Goldup physical organic y2

what is a reaction mechanism?

• the actual process by which a reaction takes place

• to state a mechanism completely, we should have to specify teh positions of all atoms, including those in solvent molecules at every point in the process

• models which explain all available data

product analysis

• if bond making/breaking is concerted, a reaction can be stereospecific

• if not concerted, stereochemical information in the starting material is often lost

tracking atoms using isotopes

• can track isotopes using MS or NMR

• provides evidence for ‘what came from where’

• crossover experiments (doubly labelled materials) can give clear info about inter- vs intra-molecular reactions

• isotopic substitution doesn’t interfere with the mechanism of a reaction but can sometimes alter the rates of reactions

but…

• chemical labelling can influence the mechanism fairly easily

• not cheap to isotopically enrich the starting materials

chemical labelling for crossover experiments

to determine whether a reaction proceeds via intermolecular or intramolecular pathways- or whether intermediates freely exchange between molecules

• a whole molecule or functional group is chemically modified so its distinguishable from an otherwise identical molecule

• two similar reactants are prepared, but one carries a chemical tag ie. a different substituent, protecting group or marker

if crossover products form - intermediates are free and intermolecular

if crossover products don’t form - intermediates are intramolecular or tightly associated

isotopic labelling for atom tracking

to determine where specific atoms go during a reaction and which bonds are broken or formed

• a specific atom is replaced by an isotope eg. 2H, 13C, 15N, 18O

• the position of the isotope in the product is identified using spectroscopy or mass spec

• tells you which bonds are broken or retained and whether rearrangements, migrations or exchange occurs

• tells you details of the reaction mechanism at the atomic level

characterisation of intermediates - isolation

• molecules that can be isolated form the reaction mixture might be intermediates - if our proposed mechanism requires an intermediate then its a good indication its correct

• but only works if intermediates are stable, isolable molecules

• can test by resubjecting potential intermediate to reaction conditions and see if product forms

characterisation of intermediates - “in situ” detection

can be done via invasive or non invasive means

• non-invasive : NMR, IR, UV-vis or fluorescence spectroscopies

• invasive : mass spec, HPLC or GC

• advantages : non-invasive techniques can allow detection of species during a reaction, can detect unstable intermediates at low concentration, can monitor the reaction in real time

• disadvantages : detected species are often hard to fully identify, if you cant isolate it you cant test it under the same reaction conditions, ‘intermediate’ may be a by-product produced and consumed off pathway

characterisation of intermediates - trapping

• use known chemistry of reactive intermediate to provide evidence - can provide indirect evidence of intermediates present

• ie. test a mechanistic hypothesis

• if a reaction really goes through a particular reactive intermediate, then adding a substance that is known to react selectively and rapidly with that intermediate should intercept “trap” it and give a diagnostic product

• BUT just because its there doesn’t mean it’s an intermediate - could be a side product, off pathway byproduct - even resubjecting isn’t a perfect test and its easy to get wrong so you always need more evidence

general rules of rate equations

• for an elementary step order of reaction = molecularity

• in multistep reactions order does not necessarily equal molecularity of any step

• general rule 1 - if order >2 reaction is multistep

• general rule 2 - if species appears in rate law it is involves before RDS

competing reactions - curtin-Hammet principle

• simple kinetic competition - if two processes compete the outcome depends on the relative rates of the different pathways - construct rate equations for both pathways and take ratio - if a single reactant can proceed by two or more competing pathways, the product distribution depends of the kinetics of each pathway not on product stability

• pre-equilibria - the curtin Hammet principle - if competing processes are connected by a rapid equilibrium we can assume Keq is always satisfied - include the effect of the equilibrium and take ratios - if two rapidly interconverting species lead to different products, the product ratio depends only on the transition states leading to products, not on the equilibrium populations of the intermediates - product ratio is determined only by the relative heights of the TSs - even a minor conformer can dominate it if reacts through much lower barrier

qualitative correlation analysis applied to equilibria

• acidity increases (lower pKa) with substituent electronegativity - consistent with electron withdrawing groups stabilising conjugate base

qualitative correlation analysis applied to kinetics

• increasing reactivity/faster rate with increasing substituent electronegativity

• used to determine which step in mechanism is the RDS

Hammond postulate

• a transition state will closely resemble an adjacent species on the reaction diagram if it’s close in energy

• changes which stabilise the species closest in energy to TS will stabilise TS

• changes which will destabilise intermediates close to TS will destabilise TS

• allows us to predict how changes in substrate structure reaction conditions will affect reaction rates

rule of thumb for determining is substituents accelerate a reaction or not

• if electron density increases as we move towards to TS then electron withdrawing groups will accelerate the reactions

• if electron density decreases as we move towards the TS then electron withdrawing groups will decelerate the reaction

The Hammett Equation

• relates reaction rates/position of equilibria to the nature of a substituent on an aromatic ring

• tells us how changes in substituents affect reaction rates or equilibria assuming the mechanism stays the same

• origin of correlation is the effect of X on the partial charge at the ipso-carbon (c directly bonded to substituent)

• we measure the rates of reaction for substrates with different X and plot a graph of log(k(X)/k(H)) vs sigma_x (the substituent constant of x)

• log(k(X)/k(H)) = rho sigma x

• sigma x = pKa (H) - pKa (X)

• k x : rate constant for a substituted compound

• k H : rate constant for reference compound

• rho = reaction constant, measures how sensitive the reaction is to substituent effects

value of sigma x in hammett plots

• values are derived from benzoic acid dissociation equilibria

• depends on nature of X and position on aromatic ring

• p-x are conjugates to ipso c m-X aren’t

• if negative then substituent is an electron donating group eg. CH3, OCH3, NH2

• if positive then substituent is an electron withdrawing group eg. NO2, CN, CF3

• sigma m (meta) show mostly inductive effects

• sigma p (para) show inductive and resonance effects

the rho constant in hammett plots

• positive rho means EWGs accelerate the reaction - negative charge develops in TS or product

• negative rho means EDGs accelerate the reaction - positive charge develops in the transition state or product

• the magnitude of rho indicates how much charge is developed

• small rho (0-1) - little charge development

• large rho (>3) - significant charge development

• by definition the ionisation of benzoic acid has a rho of 1

• steep slope (rho) = a high sensitivity to substituents

problems with using hammett plots

• often fail. when strong steric effects dominate

• often fail when solvent effects change

• often fail when the substituent participates directly in the mechanism

• only works well for para and meta substituents not ortho