State University of New York at Albany State University of New York at Albany

Alkyl HalidesAlkyl Halides

Nucleophilic Substitution and Nucleophilic Substitution and EliminationElimination

Nomenclature of Alkyl HalidesNomenclature of Alkyl Halides Name halogen as substituent on alkane or Name halogen as substituent on alkane or

cylcoalkane.cylcoalkane. Learn common names for some of the simple Learn common names for some of the simple

structures. e.g. chloroform, methylene chloride.structures. e.g. chloroform, methylene chloride. Note degree of substitution - name as type of C Note degree of substitution - name as type of C

it is bonded to (i.e. 1it is bonded to (i.e. 100, 2, 200, 3, 300).). Geminal (Geminal (gem-gem-) dihalide has two halogen atoms ) dihalide has two halogen atoms

bonded to the same carbon. bonded to the same carbon. Vicinal (Vicinal (vic-vic-) dihalide has two halogens bonded ) dihalide has two halogens bonded

to adjacent carbons.to adjacent carbons.Do problem 6-1, 6-2 and 6-3 of the textDo problem 6-1, 6-2 and 6-3 of the text..

CH3CH2CBr2CH2CH2CH3(CH3)2CHCCH3

CH3

Br

Cl

Br

CH3

CH(CH3)2

I

Cl

Cl

H

CH3

Example Problems:Example Problems:

Uses and General ChracteristicsUses and General Chracteristics BOND DIPOLE (BOND DIPOLE (): ): + at C, + at C, - at X- at X

» all reactions based on this.all reactions based on this.

» The bond dipole moments increase in the order: The bond dipole moments increase in the order: CC—I < C—Br < C—F < C—Cl—I < C—Br < C—F < C—Cl

Physical propertiesPhysical properties» generally, trends are similar to those seen in generally, trends are similar to those seen in

alkanes.alkanes.» bp affected by London forces and dipole-dipole bp affected by London forces and dipole-dipole

attractions.attractions. Common uses: solvents, anesthetics, freons Common uses: solvents, anesthetics, freons

(refrigerants), pesticides. (refrigerants), pesticides.

Preparation of alkyl & allylic Preparation of alkyl & allylic halideshalides

Free radical halogenation of alkanes (Chpt 4)Free radical halogenation of alkanes (Chpt 4)

You are expected to know the mechanism by You are expected to know the mechanism by which this transformation takes place.which this transformation takes place.

Br2

h

Br

Free radical halogenation of alkenes at allylic Free radical halogenation of alkenes at allylic positionposition

need to know resonance structures for need to know resonance structures for intermediate & predict major/minor productintermediate & predict major/minor product

Br2

h

NBS

h+

BrBr

OR

Preparation of Alkyl HalidesPreparation of Alkyl Halides

See pages 235-236 of the text. Do problems 6-8 and 6-9.See pages 235-236 of the text. Do problems 6-8 and 6-9.

Nucleophilic Substitution (SNucleophilic Substitution (SNN))

R—LG + Nuc: R—LG + Nuc: R—Nuc + LG: R—Nuc + LG:

SubstrateSubstrate Reagent/Nucleophile (Nuc)Reagent/Nucleophile (Nuc) Leaving Group (LG)Leaving Group (LG) Solvent/Reaction ConditionsSolvent/Reaction Conditions

Br OH+ HO

solvent

1. Identify electrophilic carbon in substrate1. Identify electrophilic carbon in substrate

2. Identify nucleophilic electrons in nucleophile2. Identify nucleophilic electrons in nucleophile

3. Identify leaving group in substrate3. Identify leaving group in substrate

Then draw product(s)Then draw product(s)

4. Draw substrate without LG but with bond4. Draw substrate without LG but with bond

5. Add Nuc to bond where LG used to be5. Add Nuc to bond where LG used to be

OH

Factors influencing what Factors influencing what products are formedproducts are formed

Substrate/steric effectsSubstrate/steric effects Strength of nucleophile vs. basicity of Strength of nucleophile vs. basicity of

nucleophilenucleophile Stability of leaving groupStability of leaving group Reaction conditionsReaction conditions

» Polarity of solventPolarity of solvent» acidic/neutral/basicacidic/neutral/basic

Substitution MechanismsSubstitution Mechanisms Continuum of possible mechanismsContinuum of possible mechanisms

Mechanism determined primarily by Mechanism determined primarily by substrate steric effectssubstrate steric effects

SSNN2 - methyl, 1º & unhindered 2º2 - methyl, 1º & unhindered 2º

SSNN1 - 3º, hindered 2º1 - 3º, hindered 2º

LGNuc + LG

Bimolecular (SBimolecular (SNN2) Nucleophilic 2) Nucleophilic

SubstitutionSubstitution concerted reaction; Nuc attacks, LG leaves concerted reaction; Nuc attacks, LG leaves pentacoordinate carbon in transition statepentacoordinate carbon in transition state rate depends on conc. of rate depends on conc. of bothboth reactants reactants Me = methyl group; Et = ethyl groupMe = methyl group; Et = ethyl group

Et

BrHMe

HOEt

HMeBrHO

(S)-2-bromobutane

Reaction is “stereospecific”Reaction is “stereospecific” 100 % inversion of configuration100 % inversion of configuration

Et

HMeBrHO

Et

HO MeH + Br

(R)-2-butanol

You should know how to represent this You should know how to represent this mechanism in an energy diagram!!mechanism in an energy diagram!!

Factors that Affect SFactors that Affect SNN2 Reaction 2 Reaction

RatesRates Strength of NucleophileStrength of Nucleophile: species with negative charge : species with negative charge

is a stronger nuc than an analogous neutral species is a stronger nuc than an analogous neutral species (e.g. (e.g. --OH > HOH > H22O; O; --NHNH22 > NH > NH33).).

Nucleophilicity Nucleophilicity increases from left to right across the increases from left to right across the periodic chart (e.g. periodic chart (e.g. --OH > OH > --F).F).

Nucleophilicity increased down the periodic table Nucleophilicity increased down the periodic table (I(I- - > Br> Br- - > Cl> Cl- - > F> F--) or () or (--SeH > SeH > --SH > SH > --OH).OH).

SolventSolvent: Polar protic solvents (e.g. ethanol, ammonia : Polar protic solvents (e.g. ethanol, ammonia decrease nucleophilicity. Polar aprotic solvents e.g. decrease nucleophilicity. Polar aprotic solvents e.g. (acetonitrile, DMSO, acetone) increase nucleophilicity.(acetonitrile, DMSO, acetone) increase nucleophilicity.

Steric EffectsSteric Effects: When bulky groups interfere with a rxn. : When bulky groups interfere with a rxn. because of their size, this is called steric hindrance. because of their size, this is called steric hindrance. Steric hindrance affects nucleophilicity, not basicity. (e.g. Steric hindrance affects nucleophilicity, not basicity. (e.g. ethoxide ion is a stronger base than ethoxide ion is a stronger base than tt-butoxide ion). Also, -butoxide ion). Also, alkyl halide reactivity decreases from methyl to 1alkyl halide reactivity decreases from methyl to 100 to 2 to 200 to to 3300. In fact, 3. In fact, 300 alkyl halides do not react by S alkyl halides do not react by SNN2.2.

Leaving groupLeaving group: The substrate should have a good : The substrate should have a good leaving group. A good leaving group should be electron leaving group. A good leaving group should be electron withdrawing, relatively stable, and polarizable. They are withdrawing, relatively stable, and polarizable. They are weak bases. Examples are Clweak bases. Examples are Cl--, Br, Br--, I, I--, RSO, RSO33

--, RSO, RSO44--, ,

RPORPO44--, and neutral molecules such as water, alcohols , and neutral molecules such as water, alcohols

and amines. Strong bases (OHand amines. Strong bases (OH--, RO, RO--, H, H22NN--) are not good ) are not good

leaving groups!leaving groups!

Factors that affect SFactors that affect SNN2 reaction rates2 reaction rates

Unimolecular (SUnimolecular (SNN1) 1)

Nucleophilic SubstitutionNucleophilic Substitution Two-step reactionTwo-step reaction

» LG leaves, then Nuc: attacksLG leaves, then Nuc: attacks Tricoordinate carbocation intermediate Tricoordinate carbocation intermediate Solvolysis (when solvent is also the Solvolysis (when solvent is also the

nucleophile = Snucleophile = SNN1 reaction1 reaction Rate depends on substrate conc. onlyRate depends on substrate conc. only

(CH3)3C (CH3)3C Br+

(CH3)3C O-CH3

H

(CH3)3C O

H

CH3

(slow)

(fast)

(CH3)3C O

H

CH3 OH CH3+ (CH3)3C O CH3

+ OH CH3

H

(CH3)3C-Br +CH3OH (CH3)3C O CH3 +

Br

CH3OH

step 1

step 2

step 3

Mechanism of SMechanism of SNN1 reaction1 reaction

You must be able to represent this on an energy diagram!You must be able to represent this on an energy diagram!

Reaction Not StereoselectiveReaction Not StereoselectiveUnless Steric Factors ApplyUnless Steric Factors Apply

Racemization - not always exactly 50/50. Racemization - not always exactly 50/50. Carbocation can be attacked from the top or Carbocation can be attacked from the top or bottom face giving both enantiomers.bottom face giving both enantiomers.

Steric hindrance gives attack at one side Steric hindrance gives attack at one side preferentiallypreferentially

Longer-lived carbocations give more Longer-lived carbocations give more racemization, shorter-lived give more inversionracemization, shorter-lived give more inversion

Factors Influencing SFactors Influencing SNN1 1

Reaction RatesReaction Rates Stability of the carbocation*Stability of the carbocation*Allylic 3° >> 3° Allylic 3° >> 3° allylic 2° > 2° allylic 2° > 2° allylic 1° >> 1° > Me allylic 1° >> 1° > Me

Carbocations are stabilized by alkyl groups (through Carbocations are stabilized by alkyl groups (through hyperconjugation and the inductive effect) and by hyperconjugation and the inductive effect) and by resonance.resonance.

Leaving group stability: the better the leaving group, Leaving group stability: the better the leaving group, the faster the reaction.the faster the reaction.

Solvent polarity: the reaction is favored in polar Solvent polarity: the reaction is favored in polar protic solvents.protic solvents.

** must have neutral to acidic conditions to form must have neutral to acidic conditions to form carbocationcarbocation

Rearrangement of CarbocationsRearrangement of Carbocations Large difference in energy (stability) of 3° Large difference in energy (stability) of 3° vsvs. .

2° C+2° C+ HH- - (hydride) or R(hydride) or R-- will shift (migrate) to adjacent will shift (migrate) to adjacent

position to form more stable carbocation. E.g. position to form more stable carbocation. E.g. when neopentyl bromide is boiled in methanol, when neopentyl bromide is boiled in methanol, only rearranged product is formed.only rearranged product is formed.

CH3 C C CH3

H CH3

H

CH3 C C CH3

H CH3

H

secondary carbocation tertiary carbocation

Elimination ReactionsElimination Reactions

May proceed by a unimolecular (May proceed by a unimolecular (E1E1) or ) or bimolecular (bimolecular (E2E2) mechanism.) mechanism.

In an alkyl halide, when a halide ion leaves In an alkyl halide, when a halide ion leaves with another atom or ion, the reaction is an with another atom or ion, the reaction is an eliminationelimination..

If the halide ion leaves with HIf the halide ion leaves with H++, the reaction , the reaction is called a is called a dehydrohalogenation.dehydrohalogenation.

Elimination MechanismsElimination Mechanisms Mechanism determined primarily by Mechanism determined primarily by

substrate steric effectssubstrate steric effects

2o, hindered 1o, or bulky strong base

3o, -branched 2o

E2 E1

H

LG

B:

LG

H

BrC

H3C CHH

step 1 - same as for SN1

CH3H

H3C CCHH

CH3H

step 2

H3C CC

HCH3

H

CH3OH +major

+CH3OH2+

EE11 mechanism mechanism

E1 & SE1 & SNN11 CompetitionCompetition

AlwaysAlways» by definition a nucleophile is Lewis Baseby definition a nucleophile is Lewis Base

Br

H

NaOEt

EtOH+

OEt

Elimination Substitution

Carbocations generally Carbocations generally always give both productsalways give both products

Relative amounts not easily Relative amounts not easily predictablepredictable

Always assume formed in Always assume formed in approximately equal amountsapproximately equal amounts

E2E2 is Stereospecific is Stereospecific anti-coplanar elimination of H and LGanti-coplanar elimination of H and LG

H

Br

B:

HBr

B:

+ HBr

Product Distribution in E2Product Distribution in E2 Seytzeff Product, most substitutedSeytzeff Product, most substituted

» major with small base, i.e., ethoxide, small LGmajor with small base, i.e., ethoxide, small LG

Br

NaOEt

EtOH ++

majormajor minorminor

RR22C=CRC=CR2 2 > R> R22C=CHR > RHC=CHR > RC=CHR > RHC=CHR > R22C=CHC=CH22 > RHC=CH > RHC=CH22

Decreasing alkene stabilityDecreasing alkene stability

E2 MechanismE2 Mechanism

Concerted, anti-coplanar, Concerted, anti-coplanar, Stereospecific Stereospecific strong base & good LGstrong base & good LG

Br

HOEt

=

Ph

Me

Me

Ph

HBr

Me

Ph

Ph

Me

HPh

Me

PhMe Br

H

Me PhBr

MePh= =

H

Me PhBr

MePh

OEt

Me PhMePh

=

stereospecific elimination

Elimination is stereospecificElimination is stereospecific

Comparison of SComparison of SNN1 and S1 and SNN22

Base strength unimportantBase strength unimportant Substrates: reactivity order Substrates: reactivity order

is 3is 3o o > 2> 2o o > 1> 1oo

Solvent: good ionizing Solvent: good ionizing solvent requiredsolvent required

Rate: depends on substrate Rate: depends on substrate conc. onlyconc. only

Stereochemistry: no Stereochemistry: no particular geometry particular geometry required for slow step; required for slow step; Saytzeff rule followedSaytzeff rule followed

Rearrangements: very Rearrangements: very commoncommon

Strong bases requiredStrong bases required Substrates: reactivity order Substrates: reactivity order

is 3is 3o o > 2> 2o o > 1> 1oo

Solvent polarity is not so Solvent polarity is not so importantimportant

Rate: depends on conc. of Rate: depends on conc. of substrate and base. substrate and base.

Stereochemistry: coplanar Stereochemistry: coplanar arrangement required in arrangement required in transition state; Saytzeff rule transition state; Saytzeff rule followedfollowed

Rearrangements: not Rearrangements: not possiblepossible

E1E1 E2E2