CHEM 257- chapter 11: nucleophillic substitutions and eliminations

reactions of alkyl halides

C-X carbon is electrophilic, undergo two types of reactions: nucleophiles that act as a Lewis base/donates electrons (substitution) and nucleophiles that are Brønsted bases/accept protons (elimination)

nucleophillic substitution reactions

each step involves the substitution of one nucleophile (Cl-, OH-, etc.) Walden experiments of (-)-malic acid being converted to (+)-malic acid showed that some reactions in the cycle must have occured with a change, inversion, or configuration at the chirality center

tosylate

p-tolunesulfonyl, inversion reaction that uses Tos, acts as a halogen, Step 1 of adding Ts to a reaction does not change stereocenter (C-O bond), Step 3 of removing acetate does not either, Step 2 of inversion occurs in substitution of acetate for Ts (OAc for OTs)

inversion step

nucloephilic substitution of a 1° or 2° alkyl halide, or tosylate always proceeds with inversion of configuration

SN2 reaction

substitution, nucleophilic, bimolecular

one step reaction without intermediates, follows second order reaction kinetics (rate depends on concentrations of 2 reactants in this case Nu and R-X), inversion at reaction center (nucleophile comes in on one side of the substrate and bonds to the carbon, the halide or tosylate departs from the other side, thereby inverting the stereochemical configuration)

SN2 reaction mechanism

the reaction involves a transition state in which both reactants are together, the C-X bond is partially broken at the same time the C-Nu bond is partially forming (transition state), TS of an S N2 reaction is planar about the carbon (remaining three groups are in the same plane)

SN2 substrate properties

methyl-X most reactive

- 1°R -X are next most reactive

- 2° R-X can react this way but very slowly, helps if non-basic nucleophile and inversion of stereochemistry

- 3°R -X do not react by this pathway

no reaction at C=C/sp2 hybridized carbons (vinyl halides and aryl haldies)

the more alkyl groups connected to the reacting carbon, the slower the reaction

SN2 nucleophile properties

any species that is either neutral or negatively charged Lewis base (donates electrons), must have an unshared pair of electrons

-negative nucleophile yields a product (nuetral)

- neutral nucleophile yields a product with a positive formal charge

-nucleophilic strength parallels basicity (good nucleophiles are good bases, OH- > CH3CO2- > H2O)

-nucleophilicity increases going down a column of the periodic table (I- > Br- > Cl-)

-anions are more reactive than neutral nucleophiles

SN2 leaving group properties

a good leaving group reduces the barrier to a reaction and stabilizes the negative charge in the transition state

-stable anions that are weak bases are excellent leaving groups

-(OH-, NH2-, OR-) < F- < Cl- < Br- < I- < TosO-

-groups that are basic, small, do not leave!

• R-F, -OH, -OR', and -NH2 do not undergo SN2 reactions, but can be converted into something that is a good leaving group (ex: alcohols - into halides or a tosylate)

ethers as leaving groups

can happen in one case: epoxide opening!

- is due to angle strain of 3-membered ring which causes it to be more reactive than other ethers

polar protic solvents

polar solvents that can/donate hydrogen bond (-OH or -NH)

polar aprotic solvents

polar solvents that can't form hydrogen bonds (CH3CN, DMSO, DMF, HMPA)

SN2 solvent properties

-polar aprotic

-increase rate of SN2 reactions by raising the ground-state energy of the nucleophile due to solvent solvating cations more than anions

-faster SN2 reactions!!!

SN1 reaction

substitution, nucleophillic, unimolecular (single molecule involved in elementary step of a chemical process)

two step reaction that forms carbocation intermediate, leaving group leaves then nucleophile adds, follows first order reaction mechanism in which the concentration of the nucleophile does not affect rate of reaction, only alkyl halide concentration affects

SN1 mechanism

-C-X bond breaks

-C+ intermediate is formed

-nucleophile adds to C+

-rate-determining step is formation of the carbocation intermediate (rate-determining step is the highest transition-state energy)

stereochemistry of SN1 reaction

in theory:

• the planar (sp2 ) intermediate leads to loss of chirality

- a free C+ is achiral/ carbocation intermediates are planar, sp2 hybridized, and achiral (the achiral symmetry can react with a nucleophile equally well from either side, leading to a racemic 50:50 mixture of enantiomers

in reality:

• C+ is biased to react on side opposite leaving group

• suggests C+ is associated with leaving group (ion pair) during nucleophilic addition, few SN1 displacements occur with complete racemization

effects of ion pair formation

associated C+ and leaving group is an ion pair

• if ion pair forms, product has more inversion than retention

• product is partially racemic

SN1 substrate properties

the more stable the carbocation intermediate, the faster the SN1 reaction due to rate-limiting step being the formation of carbocation intermediate

- methyl < primary < allylic = benzylic = secondary < tertiary (carbocation stability)

-allylic and benzylic intermediates are stabilized by resonance delocalization of charge

SN1 leaving group properties

critically dependent on leaving group (very important to get a good-great leaving group), reactivity: the larger halides ions are better leaving groups, in acid OH of an alcohol is protonated and leaving group is H2O (if you kick out a neutral molecule as the leaving group the reaction WILL occur)

OH- < Cl- < Br- < I- = Tos < H2O (leaving group reactivity)

SN1 nucleophile properties

nucleophilic addition occurs after formation of carbocation so the reaction rate is not affected by nature or concentration of nucleophile, neutral nucleophiles are just as effective as negatively charged ones

SN1 solvent properties

-stabilizing C+ also stabilizes associated transition state, increases reaction rate

-polar solvents are best, protic solvents are common (favored in protic solvents because the transition-state energy leading to carbocation intermediate is lowered by solvation)

-SN1 reactions have a faster rate in strongly polar solvents than in less polar solvents (due to solvent molecules orienting around the carbocation so that the electron-rich ends of the solvent dipoles face the positive charge of the carbocation, thus lowering the energy of the ion and favoring its formation

elimination reactions

elimination is an alternative pathway to substitution

- opposite of addition

- generates an alkene (double bond/pi bond)

-competes with substitution, decreases yield, especially for SN1 processes (can also be the reaction you WANT to happen)

zaistev's rule

in the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates (the alkene with more alkyl substituents on the double-bond carbonds)

type of elimination reactions

E1, E1cb (conjugate base), E2

all differ in the timing and order of C-H and C-X bond breaking

E1

elimination, unimolecular

-breaking of C-X bond produces a carbocation intermediate that yields the alkene by base removal of a proton

E2

elimination, bimolecular

-simultaneous cleavage of C-H bond and C-X bond produces the alkene without intermediates

E1cb

elimination, conjugate base

-proton undergoes base abstraction, yielding a carbanion (R-) intermediate

-carbanion loses X-, yielding the alkene

E2 reaction

reaction involving treatment of an alkyl halide with a strong base

-the most common elimination pathway

-second-order kinetics (both base and alkyl halide take part in rate-limiting step, abides by the rate law, rate = k ×[RX] ×[Base]

-transition state: loss of X and transfer of H

-alkene forms stereospecifically

deuterium isotope effect

C-H bond is weaker and easier to break than C-D bond, C-H/C-D bond is broken in rate determining step which is consistent with E2 reaction being second-order kinetics and a one-step process

geometry of E2 elimination

reacting atoms in an E2 reaction, H-C-C-X, are in the same plane (periplanar), 2 possible geometries, H- and X- can either be

- eclipsed (syn), less stable, higher energy

- staggered (anti), lower energy, more stable, leaving group and H are 180 degrees apart, minimizes steric interactions and allows orbital overlap

cyclohexane conformation of E2 elimination

abstracted proton and leaving group should align trans-diaxial to be anti periplanar, equatorial groups are not in proper alignment and E2 elimination cannot occur

E1 reaction

E1 reactions compete with S N1 and E2 at 3° centers (often see E1 and SN1 reactions together)

-E1 is not stereospecific due to halide and hydrogen being lost in separate steps

-first order kinetics

-no deuterium isotope effect

-gives Zaitsev product (most substituted alkene)

E1cB reaction

forms a carbanion intermediate, common when poor leaving group (such as OH-) is 2 carbon atoms away from a carbonyl

1° R-X

-SN2 with a good nucleophile (mostly see this)

-E2 with a strong base

2° R-X

-SN2 with a weakly basic nucleophile, polar aprotic solvent

-E2 with a strong base

3° R-X

-E2 when base is present (mostly see this)

-SN1 (acidic) and E1 under neutral conditions