chap 7: nucleophilic substitution + elimination reactions

1. function of the reagent

--> determine what mechanism(s) will be favored by the reagent kinds of reagents that promote certain kinds of reactions: E1: weak base + weak nucleophile => H2O, MeOH, EtOH SN1: weak base + weak nucleophile => H2O, MeOH, EtOH weak base + strong nucleophile => I-, Br-, Cl-, RS-, HS-, RSH, H2S SN2: weak base + strong nucleophile => I-, Br-, Cl-, RS-, HS-, RSH, H2S strong base + strong nucleophile => HO-, MeO-, EtO- E2: strong base + strong nucleophile => HO-, MeO-, EtO- strong base + weak nucleophile => NaH, DBN, DBU

3. regioselectivity/stereoselectivity

--> determine which mechanism(s) will occur by: 1. drawing out all the possible regio- and stereoisomers 2. choose the major -- by using the guidelines you have learned

SN2: solvent effects

--> solvent effects nucleoiphilicity => how nucleophile reacts in SN2 reaction SN2 need polar aprotic solvent because: polar protic solvent = engage in H-bonding, and stabilize anionic species (such as good nucleophiles) -- have a hydrogen atom attached to a strong electronegative atom -- negatively. charged nuclropphiles engage -- smaller nucleophiles are more effected aprotic solvents = stabilize both cations and anions -- in this solvent nucleophiles are less stable and thus more reactive => activation energy is lower => reaction is faster -- MEMORIZE LIST OF POLAR APROTIC SOLVENT

2. analyze the substrate

--> to see which mechanism(s) will dominate primary substrate: -- strong base + weak nucleophile = E2 -- strong base + strong nucleophile = SN2(mainly), E2 -- weak base + strong nucleophile = SN2 -- weak base + weak nucleophile = none secondary substrate: -- strong base + weak nucleophile = E2 -- strong base + strong nucleophile = E2(mainly), SN2 -- weak base + strong nucleophile = SN2 -- weak base + weak nucleophile = none tertiary substrate: -- strong base + weak nucleophile = E2 -- strong base + strong nucleophile = E2 -- weak base + strong nucleophile = SN1 -- weak base + weak nucleophile = SN1, E1

3 steps to successfully predict products

1. DETERMINE THE FUNCTION OF THE REAGENT 2. ANALYZE THE SUBSTRATE AND DETERMINE THE EXPECTED MECHANISM(S) 3. CONSIDER ANY RELEVANT REGIOCHEMICAL AND STEREOCHEMICAL REQUIREMENTS

elimination reaction

1. E2 2. E1

2 main reasons why alkyl halides undergo substitution and elimination reactions

1. halogen is electron-withdrawing, creating a partial positive charge(electrophilic site) on the alpha carbon(carbon directly attached to halogen), making it susceptible to nucleophilic attack -- highest e-negativity 2. halogen acts as a leaving group, and for a substrate to undergo a substitution/elimination reaction, it must possess a good leaving group

retrosynthetic analysis

1. look at the desired product -- identify a bond in the target molecule that can be made using a reaction that you know 2. decide what substrates and reactants we would need to use to make it -- draw the substrate and the nucleophile necessary to for the reaction 3. verify that the reaction you have proposed is reasonable -- good substrate and Nu for chosen rxn

3 types of alkyl halides

1. primary alkyl halide = carbon that is connected to the halogen is only connected to 1 other carbon 2. secondary alkyl halide = carbon that is connected to the halogen is connected to 2 other carbons 2. tertiary alkyl halide = carbon that is connected to the halogen is connected to 3 other carbons certain alkyl halides are better substrates than others

leaving group summary

1. the stronger the acid the weaker the conj base 2. the weaker the conj base, the better the leaving group

(hammond postulate)

= 2 points on an energy diagram that are close in energy should be similar in structure Exothermic rxn => transition states resembles reactant(s) Endothermic rxn => transition state resembles product(s) transition state drawn: -- bonds that are being broken/formed are dashed -- [ ] -- double dagger

(unimolecular rxns)

= SN1 and E1 mechanism steps 1. ionization of the substrate -- leaving group leaves --> carbocation intermediate forms 2. depending on how carbocation reacts with the solvent/base(EtOH) --> which depends on solvent/base's strength , it will either undergo: -- elminiation (E1) -- substitution (SN1) 3. formation of substitution and elimination products follows first-order kinetics: Rate = k [substrate] -- which confirms neither SN2 nor E2 is occurring

1. E2

= When an alkyl halide is treated with a strong base, it can undergo beta elimination (1,2-elimination) to form an alkene A strong base will react in this concerted mechanism e = elimination 2 = bimolecular WHEN: substrate is sterically hindered GOAL: alkyl halide --> alkene OVERALL RXN: alkyl halide(contains a Beta Carbon + a beta hydrogens, at least 2 hydrogens) + base(-) --> alkene + halogen ion + Conj Acid RXN MECHANISMS: -- base breaks bond between beta carbon and hydrogen in alkyl halide -- electrons form pie bond between alpha and beta carbons -- causing halide bond to break --> halogen in alkyl halide leaves

substitution reaction

= When one or more atoms replace another atom or group in a molecule SN2 SN1 alkyl halide + nucleophile --> alkyl halide + functional group

Sn1/En1 rearrangment of carbocation

= alkyl halide turns into carbocation by just loosing its leaving group hydride shift: secondary carbocation was formed

elimination reaction

= breaking apart one molecule E1 E2 alkyl halide + base --> alkene

good leaving groups

= conj base of a strong acid --> stable base Cl- Br- I- H2O

bad leaving groups

= conj base of weak acids F- OH- NH2- H- R- (can convert bad leading groups into good leaving groups)

Alkyl sulfonates

= good leaving groups --> because they are very stable (like halides, they are the conjugate bases of strong acids) -- sulfonate ions are resonance stabilized are made from corresponding alcohol -- alcohols are not good leaving groups

1. concerted mechanism(SN2)

= involves the following to occur at the same time: -- breaking bond of the leaving group(halogen) -- forming bond to the nucleophile 1 step reaction that involves: -- nucleophilic attack which causes --> loss of leaving group rxn rate: 1. concentration of the alkyl halide(substrate) and nucleophile -- (bimolecular) 2. sterics of alkyl halide substrate -- methyl alkyl halide(H3C-X) > primary alkyl halide > secondary alkyl halide > tertiary alkyl halide 3. nucleophile strength -- stronger nucleophile(-) => faster reaction 4. polar aprotic or protic solvent -- polar aprotic solvent( => faster reaction requires: -- good alkyl halide substrate -- strong nucleophile -- polar aprotic solvent IF electrophilic site is a chiral center THEN it undergoes inversion of configuration

(SN2: backside attack)

= nucleophile attacks from the backside electron density repress the attacking nucleophile from the front side -- Proper orbital overlap cannot occur with front-side attack because there is a node on the front-side of the LUMO THUS nucleophile must approach the back side to allow electrons to flow from the HOMO of the nucleophile to the LUMO of the electrophile carbons hinder the backside attack (look at next card)

leaving group

= substituent that can leave as a relatively stable entity can either be: -- anion -- neutral molecule (EX: protonated alchohol) in a nucleophilic substitution reaction of R-X: -- C-X bond is heterolytically cleaved -- leaving group departs with the electron pair in that bond, forming X:- the more stable the leaving group X:- , the better able it is to accept an electron pair(break the carbon halogen bond)

2. stepwise mechanism(SN1)

= substitution rxn of a tertiary substrate in an alcohol -- substation that occurs via a carbocation intermediate s = substitution 1 = unimolecular --> rate of rxn is dependent on one reactant(alkyl halide) -- doubling the concentration of the alkyl halide doubles the rate of the reaction rate determining step(RDS): formation of the carbocation GOAL: alkyhalide --> alcohol, di-sulfide, or ether OVERALL RXN: alkyl halide(3/teritary prime) substrate + alcohol(acts as nucleophile) solvent --> carbocation --> substitution product(alkyl halide BUT halide section is replaced w/ alcohol solvent w/out the H) + halogen ion RXN MECHANISMS: 2-step(stepwise) mechanism --> 3 steps 1. loss of leaving group: bond between beta carbon and halogen in alkyl halide breaks --> halogen = leaving group(-, takes electrons from bond w/ it) --> forms planar carbocation(= intermediate) that is achiral -- degree of alkyl halide = degree of carbocation formed 2. nucleophilic attack: -- 1. alcohol oxygen attacks/bonds to + charge of carbocation --> forms alkyl alcohol molecule, w/ a + charge on oxygen group -- 2. another alcohol(OH) solvent attacks/takes hydrogen from alcohol(OH) section of molecule --> causing bond between O-H in molecule to break -- 3. bonding electrons go to +O --> forming substitution product(ether) remember: when nucleophile is neutral(OH) --> proton transfer follows nucleophilic attack solvolysis = reaction where nucleophile can also act as a solvent

kinetic isotope effects

= when B-hydrogens(C-H) are replaced with deuteriums(C-D) --> reaction occurs at a slower rate C-D bond strength > C-H bond strength THUS: breaking the C-H bond occurs during the rate determining step

elimination and substitution are competing reaction pathways

= when the reagent can act as a nucleophile or a base

Sn1 vs En1

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E1 regioselectivity

E1 elimination can also yield more than one regioisomer elimination products = major products -- this is because E1 rxns always yield the most stable alkene = major product => most substituted alkene substitution product = minor product THUS: E1 regioselectivty CANNOT be controlled (like we can with E2 rxns)

E1 stereoselectivity

E1 rxns can yield several alkene stereoisomers elimination product(alkene) = most stable product = major product substitution product = least stable product = minor product when 2 elimination stereoisomers(alkenes) are obtained: -- least sterically hindered isomer = more stable = major product THUS: E1 rxns are stereoselective BUT a mixture of all possible products are still obtained

EX: step 3

For the SN2 product, backside attack gives inversion of configuration For the E2 product(s), draw all the b-hydrogens that can be anti-periplanar to the leaving group, then draw the resulting alkenes (use Newman projections if necessary) Now we have all the products resulting from SN2 and E2 --> Now label the major product. -- E2 is major pathway, and the base is not hindered --> so the Zaitsev product is the major.

SN1 stereoselectivity

IF: a-carbon is chiral THEN: 2 substitution products w/ opposite configurations at reactive carbon are formed -- nucleophile attacks carbocation from either side mixture of configurations are obtained, BUT most products are w/ inversion configuration -- inversion products > retention products THIS IS BC: the leaving group will form and ion-pair(lurk nearby) w/ the carbocation --> making it more difficult for the nucleophile to attack from the same side

E2 stereospecificity

IF: both a and b carbons are stereocenters THEN: E2 rxn is stereospecific -- one possible product -- 2 stereoisomers will be found -- # of rotamers w/ b-hydrogen anti-periplanar to leaving group = # of stereoisomers formed to rationalize stereospecificity the E2 reaction --> consider the transition state of the reaction by: visualizing/drawing the alkene as trans alkene IF: 2 alkenes products drawn are cis and trans isomers of one another THEN: reaction is stereospecific IF: 2 alkenes products drawn are NOT cis and trans isomers of one another THEN: reaction is stereospecific trans alkene requires: --> leaving group(usually a halogen) and beta hydrogen(hydrogen taken by base) must have a anti-periplanar fashion = anti coplanar, meaning leaving group + b-hydrogen are: 1. on the same plane 2. opposite from each other = anti -- beta hydrogen and leaving group must be co-planar can be made anti coplanar by: -- rotating the sigma bonds( => wedges and dashes will be on the same side) -- by drawing Newman projections then turning it back into the bundling structure (staggered newman => lower energy) (eclipsed newman => higher energy) the requirement for an anti periplanar transition state can often lead to the less stable Z isomer

E2 stereospecificity when leaving group is attached to a ring(chair conformation), cyclohexane

IF: leaving group AND b-hydrogens are in the axial position(same plane) and opposite to each other THEN: E2 elimination can occur IF: leaving group AND b-hydrogens are in the equatorial position THEN: E2 elimination canNOT occur to see which b-H and leaving group will react and be the main product draw out the chair conformation

(stereospecific vs. stereoselective)

IF: substrate = stereoisomeric and results in 1 stereoisomer as the product THEN: rxn is stereospecific IF: substrate can produce 2 stereoisomers as products where: -- 1 major product -- 1 minor product THEN: rxn is stereoselective

synthetic strategies

The whole point to organic synthesis is to make valuable, complex compounds from cheap and readily available starting materials You now know how to make a variety of compounds starting with an alkyl halide In order to envision how a desired compound can be made, you need to be able to recall the reactions you can use (meaning you have to remember these reactions!!!)

other substrates

There are a variety of alternatives to alkyl halides for substitution and elimination reactions, such as alkyl sulfonates Mesylates, tosylates, and triflates are excellent leaving groups -- They are also quite large, and so we usually use abbreviations when drawing their structures (OMs, OTs, and OTf)

SN2: kinetics of alkyl halide substrate

alkyl halide substrate's sterics effects rate of the reaction Less sterically hindered(less branching) electrophiles react more readily under SN2 conditions -- Alkyl groups branching from carbons hinder the backside attack of the nucleophile --> resulting in a slower rate of reaction best substrates for SN2 rxn: methyl alkyl halide(H3C-X) > primary alkyl halide > secondary alkyl halide > tertiary alkyl halide fastest SN2 reaction rate = substrate is a methyl alkyl halide(H3C-X) -- followed by primary alkyl halide slowest SN2 reaction rate = substrate is a tertiary alkyl halide

alcohols

can be: -- used in substitution and elimination reactions -- used as starting materials to make alkyl halides and alkenes need strongly acidic conditions to do these reactions involving alcohol --> because OH is a bad leaving group, but H2O is a good leaving group The mechanism will be either SN1 or SN2, depending on the substrate -- 1 ̊ alcohols react via SN2 -- 2 ̊ and 3 ̊ alcohols react via SN1 protic conditions = Strongly acidic conditions -- which would favor SN1, BUT since 1 ̊ carbocations are too unstable to form, 1 ̊ alcohols react via SN2 mechanism Alcohols will undergo E1 elimination when reacted with H2SO4: -- strongly acidic conditions are protic conditions --> which favors E1 for 2 ̊ and 3 ̊ substrates

SN1: carbocation stability

degree of alkyl halide = degree of carbocations carbocation stability => increases with # of electron-donating R groups methyl < primary < secondary < tertiary increasing alkyl substitution => increasing dispersal(delocalized) of +-charge more stable carbocation = faster rxn

regioselectivity/stereoselectivity for: E2

draw all the possible alkene isomers Only alkenes which result from a b- hydrogen anti-periplanar to the leaving group can form if a bulky base is used then Hofmann product = the major if a non-bulky base is used then most stable alkene = the major zaitsev product is generally favored over Hofmann product BUT if: sterically hindered base is used then: Hofmann product = favored process is stereoselective, because: trans alkene is favored over cis alkene process is stereospecific, because: when b-position of substrate has only 1 proton --> stereoisomeric alkene resulting from anti-periplanar elimination will be obtained

regioselectivity/stereoselectivity for: E1

draw the carbocation formed from loss of the leaving group... 1. if carbocation will rearrange --> draw the rearranged carbocation 2. draw all possible alkene isomers resulting from elimination of a b-hydrogen -- All possible alkene stereoisomers will form (E1 is not stereospecific) major product: will always be the most stable alkene zaitsev product is always favored over Hofmann product process is stereoselective (when applicable) trans alkene is favored over cis alkene

regioselectivity/stereoselectivity for: SN1

draw the carbocation intermediate... IF: carbocation intermediate does not rearrange THEN: attach nucleophile to the carbocation IF: carbocation intermediate rearranges (draw the resulting carbocation) THEN: attach the nucleophile to it IF: a chiral carbon is formed by attack of the nucleophile THEN: 2 products are formed ("R" and "S") --> Draw them both nucleophile attacks the carbocation which is generally where the leaving group was originally connected UNLESS a carbocation rearrangement took place nucleophile replaces the leaving group to give a nearly racemic mixture --> BUT as a result of the effect of ion pairs, there is generally a slight preference for inversion over retention of configuration

alkene stability

due to steric strain: - cis alkenes => less stable - trans alkenes => more stable -- thus trans is the major product more alkyl groups = more stable alkene: -- alkene increases in stability when more carbons are directly bonded(branch) to the alkene(c=c bond) -- monosubstituted < disubstituted < trisubstituted < tetrasubstitituded

2. E1

e = elimination 1 = unimolecular WHEN: GOAL: alkyl halide --> alkene OVERALL RXN: alkyl halide(3 prime substrate) + alcohol(acts as base, NOT nucleophile) solvent --> alkene + halogen ion + Conj Acid @@@ RXN MECHANISMS: 2-step(stepwise) mechanism 1. loss of leaving group: bond between beta carbon and halogen in alkyl halide breaks --> halogen = leaving group(-, takes electrons from bond w/ it) --> causing carbocation(= intermediate) to form 2. b-hydrogen elimination: alcohol solvent acts as a base to deprotonate the carbocation by: attacking its b-hydrogen --> causing bonding electrons to stay with carbocation, forming a pie bond between nearest b-carbons = elimination product

E2 kinetics

follows second order of kinetics because it is concerted: base removes a b-proton, causing: 1. loss of the leaving group 2. formation of the C=C bond

drawing products of E2 rxns

many factors to consider in order to correctly: -- predict the products -- decide which is the major product factors to consider: 1. if substrate reacts stereospecifically or stereoselectivly 2. if substrate produces several regioisomeric alkenes 3. If so ^, use steric hindrance of the base to predict what will be the major product

intro to alkyl halides

most substrates in substitution and elimination rxn are alkyl halides -- the substrate(reactant) will be the same alkyl halides = alkyl chain + halogen halogen will always be connected to an sp3 carbon

E2 stereoselectivity

multiple products => major + minor product cis vs trans alkenes: trans alkene => more stable => major product => lower Ea => faster to make cis alkene => less stable => minor product => higher Ea => slower to make

studying reaction mechanisms

one way to study reaction mechanisms is by: replacing the b-hydrogen w/ its isotope(deuterium) --> and observing how this effect the rate of then rxn -- chemical reactivity of deuterium(D) = chemical reactivity of hydrogen(H) IF: rxn rate is affected THEN: that particular H atom is likely involved in the rate determining step

E1 kinetics

rate of E1 is the same for SN1 reactions --> in both cases: rate determining step = formation of carbocation intermediate -- E1 and SN2 have same rate determining step

relative nucleoophilicity in polar protic solvents

relative nucleoophilicity in polar protic solvents: I- > Br- > Cl- > F- larger nucleophilic atoms are less solvated and => therefore more reactive in polar protic solvents -- larger nucleophiles are more polarizable and can donate more electron density relative nucleoophilicity in polar aprotic solvents: F- > Cl- > Br- > I-

substitution reactions

requires: -- loss of a leaving group -- nucleophilic attack 2 possible mechanisms: 1. concerted mechanism(SN2) 2. stepwise mechanism(SN1)

E2 regioselectivity

selectivity => major + minor product IF: strong base attacks(deprontate) alkyl halide w/ 1 < b-carbon --> there are multiple different options for which b-hydrogen to get THEN: E2 elimination results in more than one alkene product(constitutional isomers) THUS: regioselectivity(which alkene will be formed) of an E2 reaction can be controlled by choosing which strong base will be used zaitsev product = more stable alkene product IF: base => small(not sterically hindered/branched) THEN: zaitsev => more stable alkene(trans) => major product Hofmann product = less stable alkene product IF: base => non-nucleophilic = bulky(sterically hindered/branched) base -- use of non-nucleophilic base ensures that no SN2 products are formed THEN: Hoffman => less stable alkene => major product

SN1: kinetics

since formation of the carbocation requires ionization of substrate --> rate of its formation(SN1 substation) only depends on the substrate, SO the rxn follows first order kinetics @@@@@@@@@ Rate = k [substrate]

SN2: nucleophilicity

strong nucleophile is needed for an SN2 rxn -- solvent effects the nucleophile strong nucleophile => fast SN2 rxn -- anions = strong nucleophiles -- polarizable atoms = good nucleophiles -- more strong a nucleophile => more unstable => more reactive it is (size matters when neutral) weak nucleophile => slow SN2 rxn MEMORIZE LIST OF STRONG NUCLEOPHILES

substitution + elimination reaction

transforms alkyl halides from one functional group to another

To envision the compounds that can be synthesized from an alkyl tosylate

treat them the same as you would an alkyl halide With a strong Nu/strong base a: --> 1 ̊ substrate gives mostly SN2, with a little E2 --> 2 ̊ substrate gives mostly E2, with a little SN2

predicting products

when reacting an alkyl halide w/ a nucleophile and/or base... 1. many factors affect the product(s) formed -- substrate -- reagent -- solvent 2. a mixture of substitution and/or elimination mechanisms thus products will be obtained 3. BUT also possible(for a given substrate) for only 1 mechanism and thus product to occur THUS: to understand how to use these reactions(how to transform alkyl halides into a desired compound) --> one must be able to predict: -- ALL products that will form -- identify major + minor products

E2 effect of the substrate

when the substrate is sterically hindered, E2 elimination will occur. beta proton is gained by base

regioselectivity/stereoselectivity for: SN2

will observe a single product => inversion of configuration at the a-carbon -- chirality swaps nucleophile attacks the alpha position, where the leaving group is connected nucleophile replaces the leaving group with inversion of configuration