CHEM 4113

ORGANIC CHEMISTRY II CHAPTER 11

Nucleophile= Lewis base KCN

LECTURE NOTES

Intermolecular Nucleophilic Substitution

NC H3C

H CH3 H CH3 H CH3 H CH3

Leaving Group

NaOH

HO H3C H3CS H3C

H
NaSCH3

H3C + CH3
Site of nucleophilic attack polarized by electronegative iodide LiOCH3

H3CO H3C

Intramolecular Nucleophilic Substitution

Br OH

NaOH

Nucleophilic Substitution Reactions

Conjugate acid NH3 CH3OH RSH RCO2H HI acid strength CH3NH2 weaker base; better leaving group + RS RCO2+ CH3I stronger base; poorer leaving group

Conjugate base NH2 CH3O RS RCO2 I-

pKa 35 16 12 5 -5

leaving group ability

arrow indicates direction of increase Case 1: Mercaptide anion with methyl amine CH3SR Keq ~ 10-23 + NH2 very strong base; very poor leaving group

base strength

Case 2: Carboxylate anion with methyl iodide CH3OCOR Keq ~ 10

15

Iweaker base; better leaving group

Direction of equilibrium based on pKa data

Reaction Rate = [product]/time = -[reactant]/time Buildup of product Loss of reactant over time over time Units: mol / l / sec = M sec-1 C [] [] The Kinetic Order of a chemical reaction is the sum of the exponents in all the concentrations in the rate law. This example would be called a second order reaction. The Rate Constant is a fundamental physical constant which is specific for the reaction involved under a defined set of reaction conditions.

A + B [C] = t The dimensions of the rate constant depend on the kinetic order of the reaction. Since the rate of every reaction is expressed in M/sec-1, the dimensions of the rate constant must be adjusted to fit this need. Reaction Rate:

For the above reaction the k has dimensions of M-1sec-1 The Rate Law for the SN2 Reaction HO- + CH3-Br rate = k[HO-][CH3Br] substrate concentration nucleophile concentration The rate law is first order in each of the two reactants. This is a general obseervation for all nucleophilic substitution reactions with all primary and most secondary alkyl halides. The rate law is second order overall This information is of critical importance in helping to determine a mechanism for the process. It means that both nucleophile and the alkyl halide substrate are present in the transition state of the ratedetermining step. Rate law for a SN2 reaction HO-CH3 + Br-

Case 1: Frontside attack on C-Br bond. RETENTION OF STEREOCHEMISTRY

H3C H C Br CH2CH3
R Enantiomer

H3C
SCH3

SCH3 + Br-

CH2CH3
Same R Stereochemistry as substrate

Case 2: Backside attack on C-Br bond. INVERSION OF STEREOCHEMISTRY

H3C
CH3S -

CH3 C Br
CH3S Br

CH3 H3CS C H CH2CH3

CH2CH3
R Enantiomer

H3CH2C H

S Enantiomer When this reaction is conducted with an optically active substrate, it has been shown that the product is exclusively the one that has been formed by backside attack.

Stereochemistry of the SN2 Reaction with an Optically Active Substrate

Nu

Nu

Nu

Tetrahedral

Planar Transition State

Tetrahedral

Mechanism of SN2 Reaction

HO - + R Br

R OH + Br -

R= CH3CH3CH2(CH3)2CH(CH3)3C-

Relative Rate 1 0.11 0.056 no Rx

Case 1: 1 alkyl halide

H3C
HO

CH3 HO H H Br HO C

CH3 H H

Fast H C Br SN2
H

Case 2: 2 alkyl halide

H3C
HO

CH3 Br Slow

CH3 Br HO C H CH3

H C H3C

SN2

HO H CH3 CH3

Case 3: 3 alkyl halide

H3C
HO

H3C H3C

C Br No

SN2
HO

Br CH3

CH3 CH3

Nucleophile blocked for backside displacement

Hydroxide acts as a base, abstracts a proton on carbon adjacent to leaving group

E2 Reaction
Steric effects on the rate of SN2 Reaction

H3C CH2 CH3

Nucleophiles are electron-rich species (Lewis Bases)... Nucleophiles have lone-pair electrons. Anionic Nucleophile Nu + R-X HO Neutral Nucleophile Nu + R-X H3N R-Nu X + CH3 Br R-Nu + + CH3 Br X

CH3 OH + Br -

CH3 NH3 Br

Nucleophilicity - Affinity of a nucleophile for forming a bond to a carbon HS NC F CH3O HO Cl H3P H3N H2O

More Nucleophilic 1. 2.

Reactivity as a Nucleophile

Less Nucleophilic

Nucleophilicity roughly parallels Basicity Nucleophilicity usually increases going down a column F- is an exception

The Nature of Nucleophiles

Effect of the Leaving Group on the SN2 Reaction: The best leaving groups are those which are the weakest bases. HO - + R X R OH + X RI > 150 RBr 50 > RCl 1 >> RF 0.0005

relative rate:

fastest................................................slowest Effect of the Nucleophile on the SN2 Reaction: Within a given row of the periodic table, the best nucleophiles are those which are the strongest bases. Nuc - + R X R2N 38 > RO 16 > R Nuc + X NC 9 > F1

relative rate:

fastest................................................slowest Effect of Leaving Group and Nucleophile on SN2 Reaction

Protic Solvents - i.e., Water (H2O), Alcohols (R-OH). Good solvents for cation and anion. -

Polarized Bond- Solvent able to Solvate both cations and ions

R - H O R - O H R - H
CATION

R O - H O

RO + H RO H H RO +
+

OR H+ + OR H
+

H OR OR

H+ OR
ANION

Stabilizing electrostatic interactions, Hydrogen Bonds

Protic Solvents are able to solvate both cation and anion...They surround the charged species in such a way that stabilizing interactions occur between the ions and polar positions in the molecule. Protic molecules form a "solvent cage" around nucleophile thus stabilizing it and reducing its reactivity.

Protic Solvents and Nucleophilicity

Polar Aprotic Solvents-i.e., Acetone, Acetonitrile, DMF, DMSO. Good cation solvents but poor anion solvents. O - O - O - + - C C S H3C + CH3 H3C C N H + N(CH3)2 H3C + CH3 Acetone H H H Acetonitrile Dimethyl formamide Dimethyl sulfoxide DMF DMSO O S H H + H H H H H H H H H + H S O O S + H H HH H H H H + H H S H H O Steric hinderence Poor solvation of Anion

H S H H H H O - H H - - H S O O S H H H HH O - H H S H H H H H H Good Solvation of Cation

Polar aprotic solvents increase the rate of SN2 substitution. Solvents solvates cation well but nucleophile poorly, leaving it free and highly reactive. Aprotic Solvents and Nucleophilicity

H3C
HO

CH3 C Br No Br HO H CH3

CH3 CH3

H3C H3C

SN2

Nucleophile blocked for backside displacement, other processes can set in; like the E2 Reaction

Hydroxide acts as a base, abstracts a proton on carbon adjacent to leaving group

E2 Reaction

H3C CH3

Rate = k [HO ][ t-butylbromide]

Second Order (bimolecular CH2 Elimination

The E2 Reaction, Rate Law and Mechanism

RO

H C CH2 X CH3 CH3

E2 Mechanism is a concerted process; Base abstracts proton on -carbon, the electrons in the C-H bond begin to form a C=C bond while the C-X bond breaks and the electrons go away with X-.

partial O-H Partially bond H broken RO C-Hbond

RO H H H
Br

H H3C H3C
Partial C=C bond

H3C H3C

H3C H3C

H H
Br-

Br

Mechanism of E2 Reaction Primary alkyl halides always give SN2 products H3C
Nu

H H

Br

SN2 Nu C

CH3 H H + Br

Tertiary alkyl halides always give E2 products H3C

Nu

H3C H3C

C Br

E2 H2C C

CH3 CH3

+ Nu H + Br

Secondary alkyl halides often give mixtures of SN2 and E2 products CH3 H3C
Nu

SN2 C Br E2

Nu

C H

CH3

+ Br

H3C H

CH3 H2C C CH3 + Nu H + Br

Backside partially blocked,SN2 slowed but nucleophile can swing over to side bearing the CH to attain easier access for substitution. If SN2 is slowed too much E2 occurs SN2, E2 and Substrate Structure

Factors which Effect SN2 vs E2 for Secondary Alkyl Halides 1. Nucleophile Basicity- Stronger bases give more E2 product CH3O Br CH3CHCH3 Strong Base O CH3CO Weak Base OCH3 CH3CHCH3 + CH3CH CH2 E2 Product SN2 Product 80% 20% O OCCH3 CH3CHCH3 100% SN2 Product

2. Solvent - Polar Aprotic Solvents give more E2 product N C Br CH3CHCH3 CH3OH (protic solvent) CN CH3CHCH3 + CH3CH CH2 E2 Product SN2 Product 27% 73%

CN N C CH3CHCH3 + CH3CH CH2 DMSO E2 Product (aprotic solvent) SN2 Product 90% 10% 3. Steric Hinderance - -Branching gives more E2 product Br CH3CHCH3

CN N C CH3CHCH3 + CH3CH CH2 E2 Product SN2 Product 27% 73% CNCH3 N C CH3 CH3CHCH2 + CH3CH CH E2 Product SN2 Product 62% 38% CH3 CH3CH C 100% E2 Product CH3

Increase branching at position

Br CH3 CH3CHCH2

Br CH3 CH3CHCH

N C

CH3

10

Na EtO
E2 and/or SN2

E2

SN2

H CH2 CH2 X
Na EtO
E2 and/or SN2

none

CH3 CH2 OEt

100%

CH CH2 X

CH3
Na EtO
E2

CH CH2 CH3
10%

CH CH2 OEt CH3

90%

and/or SN2

CH3 CH X 3

CH2

CH3 C CH3

CH2

CH3 C CH2 OEt CH3

48%

62%

Substitution at the -carbon slows the SN2 process by steric henderance and provides a chance for the E2 process to take over. Effect of -branching on SN2/E2 ratio Less Substituted ALkene More Substituted ALkene

Na EtO

H CH3
Na EtO

H CH2 CH CH X H CH2 C CH

H CH3
35%

CH2

CH CH

CH CHCH3 CH3
65%

CH2

CH3 CH X 3

C CH CH3 CH 3
18%

CH3 C CH3

CHCH3
82%

E2 reactions give mixtures of products, however the major product can be predicted: Zaitsev's Rule tells us that the more highly substituted alkene is the major product when an unhindered base such as ethoxide (CH3CH2O-) is used. Zaitsev's Rule

11

CH3CH2O

E2
E2 and/or SN2

SN2

H CH2 C CH3 CH X 3 CH3 CH3 C O E2 CH3 H

CH3 C CH3

CH2

CH3 C CH2 OCH2CH3 CH3

48%

62%

and/or SN2

CH3 CH X 3

CH2

CH3 C CH3

CH2

CH3 CH3 C CH2 O C CH3 CH3 CH3

8%

92%

The more bulky t-butoxide has an even tougher time attaining a position behind a hindered base. The slows the SN2 process even more, making E2 more likely. Base Structure and SN2/E2 Ratio

Br H3C C CH2 CH3 CH3

least hindered, protons

OR

H2C
R = CH3CH2(CH3)3C-

CH3 C CH2 CH3

20% 80%

H3C H3C

C CH CH3
80% 20%

The more bulky t-butoxide base has a tough time reaching the more hindered protons...the Anti-Zaitsev alkene is formed.

Base Structure and E2 Product Composition

12

Case 1: Syn Elimination B

H R1 R2

Br R2 R1

Br H R1R
1

R R22

R1 R2

R1 R2

R1 is cis to other R1

Case 2: Anti Elimination B

H R2 R1

R1 R2 Br

R1 R2

H R 2 R1 Br

R1 R2

R2 R1

R1 is trans to other R1

The Anti Elimination mode is preferred in all cases where both may operate. The rate of Anti Elimination is much faster than Syn Elimination. Note that the geometry of the alkene can be predicted from the anti mode The Anti mode is favored because of three factors: 1. THE ELIMINATION OCCURS FROM A STAGGERED FORM 2. THE ELIMINATION HAS THE BASE AND LEAVING GROUPS OPPOSED, THUS MINIMIZING REPULSIVE INTERACTIONS. 3. THE C-H and C-X ORBITALS ARE ARRANGED FOR BEST OVERLAP IN THE TRANSITION STATE. Stereochemistry of the E2Reaction

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The SN2 Reaction 1 NaOEt + CH3CH2Br 2 NaOEt + CH3CHBrCH3 CH3CH2OEt + NaBr

rel rate 1

rate =k[OH][RBr] SN2

CH3CH(OEt)CH3 + NaBr 0.0025

3 NaOEt + (CH3)3CBr NO SN2 REACTION 0 NaOEt - Soldium Ethoxide: strong base, strong nucleophile The SN1 Reaction 1 EtOH + CH3CH2Br 2 EtOH + CH3CHBrCH3 3 EtOH + (CH3)3CBr CH3CH2-OEt + HBr rel rate 0.0003 rate =k[OH][RBr] SN2 rate =k[RBr] SN1 rate is independent of ethanol concentration

CH3CH(OEt)CH3 + HBr 0.05 (CH3)3C-OEt + HBr 1

No added base, not ethoxide, but neutral ethanol The SN1 mechanism is much faster than the SN2 mechanism!! Mechanism of SN1 reaction is a multi-step process 1st Step is rupture of C-X bond R R C X Et-OH R
C-X bonds are typically weak, easy to break Ethanol is like water, a strong "ionizing"solvent

R R

R + X

Stable 3 carbocation is further stabilized by solvation in hydroxylic solvent

The rate determining step involves cleavage of the C-X bond. No nucleophile is involved. The rate law is unimolecular

2nd Step is nucleophilic attack on electrophilic carbocation R R H R + O Et R R C H O R Et

Ethanol is a "weak" nucleophile, but easily adds to carbocation

R X + HX R C O R Et

3 Carbocation is strong electrophile

Proton is lost by oxygen, electrons remain to form neutral compound

The SN1 Reaction

14

SN2-Inversion HO + H CH3CH2 CH3 C Br CH3 C H HO CH2CH3 (S)-2-butanol CH3 CH3 C H + H C OEt EtO CH2CH3 CH3CH2 (R)-2-butanol (S)-2-butanol 50% 50%

(R)-2-bromobutane SN1-Racemic Mixture CH3 H C Br CH3CH2 H2O

(R)-2-bromobutane

Racemic mixture is a consequence of the trigonal planar carbocation intermediate OH H O H H CH3CH2 H CH3CH2 H CH3CH2 CH3 (S) CH3 (R) OH

CH3

Nucleophilic attack on the empty p orbital above or below the plane of the carbocation is equally likely

Sometimes Ion Pairing can Prevent complete racemization, i.e. the enantiomers are not formed in equal amounts X H O H H CH3CH2 one side is partially blocked Ion Pair - The two ions have not moved away from one another

CH3

Stereochemical Consequences of SN1 Reaction

15

1. Nucleophile Effects - Unlike the Sn2, the nature of the nucleophile plays no role in affecting the rate of the SN1 reaction. The nucleophile does not enter into the reaction until after the rate limiting step has occured However In order to avoid a competing process (the E2 reaction) the nucleophile should be non-basic or a very weak base. CH
3

NaBr +

CH3 CH3 C I CH3

CH3 C Br 20% via SN1 CH3 CH3 80% via E2 H3C C CH3

Even though Br is a very weak base, it is able to cause the E2 process to take over! If silver salts are used E2 processes can be avoided AgBr +

CH3 CH3 C I CH3

acetone

CH3 CH3 C Br + AgI CH3

The silver cation helps to "pull off" the iodide anion

CH3 CH3 C I CH3

Ag

CH3 CH3 C + AgI CH3

Nucleophile and SN1 Reaction

2. Leaving Group Effects - The effect of leaving group in SN1 reactions is the same as that in SN2 reactions- that is, the best leaving groups are the ones that are the most stable...conjugate bases of strong acids. I ~ TsO > Br > Cl ~ OH2 >>>HO less reactive

more reactive

REACTIVITY

Leaving Groups and SN2 Reaction

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