleophilic substitution and elimination

30

Label electrophilic/nucleophilic andacidic/basic sites of all reactants,and number identical atoms in thestarting material and product.

Identify the most reactive sites, if morethan one exists.

Recall the characteristic reactions ofthe most reactive functional groups; andby considering the reaction conditions,decide which is the most appropriate.

Work through the mechanismleading to the intermediate product.

Repeat the above four steps.

Write down the structure of thefinal product.

Recognise that this is not the finalproduct, but is closely related to it.

1.15

MeOH

MeO

CN

Br Cl

(i) n-BuLi(ii)

(iii) NaCN123

Acetylenes are weakly acidic. n-BuLi is a excellent base. Alkyl chlorides and bromides are electrophiles, since chlorine and bromine are electronegative and both are good leaving groups. Sodium cyanide is a good nucleophile.

The acetylenic hydrogen is the most acidic site, and alkyl bromides are more reactive to nucleophilic attack than alkyl chlorides (bromide is a better leaving group).

n-BuLi is a strong base; it �rst deprotonates the acetylenic function to give an acetylide anion. Alkyl bromides easily undergo SN2reactions, especially with good nucleophiles such as a carbanion.

Alkyl chlorides easily undergo SN2 reactions,especially with good nucleophiles such as cyanide.

Not needed here.

Acetylide anions are easily alkylated at thetriple bond. Alkyl halides are very susceptibleto nucleophilic substitution reactions, whichcan be either by an SN1 or SN2 mechanism,depending on the substrate and solvent.

0002195062.indd 30 12/20/2014 9:55:30 AM

Page 31: 1 Nucleophilic substitution and elimination

31

n-Bu

a

b

a

b

H

MeO MeO

CN

Br Cl

321 321

Li

CN

δ+ δ+ 6

5

4

6

5

4

H

MeOH

MeO

–CH3CH2CH2CH3

MeO

Cl Br

MeOMeO

MeO

CN

–Cl

–BrCl

MeO

Cl

a

b

CN

δ+

+NaCN

+n-BuLi

Now try questions 1.21 and 1.22

Summary: This question involves several examples of nucleophilic substitution (SN2) reactions:

Nu R-Nu+ +R-X X– –

+

––

n-Bu– +

–Na

+

0002195062.indd 31 12/20/2014 9:55:30 AM