Factors affecting rate of nucleophilic substitution

Factors affecting the rate of nucleophilic substitution
Saturday, August 8, 2020 1
Topic:

 In approach to SN2 transition state, carbon atom under attack gathers in another ligand and
becomes five-coordinate
 Angles between the substituents decrease from tetrahedral to about 90°
 In starting material there are four angles of about 109°
 In transition state there are three angles of 120°and six angles of 90°
 Significant increase in crowding
 The larger the R group, the less favourable is the SN2 mechanism

 Effect of Alkyl Halides
 Methyl: CH3–X:
very fast SN2 reaction
 Primary alkyl: RCH2–X:
fast SN2 reaction
 Secondary alkyl: R2CH–X:
slow SN2 reaction
 Tertiary alkyl: R3CH–X:
slowest SN2 reaction

 Slow step is simply the loss of the leaving group
 Starting material tetrahedral (four angles of about 109°)
 Intermediate cation three angles of 120°
 Fewer less serious interactions
 Transition state on the way towards the cation, rather closer to it than to the starting
material
SN1Reaction

 In transition state, angles increasing towards 120°
 All interactions with the leaving group are diminishing as it moves away
 Steric acceleration in SN1 reaction rather than steric hindrance
 Stability of t-alkyl cations, that is why t-alkyl compounds react by SN1 mechanism

Solvent Effects
 Acetone used as a solvent for SN2 reaction
 Formic acid (HCO2H) as solvent for SN1 reaction
 Less polar solvent for SN2 reaction (polar enough to dissolve the ionic reagents)
 Polar protic solvent for SN1 reaction
 Needs a polar solvent as the rate-determining step usually involves the formation of ions
 Rate of this process will be increased by a polar solvent
 Transition state is more polar than starting materials and so is stabilized by the polar
solvent
 Solvents like water or carboxylic acids (RCO2H) are ideal

 Polar solvent solvates the anionic nucleophile
 Slows the reaction down
 Nonpolar solvent destabilizes the starting materials more than it destabilizes the transition
state
 Speeds up the reaction
 Reason for using acetone for this particular reaction
 NaI is very soluble in acetone but NaBr is rather insoluble
 NaBr product precipitates out of solution which helps to drive the reaction over to the right

 If SN2 reaction has neutral starting materials an ionic product
 Polar solvent is better
 Good choice is DMF, a polar aprotic solvent often used for the synthesis of phosphonium
salts by SN2 reaction

Polar Aprotic Solvents
 Water, alcohols, and carboxylic acids are polar protic solvents able to form hydrogen bonds
 Solvate both cations and anions
 Nucleophilic reagent, bromide ion must be accompanied by a cation
 Sodium ion, and hydroxylic solvents dissolve salts such as NaBr by hydrogen bonding to
 Anion and Electron donation to the cation
 Do not ‘ionize’ the salt, which already exists in the solid state as ions
 Separate and solvate the ions already present

 Polar aprotic solvents have dipole moments
 Still able to solvate cations by electron donation from an oxygen atom
 Lack the ability to form hydrogen bonds because any hydrogen atoms they may have are on
carbon
 Examples DMF and DMSO

The Leaving Group
 Halides and water from protonated alcohols as leaving groups in both SN1 and SN2
reactions
 Considering an SN1 reaction
 Considering an SN2 reaction
 Both have a leaving group, which we are representing as ‘X’ in these mechanisms
 In both cases the C–X bond is breaking in the slow step

 Starting with the halides
 Two main factors
 strength of the C–halide bond
 Stability of the halide ion
 Strengths of the C–X bonds have been measured
 How shall we measure anion stability?
 use the pKa values of the acids HX
 Bond strength can be used to explain pKa values so these two factors are not independent

 Easiest to break a C–I bond
 Most difficult to break a C–F bond
 Iodide the best leaving group
 from the pKa values
 HI is the strongest acid, must ionize easily to
H+ and I
 Iodide is an excellent leaving group
 Fluoride a very bad one with the other
halogens in between

Nucleophilic Substitutions On Alcohols
 What about leaving groups joined to the carbon atom by a C–O bond?
 Most important are OH itself, the carboxylic esters, and the sulfonate esters
 Alcohols do not react with nucleophiles
Why not?
 Hydroxide ion is very basic, very reactive, and a bad leaving group
 If nucleophile were strong enough to produce hydroxide ion
 It would be more than strong enough to remove the proton from the alcohol

 Use alcohols in nucleophilic substitution reactions because they are easily made
 Protonate the OH group with strong acid
 Work only if the nucleophile is compatible with strong acid, but many are
 Preparation of t-BuCl from t-BuOH by shaking it with concentrated HCl
 SN1 reaction with the t-butyl cation as intermediate

 Similar methods used to make secondary alkyl bromides with HBr alone
 Primary alkyl bromides using a mixture of HBr and H2SO4
 Second is certainly an SN2 reaction
 One stage in a two-step process that is very efficient

 Convert the OH group into better leaving group by combination with an element that forms
very strong bonds to oxygen
 Most popular choices are phosphorus and sulfur
 Making primary alkyl bromides with PBr3 works well
 Phosphorus reagent is first attacked by the OH group ( SN2 reaction at phosphorus)
 Displacement of an oxyanion bonded to phosphorus is a good reaction because of the anion
stabilization by phosphorus

Tosylate, TsO–, is an important leaving group made from alcohols
 Most important of all these leaving groups are those based on sulfonate esters
 Intermediates in the PBr3 reaction are unstable
 Easy to make stable, crystalline toluenepara- sulfonates from primary and secondary
alcohols
 Isolable but reactive compounds
 Trivial name (‘tosylates’)
 Functional group has been allocated an ‘organic element’ symbol Ts

 Cyanide ion is a good small nucleophile
 Displaces tosylate from primary carbon atoms
 Adds one carbon atom to the chain.
 Cyanide (nitrile) group converted directly to a carboxylic acid or ester, useful chain
extension
 Tosyl derivative of a primary alcohol reacts with this lithium derivative SN2 reaction
follows
 Alkyne provides the carbanion for the displacement of the tosylate

Epoxides
 Ether reacts in nucleophilic substitution without acids or Lewis acids
 Leaving group, alkoxide anion RO
 Ring strain making them unstable
 They are the three-membered cyclic ethers called epoxides (or oxiranes)
 Ring strain comes from the angle between the bonds in the three-membered ring
 60°M instead of the ideal tetrahedral angle of 109°
 ‘49° of strain’ at each carbon atom, about 150°of strain in the molecule
 Strain is that the molecule wants to break open
 Restore the ideal tetrahedral angle at all atom
 done by one nucleophilic attack.Saturday, August 8, 2020 25

 Epoxides react with amines to give amino-alcohols
 Not amines as nucleophiles because their reactions with alkyl halides are often be-devilled
 With epoxides they give good results

 Inversion occurs in these SN2 reactions if put epoxide on the side of another ring
 With a five-membered ring only cis-fusion of the epoxide is possible
 Nucleophilic attack with inversion gives the trans product
 As the epoxide is up, attack has to come from underneath
 New C–N bond is down and that the H atom at the site of attack was down in the epoxide
, up in the product
 Inversion has occurred

 Product is used in the manufacture of the antidepressant drug eclanamine, Upjohn
Company
 Starting material must be a single diastereoisomer (the cis or syn isomer)
 Inversion occurred at one carbon atom, product must be trans or anti diastereoisomer
 Starting material cannot be a single enantiomer it is not chiral
 Product is chiral, Cannot be optically active
 Biological activity in the drug requires this diastereoisomer

Esters
 Nucleophilic attack on esters in acidic or basic solution occurs at the carbonyl group
 Hydrolysis of simple esters in acid solution as the alkyl group varies in size
 Slow step is the addition of water, increases the crowding at the central carbon atom
 Alkyl group R is larger, reaction gets slower and slower
 Alkyl group R is tertiary, the reaction suddenly becomes very fast
 Faster than when R was methyl under the same conditions
 No normal ester hydrolysis in acid solution

 Longer the normal ester hydrolysis, an SN1 reaction at the alkyl group
 Substitution reaction at the saturated carbon atom rather than at the carbonyl group
 First step is the same, protonated ester is a good leaving group
 Intermediate decomposes to the t-alkyl cation without needing water at all

Factors affecting rate of nucleophilic substitution

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Factors affecting rate of nucleophilic substitution