Chapter 13

Hydrolysis and Nucleophilic Reactions

Why are nucleophilic reactions important?

Common nucleophilesClO4

-

H2ONO3

-

F-

SO42-, CH3COO-

Cl-

HCO3-, HPO3

2-

NO2-

PhO-, Br-, OH-

I-, CN-

HS-, R2NHS2O3

2-, SO32-, PhS-

Whenever bonds are polarized, they have permanent dipoles, i.e. areas of parital positive and negative charge.

These charges are attractive to nucleophiles (positive-loving) and electrophiles (negative-loving)

Because there are lots of nucleophiles out there, electrophiles are rapidly destroyed (except in light-induced or biologically mediated processes)

What are nucleophiles?

ClO4-

H2ONO3

-

F-

SO42-, CH3COO-

Cl-

HCO3-, HPO3

2-

NO2-

PhO-, Br-, OH-

I-, CN-

HS-, R2NHS2O3

2-, SO32-, PhS-

increasing nucleophilicity for reaction at saturated carbon

nucleophiles possess either a negative charge or lone pair electrons which are attracted to partial positive charges

These electrons form a new bond at the carbon they attack

Example: SN2 reaction

OH-C

H

HH

BrHOC

H

HBr

HC

H

HH

HO+ Br-

-

the lone pair electrons on the nucleophile (in this case OH-) form a new bond with C.

something has to go!

“Leaving Group” in this case is Br-

common leaving groups

halides (Cl-, Br-, I-)

alcohol moieties (ROH)

others such as phosphates (PO4-)

anything that forms a stable species in aqueous solution

For negatively charged leaving groups, the lower the pKa, the better the leaving group.

Examples

Unsure about electronegativity?

Check the Periodic Table

Hydrolysisbecause water is so abundant, it is an important nucleophile

reaction where water (or OH) substitutes for a leaving group is called “hydrolysis”

the products of this reaction are necessarily more polar

Examples:

methyl bromide methanol

ethyl acetate acetate and ethanol

Thermodynamics:

at ambient pH, reactant and product concs, most hydrolysis reactions are spontaneous and irreversible

Example 13.1

CH3Br + H2O CH3OH + H+ + Br- rGº = -28.4 kJ/mol

RT

G

BrCH

OHCHHBrK rr exp

][

]][][[

3

3

][

]][10][10[106.9

3

373

4

BrCH

OHCHKr

14

3

3 106.9][

][

BrCH

OHCH Note that other nucleophiles may compete with water here!

Another example

CH3COOC2H5 + H2O CH3COO- + HOCH2CH3 + H+

rGº = +19.0 kJ/mol

4

523

323 107.4][

]][][[

HCOOCCH

CHHOCHCOOCHHK r

3

523

323 107.4][

]][[

HCOOCCH

CHHOCHCOOCH

Nucleophilic displacement of halogens at saturated carbon

The SN2 mechanism:

substitution, nucleophilic, bimolecular

Note stereochemistry

SN2 rate depends on:Nucleophile: strength

Substrate: charge distribution at the reaction center

goodness of leaving group,

steric effects

For leaving groups: I ~ Br > Cl > F and lowest pKa

Rate law: second order kinetics

]][[][

33 NuClCHk

dt

ClCHdr

SN1 mechanismsubstitution, nucleophilic, unimolecular

Note stereochemistry

SN1 Mechanism:

rate determining step is formation of carbocation:

C6H5-CH2Br C6H5-CH2+ + Br-

carbocation is then captured by the nearest nucleophile, almost always water.

Important for {secondary}, tertiary, allyl, benzyl halides

Rate depends on goodness of leaving group and stability of carbocation (better if resonance stabilized).

Nucleophilicity of nucleophile doesn’t matter!

Rate law: first order: ])[(])[(

3333 CClCHk

dt

CClCHdr

nsk

k

ref

log

Swain-Scott model for SN2 reactions

k = rate constant for given reaction

k ref = rate constant for same reaction with reference nucleophile

s = susceptibility of structure to nucleophilic attack

n = nucleophilicity of nucleophile

All these methyl halides show the same relative reactivity towards a series of nucleophiles

Two references:

methyl bromide in water

methyl iodide in methanol

the two reference systems yield similar nucleophilicities

0.98)(R

68.02

,, 33

ICHNuBrCHNu nn

Important nucleophiles

some organic nucleophiles are quite strong (NOM constituents?)

Reduced sulfur species are some of the strongest nucleophiles in the environment

Conc of each nucleophile needed to compete with water

Nucleophile M conc.NO3

- 6F- 0.6SO4

2- 0.2Cl- 0.06HCO3

-, HPO32- 0.009

Br- 0.007OH- 0.004I- 0.0006CN- 0.0004HS- 0.0004S2O3

2- 0.00004S4

2- 0.000004

BrCHNunNu 3,103.55][ %50

BrCHNuOH

Nu nsk

k3

2

,log

][][ 2%50 2OHkNuk OHNu

Assume s =1

If reaction not acid catalyzed, hydrolysis independent of pH (4-9) (alkyl halides)

What factors determine nucleophilicity?

The ease with which it can leave the solvent and attack the reaction center(nucleophilicity inc with dec solvation of nuc)

Ability of bonding atom to donate its electrons(larger, softer species are better nuc)

F- < Cl- < Br- < I-

HO- < HS-

HSABHard and soft acids and bases

Lewis acids = electrophiles, Lewis bases = nucleophiles

Hard = small, high electronegativity, low polarizability

Soft = large, low electronegativity, high polarizability

Rule 1: Equilibrium: hard acids prefer to associate with hard bases and soft acids with soft bases.

Rule 2: Kinetics: hard acids react readily with hard bases and soft acids with soft bases

Hard: OH-, H2PO4-, HOC3

-, NO3-, SO4

2-, F-, Cl-, NH3, CH3OO

Borderline: H2O, SO32-, Br-, C6H5NH2

Soft: HS-, Sn2-, RS-, PhS-, S2O3

2-, I-, CN-

Range of s

Leaving groups:

0.83-0.96 Hard (oxygen) leaving groups

1-1.2 Softer leaving groups

Substrate properties

1.6 strong interaction with nuc in transition state (alachlor and propachlor)

Leaving groups

SN1 vs SN2 depends on stability of carbocation AND on strength of nucleophile

SubstituentsNuc = water

Fig 13.5

Secondary bromides react via SN1. Will not react via SN2 with water, but will with reduced sulfur nucleophiles

Polyhalogenated alkanes: SN2 blocked

SN2 is blocked by steric hindrance and back-bonding of extra halogens.

Why do tetrachloroethane and pentachloroethane react relatively rapidly?

Elimination mechanisms— C—C —

H LC=C + H+ + L-

b-elimination (dehydrohalogenation)

Important for molecules in which multiple halogens block Sn2 and render the proton acidic

OF COURSE, the molecule must have an acidic proton beta to a good leaving group (halogen)

1,1,2,2-tetrachloroethane and pentachloroethane undergo an E2 mechanism (elimination, bimolecular)

OH- base interacts with acidic proton in the transition state

rate = -k[OH-][polyhalide]

Transition state has negative charge on carbonAnything that can stabilize this charge will speed up the reaction

steric effects not as important as for SN2

Summary: For SN and E reactions:Activation energies are between 80-120 kJ/mol

(big temperature dependence!)

Overall rate of disappearance is the sum of all processes:

iwj

jNuEBBENN CNukOHkkkkratej

jjNuEBBENNobs NukOHkkkkk

j

kobs may not be a simple function pH and T

Products and rates can depend strongly on pH and T

Vinyl and aromatic halides are (for the most part) unreactive by SN and E mechanisms

Hydrolysis of carboxylic and carbonic acid derivatives (neutral, acid, or base catalyzed):

X

Z L

HO-

Z L

HO

X-

Z OH

X

+ L-

Z O-

X

+ HL

Where Z = C, P, S

X = O, S, NR

L- = RO-, R1R2N-, RS-, Cl-

endosulfan Malathion(organophosphorus pesticide)

Aldicarb (carbamate)

Benzyl butyl phthalate

Good leaving groups favor neutral mechanism

RLS?Neutral Mechanism

How strong a base is the ester function? (ie how many molecules are protonated?)

RLS(?)

Important when no electron withdrawing groups and poor leaving group

Acid-catalyzed mechanism

RLS with good leaving groups

RLS with poor leaving groups

Base-catalyzed mechanism

LFERs for hydrolysis: Hammett (aromatic systems):

predicts acid-base equilibrium:

logK

Ka

aHi

i

logk

ka

aHi

i

Likewise predicts hydrolysis kinetics:

C-OCH2CH3

O

X

+ H2O C-OH

O

X

+ HOCH2CH3

Taft relationship (aliphatic systems):

commonly applied to ester hydrolysis of aliphatic systems (reactivity only)

quantifies steric and polar effects

defined for methyl substituent (methyl = 0)

log * *k

kE

refs

Where * = sensitivity to polar effects * = polar constant = sensitivity to steric effectsEs = steric constant

Assume only steric effects are important for acid-catalyzed hydrolysis.

Both steric and polar effects are important for base-catalyzed hydrolysis.

What does the transition state look like?

Does it possess positive or negative charge?

Taft relationship:

assume that electronic effects are zero for the acid catalyzed hydrolysis mechanism:

OH

HO

OR2R1

H+

Acid catalyzed TS (no charge)

O

HO

OR2R1

Base catalyzed TS (negative charge)

Phosphoric and thiophosphoric acid triesters