topic+6+ substitutions

7/29/2019 Topic+6+ Substitutions

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TOPIC&6.&NUCLEOPHILIC&AND&RADICAL&

SUBSTITUTIONS&(chapter&6&and&parts&of&chapters&10&and&11)&

L



OBJECTIVES&1. &Describe&two&pathways&(mechanisms)&to&account&for&subsKtuKon&at&sp3&carbons&

bearing&an&electronegaKve&atom&(leaving&group)&

2. Discuss&the&effect&of&starKng&material&(substrate),&leaving&group,&reagent&(a&

nucleophile)&and&reacKon&condiKons&on&the&course&of&a&reacKon&

3. Recognize&funcKonal&group&transformaKons&and&synthesis&of&new&molecules&in&

one&step&by&subsKtuKon&of&an&appropriate&material&4. Explore&the&subsKtuKon&chemistry&of&alcohols&and&ethers&

5. Explore&the&mechanism&of&radical&subsKtuKon&



OVERVIEW:((

NUCLEOPHILIC(SUBSTITUTIONS(

S:6.1-6.5



Introduc9on(

The&polarity&of&a&carbonWhalogen&bond&leads&to&the&carbon&having&a&parKal&posiKve&

charge.&&In&alkyl&halides&this&polarity&causes&the&carbon&to&become&acKvated&to&

subsKtuKon&reacKons&with&nucleophiles.&

CarbonWhalogen&bonds&get&less&polar,&longer&and&weaker&in&going&from&fluorine&to&iodine&



Structural(Types(of(Organic(Halides(



Nucleophilic(Subs9tu9on(Reac9ons(

In&these&types&of&reacKons&a&nucleophile& (a&species&with&an&unshared&electron&pair)&

reacts&with&an&electron&deficient&carbon&bearing&a&leaving(group.&&&The&leaving&group&

is&displaced&by&a&nucleophile&and&separates&from&the&carbon&with&its&pair&of&electrons.&

Examples&of&nucleophilic&subsKtuKon:&



A&leaving(group(is&a&subsKtuent&that&can&leave&as&a&relaKvely&stable&enKty&with&the&

pair& of& electrons& originally& bonding& it& to& carbon.& & It& can& leave& as& an& anion& or& a&

neutral&species.&

We are only considering sp3 (alkyl) substrates in this section. Molecules

with leaving groups on sp2 (e.g., vinyl, aryl, acyl (C=O)) or sp (ethynyl)

carbons do not react in fashion described in this section((



• Nucleophiles&• Donate'a'pair'of'electrons:'to'an'electrophile'(lone'pair'or'pi'bond)'

• Neutral&

• Anionic&

• Electrophiles&• Receive'a'pair'of'electrons:'from'a'nucleophile'

• CaKonic&

• Polar,&electrophilic&



• Effect&of&Leaving&Groups&on&Electrophilicity&

• CWL&bond&must&be&relaKvely&weak&

• CWL&bond&must&be& polarizable'(the&ease&with&which&the&electron&distribuKon&in&the&

bond&is&distorted&in&an&electric&field)&

• L&needs&to&be&able&to&accommodate&a&pair&of&electrons&

• ⇒&Good&leaving&groups&are&weak&bases&&



TO&CLASSES&OF&REACTION&• SubsKtuKon&reacKons&can&be&performed&under&different&condiKons&which&give&rise&

to&dramaKcally&different&outcomes.&&Nucleophilic(subs9tu9on(reac9ons(can(be(

classified(as(one(of(two(types,&based&on&these&experimental&observaKons.&&&

• In&order&to&develop&predicKve&tools,&we&need&to'understand'reasons'why'these&

observaKons&are&important.&&That&is,&we&need&to&develop&proposals&for&two(

different(mechanisms(which&are&consistent&with&the&two&sets&of&data&and&which'we'

can'use'to'predict'the'outcome'of'other'reac<ons.'



SUBSTITUTION(AT(1°(SUBSTRATES:(

BIMOLECULAR(NUCLEOPHILIC((

SUBSTITUTION(SN2)(

• Examples&

S:6.6-6.8



A(Mechanism(for(the(SN2(Reac9on(

A&transi<on'state&is&the&high&energy&state&of&the&reacKon.&&It&is&an&unstable&enKty&with&a&

very&brief&existence&(10W12&s).&&In&the&transiKon&state&of&this&reacKon&bonds&are&parKally&

formed&and&broken.&&Both&chloromethane&and&hydroxide&ion&are&involved&in&the&

transiKon&state&and&this&explains&why&the&reacKon&is&second&order.&



Kine9cs(of(an(SN2(Reac9on(

The&iniKal&rate&of&the&following&reacKon&is&measured.&

The&rate&is&directly&proporKonal&to&the&iniKal&concentraKons&of&both&methyl&chloride&and&

hydroxide&ion.&&The&rate&equaKon&reflects&this&dependence.&&Methyl&chloride&and&

hydroxide&ion&are&involved&in&the&rateWcontrolling&step&of&the&reacKon&or&in&a&step&prior&to&

the&rateWcontrolling&step.&

SN 2$reac)on:$subsKtuKon,&nucleophilic,&2nd&order&(bimolecular).&



Transi9on(State(Theory:(FreeEnergy(Diagrams(

Exergonic'reac<on:'negaKve&ΔGo&(products&favored).&

Endergonic'reac<on:'posiKve&ΔGo&(products&not&favored).&

The&reacKon&of&chloromethane&with&hydroxide&is&highly&exergonic. & &&

The&equilibrium&constant&is&very&large.&



A(Free(Energy(Diagram(of(a(Typical(SN2(Reac9on(An&energy&barrier&is&evident&because&a&bond&is&being&broken&in&going&to&the&transiKon&

state&(which&is&the&top&of&the&energy&barrier).&&The&difference&in&energy&between&

starKng&material&and&the&transiKon&state&is&the& free'energy'of'ac<va<on'( ΔG‡').''The&difference&in&energy&between&starKng&molecules&and&products&is&the& free'energy'change'

of'the'reac<on,''ΔGo.'



In&a&highly&endergonic&reacKon&of&the&same&type&the&energy&barrier&will&be&even&

higher&(ΔG‡&is&very&large).&

There&is&a&direct&relaKonship&between&ΔG‡&and&the&temperature&of&a&reacKon.&&The&

higher&the&temperature,&the&faster&the&rate.&

here&e&=&2.718&and&ko&is&the&absolute&rate&constant&[the&rate&at&which&all&transiKon&

states&proceed&to&products&(6.2&x&1012&secW1)].&&Near&room&temperature,&a&10oC&increase&

in&temperature&causes&a&doubling&of&rate.&&Higher&temperatures&cause&more&molecules&

to&collide&with&enough&energy&to&reach&the&transiKon&state&and&react.&



The&energy&diagram&for&the&reacKon&of&chloromethane&with&hydroxide:&

A&reacKon&with&ΔG‡&above&84&kJ&molW1&will&require&heaKng&to&proceed&at&a&reasonable&

rate.&&This&reacKon&has&ΔG‡&=&103&kJ&molW1&so&it&will&require&heaKng.&



In'Class'Problem:'

hat&is&the&effect&of&doubling&the&concentraKon&of&potassium&acetate&in&the&following&SN2&reacKon?&



The(Stereochemistry(of(SN2(Reac9ons(

Backside&aack&of&nucleophile&results&in&an&inversion'of'configura<on.&&ConfiguraKon&

describes&a&parKcular&arrangement&of&atoms&around&the&reacKng&carbon&center.&

In&cyclic&systems&a&cis&compound&can&react&and&become&trans&product.&

SN2'reac<ons'always'occur'with'inversion'of'configura<on.'



Nucleophilicity

Basicity and nucleophilicity are not the same, but they are relatedphenomena

A negatively charged nucleophile is more reactive than its conjugateacid.

¯ CN > HCN ¯ OH > H2O RO ¯ > ROH

In a group of nucleophiles in which the nucleophilic atom is the same,

nucleophilicity parallels trends in basicity.

RO ¯ > HO ¯ >> RCO2 ¯ >> ROH > H2O

Steric bulk hinders nucleophilicity

Across a row in the periodic table, nucleophilicity parallels trends in

basicity.

CH3 ¯ > H2N

¯ > HO ¯ > F ¯

NH3 > H2O



H2Opolar CH3CO2H

protic MeOHEtOH

(CH3)2SO – DMSO dimethyl sulfoxide

CH3CN – AN actonitrile

polar (CH3)2NCHO – DMF N,N -dimethylformamide

aproticCH3COCH3 acetone

CH2Cl2 methylene chloride

- THF tetrahydrofuran

Et2O – “ether” diethyl ether

non-polar CH3(CH2)4CH3

benzene

• Choice&of&Solvents&for&Nucleophilic&SubsKtuKons&• The&solvent&dissolves&the&organic&substrate&(alkyl&halides&are&not&very&polar),&and&

the&source&of&the&nucleophile&(oen&a&salt)&



• Pro<c'solvents'solvate&the&anions&(nucleophiles)&by&HWbonding&and&caKons&(counterions).&&Small&electronegaKve&anions&are&parKcularly&well&solvated,&lowering&their&nucleophilicity.&&

• Trends'in'nucleophilicity'in'polar'pro<c'solvents'increases'going'down'a'column'of'the'periodic'

table'• & F&j&• & Cl&j&• & Br&j&• & I&j&

• Polar'apro<c'solvents&cannot&hydrogen&bond&to&anions&(but&do&solvate&caKons).&&

• Trends'in'nucleophilicity'in'polar'apro<c'solvents'

parallels'trends'in'basicity.''

• & F&j&

• & Cl&j&• & Br&j&• & I&j&

• Polar&aproKc&solvents&are&oen&a&good&choice&for&SN2&reacKons&(Ij&is&sKll&sufficiently&nucleophilic)&



¯ CH3 ¯ NH2 ¯ OH F ¯

¯ SH Cl ¯

¯ SeH Br ¯

I ¯

Nucleophilicity of anions

Neutral nucleophiles

H2S, R3P are highly polarizable and can donate more electron density than

smaller neutral nucleophiles (e.g., H2O; R3N), independent of solvent.

base strength ↑

b a s e s t r en g t h ↑

n u c l e o ph i l i c i t

y i nA P R OT I C

s o

l v en t s ↑(

n u c l e o ph i l i c i t y i n pr o t i c s ol v en t s ↑(

nucleophilicity ↑



Relative Nucleophilicity

Excellent Nucleophiles CN ¯ Cyanide 126,000

HS ¯

Thiolate 126,000I ¯ Iodide 80,000

Good Nucleophiles ¯ OH Hydroxide 16,000

Br ¯ Bromide 10,000

N3 ¯ Azide 10,000

NH3 Ammonia 8000

NO2 ¯ Nitrite 5000

Fair Nucleophiles Cl ¯ Chloride 1000

CH3COO ¯ Acetate 630

F ¯ Fluoride 80

CH3OH Methanol 1

H2O Water 1

Nucleophilic relative strength is measured by relative rate in an SN2 reaction(but depends on substrate, solvent type, etc.)

Relative Nucleophilicity (in MeOH)&&



• Remember&W&anions&can&act&as&nucleophiles&or'bases;&you&cannot&use&a&strongly&basic&nucleophile&in&a&proKc&solvent!&

• The&solvent&needs&to&be&less&acidic&than&NuWH&



• &&&&Leaving&Group&Ability&

• ''&&&Rate:&IW&>&WBr&>&WCl&>>&WF&

• CWL&bond&must&be&broken&–&weaker&bonds&are&more&polarizable,&easier&to&break&

• & Bond&strengths&(kcal/mole):&&

& & &CWF&&&&&&&&116&

& & &CWCl&&&&&&&&79&

& & &CWBr&&&&&&&66&

& & &CWI&&&&&&&&&&52&

• Overall:&&A&good&substrate&for&bimolecular&nucleophilic&subsKtuKon&should&have:&

1. Weak(CL(bond(

2. Polarizable(CL(bond((

3. Leaving(group(that(can(accommodate(a(pair(of(electrons(

L



Leaving

group

pK a of

conjugate acid

Good Leaving Groups I ¯ Iodide -10

Br ¯ Bromide -9

Cl ¯ Chloride -7

RSO3 ¯ Sulfonate -6.5

H2O Water -1.7

Very Poor Leaving

Groups F ¯ Fluoride 3.2

HS ¯ Thiolate 7

¯ CN Cyanide 9.2

HO ¯ Hydroxide 15.7

RO ¯

Alkoxide 16-18H ¯ Hydride 35

¯ NH2 Amino 38

¯ CH3 Methyl 48



• How&can&iodide&be&a&good&nucleophile&and &a&good&leaving&group?&

• E a&for&RL&→&RI&&is&lower&than&for&RL&→&RCl&&»»&&Ij&is&a&beer&nucleophile&

• E a&for&RI&→&RL&&is&lower&than&for&RCl&→&RL&&»»&I&j&is&a&beer&leaving&group&

Reaction Coordinate

E n e r g

y



Nu ¯

Nu ¯

Polarizability of I¯ as a nucleophile

Polarizability of C-I bond: I¯ as a leaving group



Alkyl Substrates

Rate: methyl > 1° > 2° ( 3° unreactive)

Adjacent alkyl groups also slow the reaction

Me

Et

iPr

tBu



One-step (concerted) mechanism

Substrate: Methyl>1°>2°>>3°- Steric bulk hinders attack of Nu

Rate = k [substrate] [nucleophile]

Chirality- Inversion

Often performed in polar aprotic solvents, e.g., DMF

(Me2NCHO), DMSO (Me2SO) to dissolve substrate and ionic

reagent, and increase reaction rate

SUMMARY: FACTORS EFFECTING

SN2 REACTIONS

S:6.15;



• Prac9cal(Applica9ons(of(SN2(Reac9ons:(Func9onal(Group(

Transforma9ons(at(1o(and(2o(Carbons(source of nucleophile



Synthesis(of(Alkynes(and(Alkanes:(Alkyla9on(of(

Acetylide(Anions(



• Problem:&How&would&you&prepare&2Wphenylethanethiol&from&1WiodoW2W

phenylethane?&

• Problem:'How&would&you&make&the&following&compound&from&1W

bromopropane&and&any&other&starKng&materials?&



Problem:'Which'of'the'following'would'undergo'the'fastest'reac<on'with'1

bromopropane?'

• (a)&&&Ph3N&&&&or&&&&&&Ph3P&

• (b)&&1.0&M&CH3ONa&&&&&&or&&&&&&2.0&M&CH3ONa&



'''''''''''''''''''''''''''''''''''''front'''''''''''''''''''''back'

~ MAKE FLASHCARDS ~

Substrate&+&Reagent&

(and&condiKons)&

Reagent&(and&

condiKons)&and&

Product&

Substrate&&

and&Product&

Product(s)&

Substrate&

Reagents&(and&

condiKons)&



SUBSTITUTION(AT(3°(SUBSTRATES:(

UNIMOLECULAR(NUCLEOPHILIC(SUBSTITUTION(SN1)(

L S:6.9-6.13

tert WButyl&chloride&undergoes&subsKtuKon&with&hydroxide.&&The&rate&is&independent&of&

hydroxide&concentraKon&and&depends&only&on&concentraKon&of&tert Wbutyl&chloride.&&The&

rate&equaKon&is&first&order&with&respect&to&tertWbutyl&chloride&and&first&order&overall.&

SN1'reac<on:'SubsKtuKon,&nucleophilic,&1st&order&(unimolecular).&

The&rate&depends&only&on&the&concentraKon&of&the&alkyl&halide.&&Only&the&alkyl&halide&(and&

not&the&nucleophile)&is&involved&in&the&transiKon&state&of&the&step&that&controls&the&rate.&



Mul9step(Reac9ons(and(the(RateDetermining(Step(

In&mulKstep&reacKons,&the&rate&of&the&overall&reacKon&will&be&essenKally&the&same&as&the&

rate&of&the&slowest&step.&&This&is&called&the&rateWlimiKng&step&or&the&rateW&determining&step.&&In&the&case&below&k1<<k2&or&k3&and&the&first&step&is&rate&determining.&



A(Mechanism(

for(the(SN1(

Reac9on(

Step&1&is&rate&

determining&

(slow)&because&

it&requires&the&formaKon&of&

unstable&ionic&

products.&&In&

step&1&water&

molecules&help&

stabilize&the&

ionic&products.&



Carboca9ons(

A&carbocaKon&has&only&6&electrons,&is&sp2&hybridized&and&has&an&empty& p&orbital&

normal&to&the&caKonic&center&and&the&three&atoms&aached&to&this&center.&

The&more&alkyl&groups&aached&to&the&carbocaKonic&center&the&more&stable&the&

carbocaKon.&&The&more&stable&a&carbocaKon&is,&the&easier&it&is&to&form.&



Hyperconjuga<on&stabilizes&the&carbocaKon&by&donaKon&of&electrons&from&an&adacent&

β&carbonWhydrogen&or&carbonWcarbon&σ&bond&into&the&empty& p&orbital.&&&More&

subsKtuKon&provides&more&opportunity&for&hyperconugaKon.&



Kinetics"

Result: Rate = k [R-L] independent of concentration of Nu"

[t -Bu-Hal] [H-Nu:] relative rate"0.01 M " 0.01 M "1"0.02 M 0.01 M "2"0.01 M " 0.02 M "1"0.02 M " 0.02 M "2"



Solvolysis(

A&molecule&of&the&solvent&is&the&nucleophile&in&a&subsKtuKon&reacKon.&&If&the&solvent&is&

water&the&reacKon&is&a&hydrolysis.&&If&the&solvent&is&methanol&or&formic&acid,&the&reacKon&is&methanolysis&or&formolysis,&repecKvely.&

These&reacKons&arise&because&solvents&which&are&polar&enough&to&facilitate&dissociaKon&

of&the&substrate&are&also&nucleophilic.&




hen&the&leaving&group&leaves&from&a&stereogenic&center&of&an&opKcally&acKve&compound&in&an&SN1&reacKon&racemizaKon&will&occur.&&The&reason&is&that&an&achiral&

carbocaKon&intermediate&is&formed.&

Racemiza<on:&transformaKon&of&an&opKcally&acKve&compound&to&a&racemic&mixture.&



In'Class'Problem:'

Explain&the&following&observaKon.&&(S)W3WBromoW3Wmethylhexane&reacts&in&aqueous&acetone&to&give&racemic&3WmethylW3Whexanol.&



Factors(Affec9ng(the(Rate(of(SN1(and(SN2(Reac9ons(

The(Effects(of(the(Structure(of(the(Substrate &

(1) Structure&of&the&substrate.&

(2) ConcentraKon&and&reacKvity&of&the&nucleophile&(for&bimolecular&reacKons).&

(3) Effect&of&solvent.&

(4) Nature&of&the&leaving&group.&



Factors(Affec9ng(the(Rate(of(SN1(and(SN2(Reac9ons(

The(Effects(of(the(Structure(of(the(Substrate(

SN 2$Reac)ons:$

In&SN2&reacKons&alkyl&halides&show&the&following&general&order&of&reacKvity.&

Steric'hinderance:'the&spaKal&arrangement&of&the&atoms&or&groups&at&or&near&a&reacKng&

site&hinders&or&retards&a&reacKon.&&In&terKary&and&neopentyl&halides,&the&reacKng&carbon&is&too&sterically&hindered&to&react&at&an&appreciable&rate&by&the&SN2&mechanism.&



SN 1$reac)ons$

Organic&compounds&that&undergo&reacKon&by&an&SN1&path&at&a&reasonable&rate&are&those&

that&are&capable&of&forming&relaKvely&stable&carbocaKons&such&as&terKary&halides,&allyl&

halides&and&benzyl&halides.&

The$Hammond5Leffler$Postulate$

The&transiKon&state&for&an&exergonic&reacKon&looks&very&much&like&starKng&material.&&The&

transiKon&state&for&an&endergonic&reacKon&looks&very&much&like&product.&&Generally&the&

transiKon&state&looks&most&like&the&species&it&is&closest&to&in&energy&



In&the&first&step&of&the&SN1&reacKon&the&transiKon&state&looks&very&much&like&

carbocaKon&intermediate.&&The&carbocaKonWlike&transiKon&state&is&stabilized&by&all&the&

factors&that&stabilize&carbocaKons.&&The&transiKon&state&leading&to&terKary&

carbocaKons&is&much&more&stable&and&lower&in&energy&than&transiKon&states&leading&

to&other&carbocaKons&such&as&secondary&carbocaKons.&

Vinylic(and(phenyl(halides&are&generally&unreacKve&in&SN1&and&SN2&reacKons.&



The(Effects(of(the(Concentra9on(and(Strength(of(

Nucleophile(S

N1(Reac9on:(

Rate&does(not(depend(on(the(iden9ty(or(concentra9on(of(nucleophile(

SN2(Reac9on:(

Rate&is&directly(propor9onal(to(the(concentra9on(of(nucleophile.&&Stronger&

nucleophiles&also&react&faster.&&A&negaKvely&charged&nucleophile&is&always&more&

reacKve&than&its&neutral&conugate&acid.&&hen&comparing&nucleophiles&with&the&same&

nucleophilic&atom,&nucleophiliciKes&parallel&basiciKes.&

Methoxide&is&a&much&beer&nucleophile&than&methanol.&



Solvent(Effects(on(SN2(Reac9ons:(

Polar(Pro9c(and(Apro9c(Solvents(

Polar(Pro9c(Solvents:(Polar&solvents&that&have(a(hydrogen(atom(aached&to&strongly&

electronegaKve&atoms.&&They&solvate&nucleophiles&and&make&them&less&reacKve.&

Larger&nucleophilic&atoms&are&less&solvated&and&therefore&more&reacKve&in&polar&proKc&

solvents.&&Larger&nucleophiles&are&also&more&polarizable&and&can&donate&more&electron&

density.&

RelaKve&nucleophilicity&in&polar&solvents:&



Polar(Apro9c(Solvents:(Polar&aproKc&solvents&do(not(have(a(hydrogen &aached&to&an&

electronegaKve&atom.&

They&solvate&caKons&well&but&leave&anions&relaKvely&unsolvated.&

Polar&proKc&solvents&lead&to&generaKon&of&“naked”&and&very&reacKve&nucleophiles.&&

Trends&for&nucleophilicity&are&oen&the&same&as&for&basicity.&&They&are&excellent&solvents&

for&SN2&reacKons.&



Solvent(Effects(on(SN1(Reac9ons:(

The(Ionizing(Ability(of(the(Solvent(

Polar&proKc&solvents&are&excellent&solvents&for&SN1&reacKons.&&Polar&proKc&solvents&

stabilize&the&carbocaKonWlike&transiKon&state&leading&to&the&carbocaKon&thus&lowering&

ΔG‡.&&In&order&to&increase&the&solubility&of&alkyl&halides&mixed&solvent&systems&are&oen&

used.&&aterWethanol&and&waterWmethanol&mixtures&are&most&common&solvent&

mixtures.&



The(Nature(of(the(Leaving(Group(

The&best(leaving(groups(are&weak(bases(which(are(rela9vely(stable.&&&

The&leaving&group&can&be&an&anion&or&a&neutral&molecule.&

Leaving&group&ability&of&halides:&

This&trend&is&opposite&to&basicity:&

Other&very&weak&bases&which&are&good&leaving&groups:&

The&poor&leaving&group&hydroxide&can&be&changed&into&the&good&leaving&group&water&by&protonaKon.&



SN2

One-step (concerted) mechanism

Substrate: Methyl>1°>2°>>3°

- Steric bulk hinders attack of Nu

Rate = k [substrate] [nucleophile]

Chirality- Inversion

Often performed in polar aproticsolvents, e.g., DMF (Me2NCHO), DMSO

(Me2SO) to dissolve substrate and ionic

reagent, and increase reaction rate

SN1

Dissociation-Nucleohipic addition-Deprotonation

Substrate: 3°>2°>>1°or methyl

- Stability of carbocation intermediate

Rate = k [substrate]

- independent of [nucleophile] - rate depends on solvent polarity

Chirality

- racemization

Generally only useful for solvolyses

(reactions with H2O, ROH, RCO2H)

SUMMARY: FACTORS EFFECTING

SN1 AND SN2 REACTIONS

S:6.15;



Summary(SN1(vs.(SN2(

In&both&SN2&and&SN1&reacKons&alkyl&iodides&react&the&fastest&than&alkyl&bromides&which&

react&faster&than&alkyl&chlorides&because&iodide&is&a&leaving&group&than&bromide&which&is&beer&than&chloride.&



In'Class'Problems:'

For&each&of&the&following&pairs&of&reacKons,&predict&which&one&is&faster&and&

explain&why.&



Alcohols(as(Acids(

Alcohols&have&acidiKes&similar&to&water.&&Sterically&hindered&alcohols&such&as&tert Wbutyl&

alcohol&are&less&acidic&(have&higher&pa&values).&&hy?:&The&conugate&base&is&not&well&solvated&and&so&is&not&as&stable.&

Alcohols&are&stronger&acids&than&terminal&alkynes&and&primary&or&secondary&amines.&

An&alkoxide&can&be&prepared&by&the&reacKon&of&an&alcohol&with&sodium&or&potassium&

metal.&

S:11.6-11.9



Conversion(of(Alcohols(into(Alkyl(Halides(

Hydroxyl&groups&are&poor&leaving&groups,&and&as&such,&are&oen&converted&to&a&group&

that&can&depart&as&a&weak&base;&hydroxyl&groups&are&converted&to&good&leaving&groups.&Three'general'methods&exist&for&conversion&of&alcohols&to&alkyl&halides,&depending&on&

the&classificaKon&of&the&alcohol&and&the&halogen&desired.&&ReacKon&can&occur&with&

hydrogen&halides,&phosphorus&tribromide,&or&thionyl&chloride.&



Alkyl(Halides(from(the(Reac9on(of(Alcohols(

with(Hydrogen(Halides(

The&order&of&reacKvity&is&as&follows:&HI&&>&&HBr&&>&&HCl&>&HF.&&Type&of&alcohol&3o&>&2o&>&1o&<&

methyl.&

Mechanism'of'the'Reac<on'of'Alcohols'with'HX:&&SN1&mechanism&for&3o,&2o,&allylic&and&

benzylic&alcohols.&&These&reacKons&are&prone&to&carbocaKon&rearrangements.&

In&Step'1&the&hydroxyl&is&converted&to&a&good&leaving&group&by&protonaKon&to&form&the&

corresponding&oxonium&ion.&

In&Step'2&the&leaving&group&departs&as&a&water&molecule,&leaving&behind&a&carbocaKon&



In&Step'3&the&halide,&a&relaKvely&good&nucleophile,&reacts&with&the&carbocaKon.&

Primary&and&methyl&alcohols&undergo&subsKtuKon&by&an&SN2&mechanism.&

Primary&and&secondary&chlorides&can&only&be&made&with&the&assistance&of&a&Lewis&acid&

such&as&zinc&chloride.&



In'Class'Problem:'

Outline&a&reasonable&mechanism&for&the&following&reacKon:&



Alkyl(Halides(from(the(Reac9on(of(Alcohols(with(

PBr3(and(SOCl2(

These&reagents&only&react&with&1o&and&2o&alcohols&by&means&of&an&SN2&mechanism.&&In&

each&case&the&reagent&converts&the&hydroxyl&to&an&excellent&leaving&group.&&No&

rearrangements&are&seen.&

Reac<on'of'phosphorous'tribromide'to'give'alkyl'bromides:'



Oen&an&amine&is&added&to&react&with&HCl&formed&in&the&reacKon.&

Mechanism:'

Reac<on'of'thionyl'chloride'to'give'alkyl'chlorides:'



Tosylates,(Mesylates,(and(Triflates:(

Leaving(Group(Deriva9ves(of(Alcohols&

The&hydroxyl&group&of&an&alcohol&can&be&converted&to&a&good&leaving&group&by&conversion&

to&a&sulfonate&ester.&

Sulfonyl&chlorides&are&used&to&convert&alcohols&to&sulfonate&esters.&&Base&is&added&to&react&

with&the&HCl&generated.&



A&sulfonate&ion&(a&weak&base)&is&an&excellent&leaving&group.&

If&the&alcohol&hydroxyl&group&is&at&a&stereogenic&center&then&the&overall&reacKon&with&the&

nucleophile&proceeds&with&inversion&of&configuraKon.&&The&reacKon&to&form&a&sulfonate&

ester&proceeds&with&retenKon&of&configuraKon.&

Triflate&anion&is&such&a&good&leaving&group&that&even&vinyl&triflates&can&undergo&SN1&

reacKon.&



In'Class'Problem:'

Draw&the&configuraKons&of&the&products&when&(R)W1Wphenylethanol&is&first&reacted&

with&pWtoluenesulfonyl&chloride&followed&by&reacKon&with&potassium&acetate.&

S:11 11 12



Synthesis(of(Ethers(

(1)&Ethers'by'Intermolecular'Dehydra<on'of'Alcohol:''Primary&alcohols&can&dehydrate&to&

ethers.&&This&reacKon&occurs&at&lower&temperature&than&the&compeKng&dehydraKon&to&

an&&alkene.&&This&method&generally&does&not&work&with&secondary&or&terKary&alcohols&because&eliminaKon&dominates.&

The&reacKon&proceeds&by&an&SN2&mechanism:&

S:11.11-12



(2)&Williamson'Ether'Synthesis:&This&is&a&good&route&for&synthesis&of&unsymmetrical&ethers.&

The&alkyl&halide&(or&alkyl&sulfonate)&should&be&primary&to&avoid&an&E2&reacKon.&&

SubsKtuKon&is&favored&over&eliminaKon&at&lower&temperatures.&



(3)&Silyl'Ether'Protec<ng'Groups:'Silyl&ethers&are&widely&used&protecKng&groups&for&

alcohols.&&The&tert Wbutyl&dimethysilyl&(TBDMS)&ether&is&a&common&protecKng&group.&&The&

protecKng&group&is&introduced&by&reacKon&of&the&alcohol&with&the&appropriate&

chlorosilane&&in&the&presence&of&an&aromaKc&amine&base&such&as&imidazole&or&pyridine.&&&

The&silyl&ether&protecKng&group&is&easily&removed&by&treatment&with&fluoride&ion&(e.g.&

from&tetrabutyl&ammonium&fluoride).&



Reac9ons(of(Ethers(

Acyclic&ethers&are&generally&unreacKve,&except&for&cleavage&by&very&strong&acids&to&

form&the&corresponding&alkyl&halides.&&Dialkyl&ethers&undergo&sequenKal&SN2&reacKons&with&HBr&to&form&2&equivalents&of&the&alkyl&bromide.&



Intramolecular(SN2(Reac9ons(

Epoxides&are&threeWmembered&ring&cyclic&ethers.&&These&groups&are&also&called&

oxiranes.&&They&can&be&prepared&by&an&intramolecular&SN2&reacKon.&

Intramolecular&subsKtuKons&oen&results&in&the&formaKon&of&rings.&



Reac9on(of(Epoxides(

Epoxides&are&considerably&more&reacKve&than&regular&ethers.&&The&threeWmembered&

ring&is&highly&strained&and&therefore&very&reacKve.&& Acidcatalyzed'opening'of'an'epoxide&occurs&by&iniKal&protonaKon&of&the&epoxide&oxygen,&making&the&epoxide&even&

more&reacKve.&&AcidWcatalyzed&hydrolysis&of&an&epoxide&leads&to&a&1,2Wdiol.&



In&unsymmetrical&epoxides,&the&acid&catalyzed&ring&opening&reacKon&usually&proceeds&

through&the&most&stable&incipient&carbocaKon;&the&nucleophile&aacks&primarily&at&the&

most&subsKtuted&carbon&of&the&epoxide.&&&

Basecatalyzed'reac<on&with&strong&nucleophiles&(e.g.&an&alkoxide&or&hydroxide)&occurs&

by&an&SN2&mechanism.&&The&nucleophile&aacks&at&the&least&sterically&hindered&carbon&of&the&epoxide.&

Problem: How would you prepare 2-phenylethanethiol from 2-phenyl-1-



Problem: How would you prepare 2-phenylethanethiol from 2-phenyl-1-

ethanol?

Problem: How would you make the following product from 1-propanol and

any other starting materials?

S:4.16,



Homolysis(and(Radicals(Revisited(

HomolyKc&bond&cleavage&leads&to&the&formaKon&of&radicals&(also&called&free&radicals).&&

Radicals&are&highly&reacKve,&shortWlived&species.&&SingleWbarbed&arrows&are&used&to&show&

the&movement&of&single&electrons.&

Produc<on'of'Radicals:&&Homolysis&of&relaKvely&weak&bonds&such&as&OWO&or&XWX&bonds&

can&occur&with&addiKon&of&energy&in&the&form&of&heat&or&light.&

Reac<ons'of'Radicals:&Radicals&tend&to&react&in&ways&that&lead&to&pairing&of&their&

unpaired&electron.&&Hydrogen&abstracKon&is&one&way&a&halogen&radical&can&react&to&pair&

its&unshared.&&

,

10.2-10.6



Homoly<c'Bond'Dissocia<on'Energies:&Atoms&have&higher&energy&(are&less&stable)&than&

the&molecules&they&can&form.&&The&formaKon&of&covalent&bonds&is&exothermic.&&Breaking&

covalent&bonds&requires&energy&(i.e.&is&endothermic).&

The&homolyKc&bond&dissociaKon&energy&is&abbreviated&DHo.&

Homoly<c'Bond'Dissocia<on'Energies'and'Heats'of'Reac<on:&HomolyKc&bond&dissociaKon&energies&can&be&used&to&calculate&(esKmate)&the&enthalpy&change&(ΔHo)&for&a&

reacKon.&&DHo&is&posiKve&for&bond&breaking&and&negaKve&for&bond&forming.&

Example:&&

This&reacKon&below&is&highly&exothermic&since&ΔHo&is&a&large&and&negaKve.&&ΔHo&is&not&

dependant&on&the&mechanism;&only&the&iniKal&and&final&states&of&the&molecules&are&

considered&in&determining&ΔHo.&



Homoly<c'Bond'Dissocia<on'Energies'and'the'Rela<ve'Stabili<es'of'Radicals:'The&

formaKon&of&different&radicals&from&the&same&starKng&compound&offers&a&way&to&esKmate&

relaKve&radical&stabiliKes.&

Examples:'

The&propyl&radical&is&less&stable&than&the&isopropyl&radical.&

Likewise&the&tert Wbutyl&radical&is&more&stable&than&the&isobutyl&radical.&

The energy diagrams for these reacKons are shown below



The&energy&diagrams&for&these&reacKons&are&shown&below.&

The&rela<ve'stabili<es'of'radicals&follows&the&same&trend&as&for&carbocaKons.&&The&most&

subsKtuted&radical&is&most&stable.&&Radicals&are&electron&deficient,&as&are&carbocaKons,&and&are&therefore&also&stabilized&by&hyperconugaKon.&



In'Class'Problem:'

List&the&following&organic&radicals&in&the&order&of&increasing&stability.&



Radical(Subs9tu9ons:(

The(Reac9ons(of(Alkanes(with(Halogens(

Alkanes&undergo&subsKtuKon&reacKons&with&halogens&such&as&fluorine,&bromine&and&chlorine&in&the&presence&of&heat&or&light.&

Mul<ple'Subs<tu<on'Reac<ons'versus'Selec<vity:''Radical&halogenaKon&can&yield&a&

mixture&of&halogenated&compounds&because&all&hydrogen&atoms&in&an&alkane&are&

capable&of&subsKtuKon.&&In&the&reacKon&above&all&degrees&of&methane&halogenaKon&will&

be&seen.&&MonosubsKtuKon&can&be&achieved&by&using&a&large&excess&of&the&alkane.&&A&large&excess&of&methane&will&lead&to&predominantly&monohalogenated&product&and&

excess&unreacted&methane.&



ChlorinaKon&of&higher&alkanes&leads&to&mixtures&of&monochlorinated&product&(and&more&

subsKtuted&products).&&Chlorine&is&relaKvely&unselec<ve&and&does&not&greatly&disKnguish&

between&type&of&hydrogen.&&

Molecular&symmetry&is&important&in&determining&the&number&of&possible&subsKtuKon&products.&

Bromine&is&less&reacKve&but&more&selecKve&than&chlorine&(Sec.&10.6A).&



Selec<vity'of'Chlorine:'MonochlorinaKon&of&alkanes&proceeds&to&give&some&selecKvity.&&

TeriKary&hydrogens&are&somewhat&more&reacKve&than&secondary&hydrogens&which&are&more&reacKve&than&primary&hydrogens.&&E act&for&abstracKon&of&a&terKary&hydrogen&is&lower&

because&of&increased&stability&of&the&intermediate&terKary&radical.&&The&differences&in&rate&

of&abstracKon&are&not&large&and&chlorinaKon&occurs&so&rapidly&it&cannot&disKnguish&well&

between&classes&of&hydrogen&and&so&is&not&very&selecKve.&



Selec<vity'of'Bromine:&Bromine&is&much&less&reacKve&but&more&selecKve&than&chlorine&in&radical&halogenaKon.&&Fluorine&shows&almost&no&discriminaKon&in&replacement&of&

hydrogens&because&it&is&so&reacKve.&

Chl i 9 f h h i f 9



Chlorina9on(of(Methane:(Mechanism(of(Reac9on(

The&reacKon&mechanism&has&three&disKnct&aspects:&(1)&chain&iniKaKon,&(2)&chain&

propagaKon&and&(3)&chain&terminaKon.&

Chain'ini<a<on:'

Chlorine&radicals&form&when&the&reacKon&mixture&is&subected&to&heat&or&light.&&Chlorine&

radicals&are&used&in&the&chain&propagaKon&steps&below.&

Chain'propaga<on: &&

A&chlorine&radical&reacts&with&a&molecule&of&methane&to&generate&a&methyl&radical.&&A&

methyl&radical&reacts&with&a&molecule&of&chlorine&to&yield&chloromethane&and&regenerate&

chlorine&radical.&&A&chlorine&radical&reacts&with&another&methane&molecule,&conKnuing&the&

chain&reacKon.&&A&single&chlorine&radical&can&lead&to&thousands&of&chain&propagaKon&cycles.&



Chain'reac<on:'a&stepwise&mechanism&in&which&each&step&generates&the&reacKve&

intermediate&that&causes&the&next&cycle&of&the&reacKon&to&occur.&

Chain'termina<on:'

Occasionally&the&reacKve&radical&intermediates&are&quenched&by&reacKon&pathways&that&

do&not&generate&new&radicals.&&The&reacKon&of&chlorine&with&methane&requires&constant&

irradiaKon&to&replace&radicals&quenched&in&chainWterminaKng&steps.&

h K h i i h b l



The&enKre&mechanism&is&shown&below.&

Chl i < f M h E Ch



Chlorina<on'of'Methane:'Energy'Changes &&

The&chain&propagaKon&steps&have&overall&ΔHo=&W101&kJ&molW1&and&are&highly&exothermic.&

R 9 f M th ith Oth H l



Reac9on(of(Methane(with(Other(Halogens(

The&order&of&reacKvity&of&methane&subsKtuKon&with&halogens&is:&fluorine&&>&chlorine&>&

bromine&>&iodine.&&The&order&of&reacKvity&is&based&on&the&values&of&E act&

for&the&first&step&of&

chain&propagaKon&and&ΔHo&for&the&enKre&chain&propagaKon.&&FluorinaKon&has&a&very&low&

value&for&E act&in&the&first&step&and&ΔHo&is&extremely&exothermic&therefore&fluorinaKon&

reacKons&are&explosive.&&ChlorinaKon&and&brominaKon&have&increasingly&higher&values&of&

E act&and&lower&overall&ΔHo&values&which&makes&these&halogenaKon&reacKons&less&vigorous.&&

IodininaKon&has&a&prohibiKvely&high&value&for&E act&of&the&first&step&and&the&reacKon&does&not&

occur.&&The&energy&values&of&the&iniKaKon&step&are&unimportant&since&they&occur&so&rarely.&

On&the&basis&of&ΔHo&&values&for&the&iniKaKon&step&iodinaKon&should&be&most&rapid.&



R 9 th t G t T t h d l



Reac9ons(that(Generate(Tetrahedral(

Stereogenic(Carbons(

A&reacKon&of&achiral&starKng&materials&which&produces&a&product&with&a&stereogenic&carbon&will&produce&a&racemic&mixture.&

Genera9on of a Second Stereogenic Carbon in a



Genera9on(of(a(Second(Stereogenic(Carbon(in(a(

Radical(Halogena9on(

hen&a&molecule&with&one&or&more&stereogenic&carbons&undergoes&halogenaKon&to&create&another&stereogenic&carbon,&the&two&diastereomeric&products&are&not&produced&

in&equal&amounts.&&The&intermediate&radical&is&chiral&and&reacKons&on&the&two&faces&of&

the&radical&are&not&equally&probable.&

L



SUBSTITUTIONS(IN(SYNTHESIS(

You should prepare a chart of all of the types of reactions that have beencovered so far…

….we’ll add more later.

S:4.18-19



It is important to recognize transformations which can be performed in a

single step. Use the thought process:

- What can the product can be made from?

PRODUCT STARTING MATERIAL

- The synthesis itself is

STARTING MATERIAL → PRODUCT

ONE-STEP SYNTHESES

• SN&reacKons&allow&for&interconversions&of&funcKonal&groups,&which&will&be&useful&in&

f h f ld h f ll l ?



further&transformaKons.&How&would&you&prepare&the&following&nitrile?&

• & & & &

• SN2&reacKons&are&also&useful&in&preparing&larger&molecules&from&smaller&molecules&

b lk l K f lid i Th lK lk b f d i



by&alkylaKon&of&acetylide&anions.&The&resulKng&alkyne&can&be&transformed&into&

other&compounds.&How&would&you&prepare&the&following&alkyne&from&starKng&

materials&with&7&or&fewer&carbon&atoms?&

• & & & & &

An important limitation on acid catalyzed SN reactions



tert -Butanol must be protonated to make the hydroxyl group a better leaving

group. Ammonia is nucleophilic

So why doesn’t this reaction work?

Why can’t you do this sequentially? i.e.,

Acid promoted SN 2 reactions are limited to cases where the nucleophile is very weakly basic (i.e., reaction with H-Hal). For other nucleophiles, convert the

alcohol to the tosylate or mesylate first.

The role of nucleophilicity, leaving group ability, and substrate on SN processes.

Whi h f th f ll i d ffi i tl ?



Which of the following proceed efficiently?

What about secondary alkyl halides?



1° R-L:

3° R-L:

2° R-L: might display features of both SN1 and SN2 reactions (!)

Under conditions strongly favoring SN1 reactions ⇒ SN1

(polar solvent, poor nucleophile)

Under conditions strongly favoring SN2 reactions ⇒ SN2….

(good nucleophile)

…..but strongly basic nucleophiles promote elimination! (see Topic 7)

What about vinyl halides and aryl halides?



TOPIC 6 ON EXAM 3

Types of Questions

- Recognize factors which influence the mechanism of nucleophilic andradical substitutions

- Predict outcomes of substitution reactions

- Design short syntheses

- The problems in the book are good examples of the types of problems onthe exam.

Preparing for Exam 3

- Work as many problems as possible.

- Work in groups.- Do the “Learning Group Problem” at the end of the chapter.

- Work through the practice exams

REVIEW PROBLEMS



Problem: Why does the following reaction not take place?

CH3CH2CH3 + HO— CH3CH2CH2OH + H—

REVIEW PROBLEMS

Problem: Explain why reaction of 1-bromopropane with potassium

cyanide gives a mixture of CH CH CH CN (major product) and



cyanide gives a mixture of CH3CH2CH2CN (major product) and

CH3CH2CH2NC (minor)? Draw Lewis structures of the products and

nucleophiles.

Problem: How can you prepare the following two compounds from the

appropriate alkyl bromide?



appropriate alkyl bromide?

(a) Methyl phenyl ether, Me-O-Ph

(b) (S)-2-Pentanol, CH3CH(OH)CH2CH2CH3

• Problem:'How&could&you&perform&the&following&synthesis?&[An'introduc<on'to designing mul<step syntheses]



to'designing'mul< step'syntheses]'

• ''''

• '''''''''''''''''''''''''''''''''''''''''''''''from'

Problem: Predict the structure of the product of the following reaction



I Cl P bl



In'Class'Problems:'

Designate&the&nucleophile,&the&electrophile,&and&the&leaving&group&for&each&of&

the&following&reacKons.&



In'Class'Problem:'

(1) Draw&the&stereochemical&structures&for&the&reactant&and&product&for&the&

reacKon&of&(S)W2Wchloropentane&with&chlorine.&(2) Indicate&the&stereochemical&configuraKon&at&each&of&the&chiral&carbons&in&the&

products.&

(3) Are&the&products&opKcally&acKve?&

(4) Can&the&products&be&separated&by&convenKonal&means?&

topic+6+ substitutions

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