Chapter 13 Hydrolysis and Nucleophilic Reactions

Why are nucleophilic reactions important? Common nucleophiles ClO 4 - H 2 O NO 3 - F - SO 4 2-, CH 3 COO - Cl - HCO 3 -, HPO 3 2- NO 2 - PhO -, Br -, OH - I -, CN - HS -, R 2 NH S 2 O 3 2-, SO 3 2-, 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? ClO 4 - H 2 O NO 3 - F - SO 4 2-, CH 3 COO - Cl - HCO 3 -, HPO 3 2- NO 2 - PhO -, Br -, OH - I -, CN - HS -, R 2 NH S 2 O 3 2-, SO 3 2-, 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: S N 2 reaction OH - C H H H BrHO C H H Br H C H H H 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 (PO 4 - ) anything that forms a stable species in aqueous solution For negatively charged leaving groups, the lower the pK a, the better the leaving group.

Examples Unsure about electronegativity? Check the Periodic TablePeriodic Table

Hydrolysis because 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 CH 3 Br + H 2 O  CH 3 OH + H + + Br -  r Gº = kJ/mol Note that other nucleophiles may compete with water here!

Another example CH 3 COOC 2 H 5 + H 2 O  CH 3 COO - + HOCH 2 CH 3 + H +  r Gº = kJ/mol

Nucleophilic displacement of halogens at saturated carbon The S N 2 mechanism: substitution, nucleophilic, bimolecular Note stereochemistry

S N 2 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 pK a Rate law: second order kinetics

S N 1 mechanism substitution, nucleophilic, unimolecular Note stereochemistry

S N 1 Mechanism: rate determining step is formation of carbocation: C 6 H 5 -CH 2 Br  C 6 H 5 -CH 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:

Swain-Scott model for S N 2 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

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 NucleophileM conc. NO F SO Cl HCO 3 -, HPO Br OH I CN HS S 2 O S 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 -

HSAB Hard 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 -, H 2 PO 4 -, HOC 3 -, NO 3 -, SO 4 2-, F -, Cl -, NH 3, CH 3 OO Borderline: H 2 O, SO 3 2-, Br -, C 6 H 5 NH 2 Soft: HS -, S n 2-, RS -, PhS -, S 2 O 3 2-, I -, CN -

Range of s Leaving groups: Hard (oxygen) leaving groups 1-1.2Softer leaving groups Substrate properties 1.6 strong interaction with nuc in transition state (alachlor and propachlor)

Leaving groups S N 1 vs S N 2 depends on stability of carbocation AND on strength of nucleophile Substituents Nuc = water

Fig 13.5 Secondary bromides react via S N 1. Will not react via S N 2 with water, but will with reduced sulfur nucleophiles

Polyhalogenated alkanes: S N 2 blocked

S N 2 is blocked by steric hindrance and back-bonding of extra halogens. Why do tetrachloroethane and pentachloroethane react relatively rapidly?

Elimination mechanisms — C—C — H L C=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 carbon Anything that can stabilize this charge will speed up the reaction steric effects not as important as for S N 2

Summary: For S N and E reactions: Activation energies are between kJ/mol (big temperature dependence!) Overall rate of disappearance is the sum of all processes: k obs 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 S N and E mechanisms

Hydrolysis of carboxylic and carbonic acid derivatives (neutral, acid, or base catalyzed): X ZL HO - Z L HO X-X- ZOH X + L - Z O-O- X + HL Where Z = C, P, S X = O, S, NR L - = RO -, R 1 R 2 N -, 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: Likewise predicts hydrolysis kinetics: C-OCH 2 CH 3 O X + H 2 O  C-OH O X + HOCH 2 CH 3

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) Where  * = sensitivity to polar effects  * = polar constant  = sensitivity to steric effects E s = 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 OR 2 R1R1 H+H+ Acid catalyzed TS (no charge) O HO OR 2 R1R1 Base catalyzed TS (negative charge)

Phosphoric and thiophosphoric acid triesters