Nucleophilic Substitution: The SN1 and SN2 Mechanisms

WWU -- Chemistry

Nomenclature of alkyl halides -- common names
methylene chloride chloroform carbon tetrachloride CH2Cl2 CHCl3 CCl4

WWU -- Chemistry

Nomenclature of alkyl halides -- common names
methylene chloride chloroform carbon tetrachloride CH2Cl2 CHCl3 CCl4

WWU -- Chemistry

Chemistry .More common and IUPAC names isopropyl chloride sec-butyl chloride isobutyl chloride tert-butyl chloride allyl chloride vinyl chloride benzyl chloride phenyl chloride (2-chloropropane) (2-chlorobutane) (1-chloro-2-methylpropane) (2-chloro-2-methylpropane) (3-chloro-1-propene) (chloroethene) (chloromethylbenzene) (chlorobenzene) WWU -.

Chemistry .1: Overview of nucleophilic substitution • • • • • The substitution reaction: SN1 and SN2 Primary halides = SN2 Secondary halides = both mechanisms! Tertiary halides = SN1 Leaving groups: halogens most common • There are a number of different nucleophiles!! WWU -.Sect. 9.

Nucleophilic Substitution (SN2) Oxygen Nucleophiles (SN2) _ R-CH 2-X substrate + _ Nu _ R-CH2-Nu product + X nucleophile leaving group R-CH 2-X + O-H hydroxide _ R-CH 2-X + O-R alkoxide R-CH 2-X + _ O-C-R R-CH 2-O-H + alcohol R-CH 2-O-R + ether R-CH 2-O-C-R + O ester X _ X _ X _ O carboxylate WWU -.Chemistry .

Nitrogen as a nucleophile (SN2) _ R-CH 2-X substrate + Nu _ R-CH2-Nu product + + X nucleophile leaving group _ R-CH 2-X + NH 3 ammonia _ R-CH2-NH3 X + R-CH 2-NH3 X R-CH 2-NH2 primary amine + H-X WWU -.Chemistry .

Chemistry .C C-H + alkyne X _ _ X _ R-CH 2 CH2-C-R + X ketone O WWU -.Carbon as a nucleophile (SN2) _ R-CH 2-X substrate + Nu _ R-CH2-Nu product + X nucleophile leaving group _ C N R-CH 2-X + cyanide _ R-CH 2-X + C C-H _ R-CH 2-X + CH2-C-R O R-CH 2 C N + nitrile R-CH 2.

__ O: .Chemistry ..H R d- O H H C Br d- energy . R H H C Br H OH R C H H Br Reaction coordinate WWU -..

. _ : Br : .. 2) CH3 CH3 C + CH3 + : Nu _ fast CH3 CH3 C Nu CH3 CH3 slow CH3 CH3 C + CH3 + .Chemistry .The SN1 Mechanism 1) CH3 CH3 C : Br: . carbocation WWU -..

Chemistry .R C R d+ R d+ R d- Br d+R C R R Nu energy R C R intermediate R C R Nu R R R C R Br Reaction coordinate WWU -.

Sect.2 SN2 Mechanism • • • • • • • reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents WWU -.Chemistry . 9.

.. Methyl group is small WWU -.. _ : Br : . :O ... + . H .The SN2 Reaction Sterically accessible compounds react by this mechanism!! _ CH3 Br + .Chemistry . CH3 OH ..

Chemistry .SN2 Mechanism: kinetics • The reactions follows second order (bimolecular) kinetics • Rate = k 1 [R-Br] -]1 [OH WWU -.

H R d- O H H C Br d- energy . __ O: .Chemistry .. R H H C Br H OH R C H H Br Reaction coordinate WWU -..

CH3 C + _ Br H Et WWU -. O .enantiomer Inversion of configuration H .. _ O: ..SN2 Reaction: stereochemistry H .Chemistry (S) enantiomer .. CH3 C H Et Br H CH3 dO H C Et dBr (R)..

For an SN2 Reaction: EVERY REACTION EVENT ALWAYS LEADS TO INVERSION OF CONFIGURATION WWU -.Chemistry .

Chemistry .SN2 Reaction: substrate structure (Table 10-5) krel CH3 Br 150 1 CH3 CH2 Br CH3 CH Br CH3 CH3 CH3 C CH3 Br 0.008 unreactive! KI in Acetone at 25° WWU -.

Chemistry .Chloromethane + Iodide as the Nucleophile Fast I- WWU -.

tert-Butyl Chloride + Iodide as the Nucleophile No reaction I- WWU -.Chemistry .

SN2 Reaction: substrate structure CH3 CH3-Br > CH3-CH2-Br > CH3 CH CH3 primary secondary Br > CH3 C CH3 tertiary Br Reactivity order---.Chemistry .fastest to slowest! WWU -.

iodide doesn’t fit that pattern (weak base. but great nucleophile!) 3) Cyanide is an excellent nucleophile because of its linear structure 4) Sulfur is better than oxygen as a nucleophile WWU -.Relative Nucleophilicity O CH3 C _ O _ O _ OH _ OCH3 _ I _ SH _ N C CH3OH H2O Increasing Nucleophilicty 1) In general.Chemistry . stronger bases are better nucleophiles 2) However.

OTs. • Good leaving groups: – Br. OR. NH2. F WWU -. I. Cl.Chemistry .SN2 Reaction: Leaving Groups • Best leaving groups leave to form weak Lewis bases. OH2+ • “Lousy” leaving groups: – OH..

Chemistry CH3 R OTs Tosylate Br R OBs .Sulfonate Leaving Groups O R O S O para-Toluenesulfonate O R O S O para-Bromobenzenesulfonate Brosylate WWU -.

Tosylate leaving group CH3 H C OH CH3 CH2 O S O Cl [Ts-Cl] CH3 H C O Ts CH2 + H-Cl Retention of configuration (S)-(+)-1-Phenyl-2-propanol (S)-(+)-1-Methyl-2-phenylethyl tosylate CH3 H C O Ts CH3 CH2 CH O CH2 CH3 CH2 C2H5O _ Retention or inversion? 2-Ethoxy-1-phenylpropane Is this ether (R) or (S)? WWU -.Chemistry .

Inversion of Configuration CH3 CH2 O_ H CH3 C CH2 O O S O CH3 (S) CH3 CH2 O CH3 H C CH2 + CH3 O S O O _ (R) WWU -.Chemistry .

Now that the sodium ion is complexed. the oxygen in the nucleophile –OEt is more available for attack. Why are reactions accelerated? The Na+ cation is complexed by the negative part of the aprotic solvent molecule pulling it away from –OEt. WWU -. Consider Na+ -OEt as an example of a nucleophile.Chemistry .SN2 Reaction: solvents SN2 reactions are accelerated in polar. aprotic solvents.

Aprotic solvents • These solvents do not have OH bonds in them. They complex the cation through the lone pairs on oxygen or nitrogen: O Acetone H3 C CH3 O S O Dimethylf ormamide (DMF) H N CH 3 CH 3 Dimethyl sulfoxide (DMSO) H3 C CH3 Acetonitrile H3 C C N WWU -.Chemistry .

Chemistry .How cations are complexed with aprotic solvents H3C S CH3 O Na O S H3C CH3 WWU -.

the –OEt can react more easily Et O H3C Br Et O CH3 Br WWU -.Now that the Na+ is complexed.Chemistry .

protic solvents.Chemistry . Why are reactions retarded? Nucleophile is hydrogen bonded to solvent! Et O H O Et The nucleophile is hydrogen bonded to ethanol .SN2 Reaction: solvents SN2 reactions are retarded (slowed) in polar.reduces nucleophilicity WWU -. Protic solvents have O-H groups.

Protic solvents Typical protic solvents: Water H O H O CH3 HOMe abbreviations Methanol H Ethanol H O CH2 CH3 HOEt Acetic acid H O C CH3 O HOAc Formic acid H O C H O WWU -.Chemistry .

9.Sect.3: SN1 Mechanism • reaction and mechanism • kinetics • stereochemistry • substrate structure • nucleophiles • leaving groups • solvents WWU -.Chemistry .

Chemistry . CH3 CH3 C Br CH3 + H2O acetone CH3 CH3 C OH + other products CH3 + H Br WWU -.Solvolysis of tert-Butyl Bromide Acetone is used to dissolve everything! Water is the solvent and nucleophile (solvolysis).

... 2) CH3 CH3 C + CH3 + :O: H H CH3 fast CH3 C :O H 3) CH3 CH3 C :O H + CH3 H fast CH3 CH3 slow CH3 C + CH3 + .The SN1 Mechanism 1) CH3 CH3 C : Br: ..Chemistry . _ : Br : . carbocation CH3 + H CH3 CH3 C :O . CH3 H + H + 1935: Hughes & Ingold WWU -.

Chemistry .R C R d+ R dR R C R O H intermediate H Br energy R C R + R intermediate R R R C R Br R C R OH Reaction coordinate WWU -.

SN1 Reaction: kinetics • The reactions follows first order (unimolecular) kinetics • Rate = k 1 [R-Br] WWU -.Chemistry .

WWU -. the product will be racemic (50% of each enantiomer).SN1 Reaction: stereochemistry With chiral R-X compounds.Chemistry .

Chemistry .Stereochemistry in SN1 reactions – racemic product Slow Pr CH3-O-H C Br polar H3C protic Et o 3 substrate solvent! (S) enantiomer CH3-O-H front side attack Pr C H3C Et CH3-O-H Fast back side attack Pr C H3C Et planar carbocation Pr H3C Et C O CH3 H Pr H Et C O CH3 H fast 50% (S) Pr O CH3 Et 50% (R) H3C H Pr O CH3 Et H fast H3C WWU -.

R C R d+ R dR R C R O H intermediate H3C Br energy R C R + R intermediate R R R C R Br R C R O-CH3 Reaction coordinate WWU -.Chemistry .

SN1 Reaction: substrate structure
krel CH3 Br CH3 CH2 Br CH3 CH Br CH3 CH3 CH3 C CH3
Solvolysis in water at 50°C
WWU -- Chemistry

no reaction

1.00

11.6

Br

6 1.2 x 10

SN1 Reaction: substrate structure
tertiary>secondary>primary > methyl Primary and methyl halides are very unreactive! They don’t go by SN1 reactions.

WWU -- Chemistry

CH3 CH3 C CH3 tertiary Br > CH3 CH CH3 secondary primary Br > CH3-CH2-Br > CH3-Br

CH3 CH3 C+ CH3 tertiary carbocation (very stable) three methyl groups CH3

+
CH CH3 CH3

+
CH 2

+
CH3

secondary carbocation

primary carboc carbocation (unstable) one methyl group

very unstable carbocation no methyl groups

two methyl groups

WWU -- Chemistry

Chemistry . and formic acid. acetic acid.Nucleophiles • Usually SN1 reactions are run in polar protic solvents. methanol. • The polar protic solvent acts as BOTH nucleophile as well as the solvent. WWU -. • Common solvent/nucleophiles include: water. compounds with O-H groups. ethanol.

Chemistry .A protic solvent acts as both a solvent and nucleophile in SN1 reactions solvolysis: Water H O H O CH3 HOMe abbreviations Methanol H Ethanol H O CH2 CH3 HOEt Acetic acid H O C CH3 O HOAc Formic acid H O C H O WWU -.

Chemistry .Typical solvolysis reaction Slow Pr C Br CH3-O-H Pr C H3C Et polar H3C protic Et 3o substrate solvent! (S) enantiomer Polar solvent stabilizes the carbocation! Solvent is the nucleophileCH -O-H 3 planar carbocation Pr H3C Et C O CH3 H Pr H Et C O CH3 H fast Pr C H3C Et front side attack 50% (S) Pr O CH3 Et 50% (R) CH3-O-H Fast back side attack H3C H Pr O CH3 Et H fast H3C WWU -.

OTs are the usual ones. Br.Leaving groups • Leaving groups are the same as in SN2 reactions: • Cl. WWU -. I.Chemistry .

WWU -. • SN1 solvolysis reactions go slower in ethanol and acetic acid (lower ionizing power).Chemistry .SN1 Reaction: solvent polarity • SN1 solvolysis reactions go much faster in trifluoroacetic acid and water (high ionizing power).

• A tertiary alkyl halide should react by an SN1 mechanism.SN2 versus SN1 Reactions • A primary alkyl halide or a methyl halide should react by an SN2 process. in an polar aprotic solvent. such as hydroxide. methoxide. Look for a good nucleophile. Look at the solvent/nucleophile conditions!! WWU -.it will give you nothing but E2 elimination! • A secondary alkyl halide can go by either mechanism. Make sure to run the reaction under solvolysis (polar protic solvent) conditions! Don’t use strong base conditions -.Chemistry . etc.

Chemistry . • If the medium is basic. SN2 versus SN1 Reactions (continued) • If the medium is acidic or neutral.• If the reaction medium is KI or NaI in acetone. WWU -. this demands an SN1 mechanism. look for SN2. expect SN1. this demands an SN2 mechanism. • If the reaction medium is AgNO3 in ethanol.

65 0.15 b CH3 CH2 Br Neopentyl bromide 0.Effect of b-substitution on SN2 reactivity krel b H CH2 CH2 Br b CH3 CH2 CH2 Br CH3 CH3 CH CH2 Br b CH3 CH3 C 1.000026 KI in Acetone at 25° WWU -.Chemistry .0 0.

Chemistry .Neopentyl Transition State Y Y H C H R1 R1 C R2 R3 Nu Nu WWU -.

they are more reactive most other halides! They form resonance stabilized carbocations.Chemistry benzyl bromide .Allylic and Benzylic compounds Allylic and benzylic compounds are especially reactive in SN1 reactions. Even though they are primary substrates. CH2-Br CH2=CH-CH2-Br allyl bromide WWU -.

Chemistry .000 80% Ethanol-water at 50° WWU -.Solvolysis Rates: SN1 krel Ethyl chloride Isopropyl chloride Allyl chloride Benzyl chloride tert-Butyl chloride very small 1 74 140 12.

Allylic and Benzylic compounds Allylic and benzylic compounds are especially reactive in SN2 reactions. They are more reactive than typical primary compounds! CH2-Br CH2=CH-CH2-Br allyl bromide benzyl bromide WWU -.Chemistry .

Reaction with KI in Acetone: SN2 krel Ethyl chloride Allyl chloride Methyl chloride Benzyl chloride 1 33 93 93 60° C WWU -.Chemistry .

Chemistry .Vinyl and Phenyl Compounds Vinyl and Phenyl compounds are completely inert in both SN1 and SN2 reactions!! H CH2 C Cl vinyl phenyl Cl WWU -.

Chemistry .Reactivity order for SN1 CH2 R C R R Br Br R CH Br R > H H C C CH2 Br H > >> R CH2 Br >> CH3-Br >> methyl R R Br H C Br 3o 2 o 1 o Benzyl Allyl phenyl vinyl Inert!! No reaction WWU -.

Chemistry .Reactivity order for SN2 About same reactivity CH2 Br = CH3-Br R CH2 Br R R C R R Br > > R CH Br >>> >> > R R phenyl vinyl Br H C Br H H C C CH2 Br H methyl 1 o 2o 3o Can not undergo SN2 Benzyl Allyl Inert!! No reaction!! WWU -.

4: Carbocation Rearrangement 1) CH3 CH3 C CH CH3 slow CH3 CH3 C CH3 CH CH3 + _ + Br CH3 Br a carbocation 2) CH3 CH3 C CH3 CH CH3 + CH3 CH3 C + CH CH3 CH3 3) CH3 CH3 C + CH CH3 CH3 + ROH CH3 CH3 C CH CH3 + + H OR CH3 WWU -. 9.Chemistry .Sect.

CH3 CH3 C CH3 CH3 CH3 C + CH CH3 CH CH3 + CH3 CH3 C + CH CH3 CH3 CH3 transition state WWU -..A Closer Look..Chemistry .

Carbocation Rearrangement CH3 CH3 C CH3 WWU -.Chemistry CH CH3 .

Carbocation Rearrangement CH3 CH3 C CH3 WWU -.Chemistry CH CH3 .

Carbocation Rearrangement CH3 CH3 C CH3 WWU -.Chemistry CH CH3 .

Chemistry .Carbocation Rearrangement CH3 CH3 C CH CH3 CH3 WWU -.

Chemistry CH3 .Carbocation Rearrangement CH3 CH3 C CH CH3 WWU -.

Chemistry CH3 .Carbocation Rearrangement CH3 CH3 C CH CH3 WWU -.

Carbocation Rearrangement CH3 CH3 C CH CH3 WWU -.Chemistry CH3 .

Chemistry CH3 .Carbocation Rearrangement CH3 CH3 C CH CH3 WWU -.

9.Sect.5 M CH3OH inversion O CH3 CH C OCH3 (S)-(-) _ O + Br _ O CH3 CH C Br (R)-(+) _ O _ + CH3O < 0.5: Neighboring group participation O CH3 CH C Br (R)-(+) _ O _ + CH3O > 0.Chemistry _ O _ + Br .1 M CH3OH retention O CH3 CH C OCH3 (R)-(+) !!! WWU -.

. CH3 H C _O (R) O C Br dCH3 O H _O CH3 C C O dBr CH3 Inversion of configuration CH3 O C H C _O (S) O + _ Br WWU -.Chemistry .Under SN2 Conditions _ .. CH3 O : .

Chemistry .Internal SN2 reaction followed by an external SN2 reaction CH3 _ .. C H C O (R) Br slow O C O :O : CH3 H Retention of Configuration H C _ + Br H _ . C :O .... :O . O (R) CH3 CH3 C .. + WWU -.. O CH3 + H .

.Chemistry .Neighboring Group Participation 1) G: C C X slow C G C + . _ :X: . 2) C G C fast G: C C Nu G: Nu : X WWU -..

Chemistry .Neighboring group participation: Summary • Retention of configuration • Enhanced rate of reaction WWU -.

It is highly reactive compound that combines with proteins and DNA and results in cellular changes immediately after exposure.Mustard gas • Mustard gas is a substance that causes tissue blistering (a vesicant).Chemistry . Cl S Cl S Cl Cl Mustard gas Neighboring group participation Internal SN2 O-Enzyme External SN2 Cl Cl S Cl S O-Enzyme Cl WWU -. Mustard gas was used as a chemical warfare agent in World War I by both sides.

if appropriate.Chemistry . H2O CH3 CH CH CH2 OTs acetone A) B) Identify the mechanism of this reaction. Predict the product(s) of this reaction. and identify them as major or minor.In-Class Problem For the following reaction. WWU -.

aprotic solvent Strong effect. reaction favored by tertiary halide Occurs with strong base! Highly favored when strong bases (OH-. reaction favored by good leaving group Nucleophile/Base Leaving Group Strong effect.Substitution versus Elimination SN1 Substrate Strong effect. reaction favored by weak base E2 Strong effect. reaction favored by tertiary halide Does not occur Occurs under solvolysis conditions or with strong acids Can occur in polar. reaction favored by polar. reaction favored by polar. reaction favored by methyl or primary halide Highly favored Does not occur E1 Strong effect. OR-) are used Favored when strong bases are used Strong effect. reaction favored by good leaving group WWU -.Chemistry . reaction favored by good leaving group SN2 Strong effect. reaction favored by strong base Strong effect. aprotic solvents Strong effect. reaction favored by polar. protic solvents Very strong effect. protic solvents Very strong effect. reaction favored by polar. reaction favored by tertiary halide Does not occur Favored when nucleophile is the solvent – solvolysis Can occur in polar. protic solvents Weak effect. reaction favored by good nucleophile/weak base Strong effect. reaction favored by good leaving group Reactivity – primary Reactivity – tertiary Reactivity – secondary Solvent Favored by good nucleophile in polar. protic solvents Weak effect. aprotic solvents Strong effect. reaction favored by good nucleophile/weak base Strong effect.