4: mechanistic organic chem

what is the relationship between s/p character and reactivity?

higher s character = electrons held closer to the nucleus = less reactive

higher p character = electrons held further from the nucleus = more reactive

draw the molecular orbital diagram from a carbonanion

describe the different hybridisations of carbon and their relative reactivities

the extent of p orbital contribution depends on the amount available i.e. alkynes have 2 p orbitals involved in triple bond.

2s + 2p(x) = 2 sp hybrid orbitals = linear

2s + 2 2p = 3 sp2 hybrid orbitals = trigonal planar

2s + 3 2p = 4 sp3 hybrid orbitals = tetrahedral

sp = 50% s 50% p = ~unreactive

sp2 = 33% s 66% p

sp3 = 25% s 75% p = ~reactive

draw the arrangement of orbitals that gives rise to ∏ and sigma bonding

how does the separation of filled and empty orbitals affect stabilisation?

small separation = good stabilisation

large seaparation = poor stabilisation

what are the (main) conditions for orbital interaction?

1. matched symmetry

2. good overlap

3. similar energies

describe lewis acids and lewis bases in terms of orbitals

lewis base = donate electron density = high energy (unstable) HOMO

lewis acid = accept electron density = low energy (stable) LUMO

explain why lewis adducts are so stable

lewis base = high energy HOMO

lewis acid = low energy LUMO

in conjunction, this minimise the minimise the orbital separation and increase stabilisation

what is Bredit’s rule? explain

a double bond is not possible at the bridgehead of two small rings

= poot orbital overlap

label this reaction coordinate diagram

define a transition state

= maxima on the reaction coordinate diagram

= partially formed bonds

= does not exist for finite time and cannot be isolated/observed

define an intermediate

= exists between energy barriers in “well” on reaction coordinate diegram

= fully formed bonds

= isolatable/observable

define the ΔG° for a reaction in terms of entropy/enthalpy

define the ΔG° for a reaction at equilibrium

defines the position of equilibrium

how does ΔG° control the spontaneity of reaction

-ve ΔG° favours the forward reaction and product formation

+ve ΔG° favours the backwards reaction and reactant formation

how can ΔG° be altered?

-ve ΔH°:

• stronger bonds forming (-ve H) than breaking (+ve H)

• less strain in products than reactant

+ve ΔS°

• increase in disorder is favoured

describe how choice of polar solvent can favour products or reactants

polarity: reactants > products

• polar solvent favours reactants

polarity: products > reactants

• polar solvent favours products

polar solvents cluster around charges in reactants and products (solvation) so that charge is delocalised.

solvation = interactions formed = -ve H = favoured

what are the two types of solvent?

protic

= contain O-H or N-H

= solvate +ve and -ve charges

aprotic

= do not contain O-H or N-H

= solvate only +ve charges

describe the dielectric constant

= measure of polarity

large dielectric constant = polar

small dielectric constant = non-polar

= measure of ability to solvate charge

examples of protic solvents

h2o, meoh, etoh, tbuoh, acoh

examples of aprotic solvents

dmso, dmf, acn or mecn, dcm, thf, etoac, et2o

draw the structure of DMSO

draw the structure of DMF

draw the structure of ACN/MeCN

draw the structure of THF

rank protic solvents in terms of solvation ability

H2O > MeOH > EtOH > tBuOH > AcOH (delocalised = weaker)

rank aprotic solvents in terms of solvation ability

DMSO > DMF > ACN/MeCN > acetone > DCM > THF> EtOAc > Et2O

what are the 4 types of solvent; describe each

polar protic = +ve & -ve = good solvation

polar aprotic = +ve = good solvation

apolar protic = +ve & -ve = poor solvation

apolar aprotic = +ve = poor solvation

what is the rate determining step?

= step with largest activation energy

= determines the overall rate of reaction

what does the rate of the RDS depend on?

• number of collision between reacting molecules in a given period

• fraction of collisions with sufficient energy for reaction

• fraction of collisions with correct orientation for reaction

describe the role of the RDS is determining the order of reaction

reactants involved prior to and in the RDS influence the rate of reaction.

reactants involved after the RDS will not influence the rate of reaction.

describe the rate constant

fundamental property of a reaction

depends on:

• temperature

• pressure

• solvent

• DOES NOT DEPEND ON CONCENTRATION

give an equation for the ratio of product for the concurrent reactions described by the equations

define the rate of formation when:

• [CN-] = [N3-]

• 32 x [CN-] = [N3-]

given k[CN] = 16 k[N3]

define molar free energy of activation, ΔG‡

= difference in energy between a ground state and a transition state

= related to the rate constant, k.

~ analogous to activation energy

how do ΔG‡ and E(a) differ?

ΔG‡ = contains ΔS‡ and ΔH‡

E(a) = contains ΔH‡

give an equation that relates rate constant with ΔG‡

ΔG‡ = ΔS‡ and ΔH‡ related

vs

Ea = ΔH‡ related

A = ΔS‡ related

small |ΔG‡| = large k = fast reaction

large |ΔG‡| = small k = slow reaction

= analogous to activation energy

what are the ranges for enthalpy and entropy of activation?

ΔH‡ = 40 - 125 kJ mol(-1)

ΔS‡ = -150 - 60 J K(-1) mol(-1)

ΔH‡ = always positive due to breaking of bonds without reforming (forming TS) = always disfavoured

smaller = ~favoured

larger = ~disfavoured

ΔS‡:

-ve = disfavoured

+ve = favoured

describe a dissociate RDS in terms of enthalpy and entropy

favoured by entropy = increase in disorder

disfavoured by enthalpy = bonds broken

describe an associative RDS in terms of enthalpy and entropy

disfavoured by entropy = increase in order

favoured by enthalpy = balance in bond breaking/forming

describe.a diels alder reaction in terms of entropy

• requires simultaneous bond formation = highly ordered TS

• associated RDS

highly disfavoured by entropy

define an elementary reaction

= a single step in a reaction mechanism proceeding in a particular direction

define molecularity of an elementary step

= the number of molecules involved in the formation of a single transition state (ignoring those only involved in solvation)

= may be different depending on direction

what are the two molecularities of elementary steps?

• unimolecular

• bimolecular

molecularities above this are exceedingly slow since they require the simultaneous collision of ≥3 molecules

describe microscopic reversibility

= the mechanism of the (lowest energy) reverse reaction must retrace each step of the mechanism of the (lowest energy) forward reaction (in microscopic detail)

= RDS are mirrored i.e. formation of intermediate in both directions

how can reactions be accelerated?

• increase concentration(s) of reactant(s)

• increase temperature

• reduce ΔG‡ of the RDS = raise ground state energy and/or lower TS energy

describe SN2 reactions

• bimolecular; second order

• concerted; 1 step

• inversion of configuration

draw the mechanism of an SN2 reaction

describe SN2 reactions in terms of ΔS‡ and ΔH‡

associative TS

disfavoured by ΔS‡

favoured by ΔH‡

draw a reaction coordinate diagram of an SN2 reaction

what can be determined from ΔG‡ vs ΔG°?

ΔG‡ = rate constant, k = RDS varies rate

ΔG° = equilibrium constant, K = varies position of equilibrium

draw the MO diagram for the transition (Nu-C)

describe SN2 reaction in terms of orbital overlap

back lobe (opposite to L):

• phase matched

• good overlap

front lobe (at L):

• phases matched

• poor overlap

why is Nu attack favoured from the back lobe/inhibited at the front lobe?

• poor orbital overlap/alignment

• electrostatic repulsions from L and R

describe soft and hard electrophiles/nucleophiles

soft = polarisable = large, uncharged, diffuse

hard = less polarisable = small, highly charged

examples of soft and hard electrophiles/nucleophiles

nucleophiles

soft = I(-), RS(-), NC(-) = large attacking atom/charge distribution over atoms

hard = F(-), RO(-) = small attacking atom/concentrated charge

electrophiles

soft = alkyl halide (large halide i.e. I)

hard = H(+), alkyl halide (small halide i.e. Cl), carbonyls, SiMe3(+)

describe the energy of soft/hard electrophile LUMO/nucleophile HOMO

electrophiles:

soft = low LUMO

hard = high LUMO

nucleophiles:

soft = high HOMO

hard = low HOMO

what kind of electrophiles are alkyl halides and what kind of NUCLEOPHILE IS FAVOURED IN SN2?

alkyl halides = soft electrophiles = low LUMO

interact best with soft nucleophiles = high HOMO

i.e. I(-), RS(-), NC(-)

describe enolates variable nucleophilicity

soft at B carbon

hard at charged O

draw the reaction of enolate with:

• silylating agents (Me3Si-Cl)

• alkyl halides (Me-I)

describe the speed of SN2 reactions on different °s of alkyl halides

1° = YES; fast

2° = majorly no; if yes, slow

3° = NO

described the speed of SN2 reactions on different length 1° alkyl halides

smaller chain = faster SN2

describe the speed of SN2 reactions with different size of nucleophiles

bulky nucleophiles = slow

describe the SN2 reaction of Me-I with these nucleophiles

what can reduce ΔG‡ w.r.t. leaving group

• weak C-L bond

• L(-) stability

what acts as a proxy for leaving group ability?

pKa

= defines the stability of the anion

weak acids: tend to protonated form

• strong H-A bond

• poor stabilisation of A(-)

strong acids: tend to deprotonated form

• weak H-A bond

• good stabilisation of A(-)

therefore:

strong acid = small pKa = good leaving groups

weak acid = large pKa = poor leaving groups

define pKa and how it relates to acid strength

pKa ∝ 1/acid strength

describe the relative leaving group abilities of the halides

give examples of poor leaving groups

• F(-)

• RS

• CN

• OH

• OR

describe why there is no SN2 at sp2 (majorly) or sp (ever) atoms

• line of attack is blocked

• C has higher s character = stronger C-X bond

• C-X sigma bond often not the LUMO

what can reduce ΔG‡ w.r.t nucleophile

• strong C-Nu bond

• Nu instability/reactivity

what acts as a proxy for nucleophilicity (SAME ATOM/SAME SIZE)?

pKa of conjugate acid

weak conjugate acids: tend to protonated form

= conjugate base is less stabilised (less likely to be protonated) by weak conjugate acid

strong acids: tend to deprotonated form

= conjugate base is more stabilised (likely to be protonated) by strong conjugate acid

therefore:

strong conjugate acid = small pKa = poor nucleophile

weak conjugate acid = large pKa = good nucleophile

examples of nucleophiles and relative reactivities

most nucleophilic → least nucleophilic

summarise pKa and LG/Nu ability

acid strength ∝ 1/pKa ∝ LG ability

conjugate acid strength ∝ 1/pKa ∝ 1/Nu ability

describe the variable solvation of charges by protic solvents

hard negative charges = strong charge-dipole interactions = good solvation

soft negative charges = weak charge-dipole interactions = poor solvation

what does the nucleophilicity of attacking atoms of different sizes depend on?

solvent

aprotic solvents:

negative charges are not solvated = nucleophilicity ∝ basicity

protic solvents:

hard negative charges are solvated = weakly nucleophilic

(charge is delocalised in TS so less interaction with solvent)

soft negative charges are poorly solvated = strongly nucleophilic

for what kind of SN2 reactions are polar aprotic solvents particularly good for?

uncharged electrophile + charged nucleophile

polar aprotic solvents only solvate +ve charges. +ve component/counterion of nucleophile is well solvated while the -ve part is poorly solvated = naked and highly reactive.

what kind of solvent is preferred in:

• charged nucleophile + uncharged electrophile

• uncharged nucleophile + uncharged electrophile

• charged nucleophile + uncharged electrophile

= (polar) aprotic

= TS has delocalised charge w.r.t reactants/products

• uncharged nucleophile + uncharged electrophile

= polar (aprotic or protic)

= TS/products is more polar than reactants = stabilised by polar solvent

what is used to facilitate SN2 between non-polar RX and ionic compounds?

• 2 immiscible solvents

• phase transfer catalyst

example of a phase transfer catalyst

= soluble in both organic and aqueous phases

describe phase transfer catalysis

non-polar RX + ionic compound + 2 immiscible solvents

• non-polar RX will dissolve in organic phase; ionic compound will dissolve and ionise in aqueous phase

• phase transfer catalyst drags -ve ion into organic phase to balance charge; -ve ion is naked and highly reactive = SN2

• phase transfer catalyst coordinates to -ve ion product of SN2 and drags back into aqueous phase

what can be used as a nucleophilic catalyst and explain

iodide I(-)

• nucleophilicity in protic solvent: I(-) > Nu(-)

I(-) = large anion = soft = poorly solvated by protic solvent

• iodide displaces L faster than Nu(-)

• leaving group ability: I(-) > L

HI = strong acid = good LG

• Nu(-) displaces in R-I faster than in R-L

why are cyclisations favoured over bimolecular reactions?

by entropy

cyclisations:

• dissociative TS

• ΔS = 0

bimolecular:

• associative TS

• ΔS = -ve (loss of translational entropy via associative TS)

relative reactions rate for different ring sizes (cyclisations)

5 > 6 > 3 > 4 & 7 > other rings

why do cyclisation forming small (3/4) rings have slow reaction rates?

ring strain:

in products increases ΔH*

in TS increases ΔH‡

why do cyclisation forming large (>6) rings have slow reaction rates?

probability of ends colliding with correct orientations is small

what is effective molarity

EM = k(intra) / k(inter)

unimolecular: the concentration of [A] required to match k(intra)

why would effective molarity (EM) be low?

favourable orbital alignment/other stereoelectronic factor present in inter absent in intra

describe how reaction would proceed here with NaOEt

SN2 at 3° C-X possible due to favoured 3 membered ring

describe intra SN2 on cyclohexane

Nu and LG must be 1,2-trans diaxial and antiperiplanar

= orbital alignment

what does X-exo/endo-trig/tet mean?

X = ring size in the TS

exo/endo:

exo = bond broken outside ring of TS

endo = bond broken within ring of TS

trig/tet:

trig = LG attached to trigonal C (sp2)

tet = LG attacked to tetrahedral C (sp3)

what are Baldwin’s guidelines to favourable cyclic reactions

exo > endo

= favoured by good orbital alignment

3 to 7-exo-tet > 3 to 7-endo-tet

what form does the lowest energy TS of an SN2 take?

= linear

describe neighbouring group participation (= anchimeric assistance)

(strained) cyclic intermediate increases reaction rate

• sometimes lead to rearrangement

• sometimes affects stereochemistry of products

= intramolecular nucleophilic catalysis (i.e. iodide nucleophilic catalysis)

describe the effect of neighbouring group participation here

3-exo-tet cyclisation

draw the mechanism of this reaction

explain why the anti diastereomer is faster than the syn diastereomer

= neighbouring group participation

explain the Curtin Hammett principle

the ratio of products formed from one starting material present in two rapidly equilibrating conformations depends only on the energy difference between the two transition states

draw the two pathways of this reaction

LEFT IS WRONG = NEEDS TRANSDIAXIAL

describe SN1 reactions

• unimolecular; first order

• stepwise; 2 step

• loss of stereochemistry