5: reactive intermediates

how can concerted vs non-concerted reactions be differentiated?

concerted = 1 TS; NO intermediate

non-concerted = >1 TS; intermediate(s)

define transition state vs intermediate

TS = “no'“ lifetime (actually femtoseconds) = the highest energy point on the reaction pathway

intermediates = lifetime = in an energy ‘well’

describe the reactivity of intermediates

intermediates are more reactive/unstable than starting material

= cannot be isolated

what are examples of reactive intermediates?

• anion

• cation

• radical

• carbene

describe carbenes

neutral sp2 hybridised (2 bonds) carbon with 2 non-bonding electrons

singlet = lone pair in sp2 orbital

triplet = one electron in sp2 orbital; one electron in p orbital

describe radicals

unpaired electrons

organic radicals:

• unpaired e(-) typically occupies the unhybridised p orbital perpendicular to plane of sp2 orbitals = SOMO

• generally unstable

describe the stages of a radical reaction

1. radical generation / initiation

2. radical modification / propagation (may be >1 step)

3. radical capture / termination

describe radical creation

requires bond homolysis = electrons in a bond move separately = two radicals

what is a major problem during radical propagation?

dimerisation

radicals are very unstable and tend to forms bond with other radicals

describe the first organic radical

• Ag has high affinity for Cl

• Al-Cl is very stable

• triphenyl methyl radical shows no dimerisation due to steric hinderance

describe stabilisation of organic radicals

any factor which can stabilise cation/anion can also stabilise a radical centre:

• conjugation (electronic effects)

• EWG (electronic effects)

• EDG (electronic effects)

• steric effects

describe stabilisation by conjugation

• effective as ∏ and ∏* adjacent to SOMO

possible in:

• allylic radical

• benzylic radical

• radical a to a carbonyl = ∏ too stable due to CO bond stability to interact with SOMO = ∏* more important

describe stabilisation by EDG/EWG effects

EDG = destabilising

EWG = stabilising

describe stabilisation by steric effects

steric protection moderates radical reactivity

very stable radical often require steric AND electronics

describe the stabilisation of the TEMPO radical

electronic = lone pair in vertical sp3 orbital conjugated to radical

sterics = alkyl ring and alpha methyl groups

describe the stabilisation of triphenyl radical

electronic = hyperconjugation from alpha C-H’s = requires planarity

sterics = exists in twisted form to avoid clashing H’s = “propeller” shape provides steric hinderance

describe EPR (electron paramagnetic resonance)

electrons have spin of 1/2. unpaired electron spin interacts with the spin of neighbouring protons. applies only to unpaired electrons as pairs cancel out.

coupling gives rise to hyperfine splitting of spin substates

EPR coupling = NMR coupling

couples to protons since have the same spin (1/2)

what would the EPR spectrum of methoxymethyl radical look like?

what would the EPR spectrum of benzyllic radical look like?

what would the EPR spectrum of phenyl radical look like?

unpaired electron in sp2 orbital

what is BDE?

bond dissociation energy = energy required to achieve homolytic fission in the gas phase

describe the relationship between BDE and:

• bond strength

• ease of radical formation

• radical stability

lower BDE = weaker bond

higher BDE = stronger bond

lower BDE = radical more easily formed

higher BDE = radical less easily formed

lower BDE = radical more stable

higher BDE = radical less stable

how can radical be classified by polar effects?

electrophilic radicals = δ+ = neighbouring electron withdrawing group

nucleophilic radicals = δ- = neighbouring electron donating group

what kind of residues will electrophilic/nucleophilic radicals react with?

electrophilic radicals = electron rich alkenes

nucleophilic radicals = electron poor alkenes

what is a possible application of polar effects on radicals?

synthesis of alternating copolymers

during propagation, nucleophilic radical intermediate will be unreactive to electron poor alkene (itself) and react fast with electron rich alkene = alternating

describe the effect of EDG/neighbouring Nu on SOMO + consequence

interaction with lone pair increases the energy of the SOMO

= closer in energy to the empty ∏* orbital of electron poor alkene = preferential interaction

describe the effect of EWG/neighbouring El on SOMO + consequence

interaction with empty ∏* orbital decreases the energy of the SOMO

= closer in energy to the filled ∏ orbital of electron rich alkene = preferential reaction

what are methods for initiating radical reactions (radical generation)?

• thermal cleavage of weak bonds

thermolysis at elevated temperatures

ideally small BDE (=weak bonds) to minimise temp.

• photochemical cleavage of weak bonds

photolysis at room temp

• single electron transfer

one electron oxidation/reduction

what compounds readily undergo thermal cleavage?

X-X and X-Y (halides) often weak due to lone pair repulsions

• diacyl peroxides

• azo compounds

describe thermal cleavage of diacyl peroxides

weaker O-O bond due to resonance stabilisation of TS and products

driven by evolution of gaseous side product

describe thermal cleavage of azo compounds

driven by evolution of gaseous side product

what is one of the most commonly used radical initiators? draw structure and initiation

AIBN

describe photolysis of weak bonds

X-X and X-Y (halides) often weak due to lone pair repulsions

describe what occurs after photolysis of benzophenone

intermolecular atom transfer (can also be intramolecular)

what is the simplest reagent of single electron transfer

dissolving metal (Na/K) in NH3(l):

Na(+)/K(+) and e(-) free in blue solution

what are two types of single electron transfer reactions?

• Birch reduction

• Samarium iodide

describe the Birch reduction

reduction of aromatic compounds by sequential transfer of e- and H(+) to an aromatic ring

→ non-conjugated cyclohexa-1,4-diene

can be directed by EWG/EDG substituents

describe Birch reduction with EDG substituent

vinylic = attached to double bond

describe Birth reduction with EWG substituent

allylic = adjacent to double bond

*any EWG oxidising on its own i.e. NO2 will be reduced*

describe single electron transfer with Samarium iodide (SmI2)

SmI2 = lanthanide reagent

Sm can be Sm(II) or Sm(III) = easily give up electron under mild conditions = reducing agent

i.e.

what are two types of radical propagation?

• intermolecular reaction

• intramolecular reaction

describe types of intermolecular reactions

reaction of radical with a stable molecule

intrinsically slower than combination with another radical

generates new radical

• radical addition reactions (i.e. alternating polymerisation)

• atom abstraction (radical substitution reactions)

• fragmentation reactions

describe radical addition reactions

alkenes are common targets

describe intermolecular atom abstraction reactions

radical does an SN2-like attack on abstracted atom

favoured is stronger bond is formed

often Z = C

rarely Y = C

describe fragmentation reactions

i.e. AIBN thermal cleavage

loss of stable molecule

describe types of intramolecular reactions

intrinsically fast

• ring closing reaction

• intramolecular atom abstraction

• ring opening reaction

describe intramolecular ring closing reaction

alkene → single bond (ring)

= intramolecular version of radical addition

describe intramolecular atom abstraction

i.e. 1,5-hydrogen atom abstraction

describe intramolecular ring opening reaction

driving force = relief of ring strain

forms alkene = reverse of radical addition

describe termination of radical reactions

typically radical recombination

what is the most common initiator and catalyst in radical reactions?

AIBN + Bu3SnH (tributyltin hydride)

weak Sn-H = poor orbital overlap

describe the reduction of haloalkanes to alkanes with tin hydride

describe an advantage of radical reactions

= compatibility with many functional groups

i.e. O-H bond cleavage in not usually a problem = high BDE

what are three types of radical reactions?

• functional group removal

• intermolecular addition to multiple (double) bonds

• intramolecular addition to multiple (double) bond = cyclisation

what are different types of functional group removal

• removal of X from R-X (seen)

• removal of OH from R-OH: 2 types

• removal of COOH from R-COOH

what is a driving force in many Barton reactions

= strength of S-Sn bond

what are the two types of dehydroxylations?

= both follow Barton-McCombie mechanisms

LG:

• xanthate

• thiocarbonyl-imidazole

describe Barton-McCombie dehydroxylation

R-OH → R-xanthate → R-H

only for 2° or 3° alcohols

draw xanthate formation

reagents:

• NaH

• CS2

• MeI

draw xanthate removal

AIBN not catalytic = not regenerated = initiator

describe Barton decarboxylation

R-COOH → R-COCl → R-CO-thiohydroxamate ester

draw dehydroxylation via thiocarbonyl-diimidazole

draw the reagents of Barton decarboxylation

DMAP = to replace Cl and make an even better LG

K salt = to displace the LG

draw the first stage of Barton decarboxylation

= formation of thiohydroxamate ester

draw the second stage of Barton decarboxylation

describe intermolecular addition to multiple bonds

radical + alkene → alkane

(here) radical generated by cleavage of R-X bond

describe intramolecular addition to multiple bonds

radical + alkene → ring alkane

= fast = entropically favoured

how are ring closures named?

X-exo/endo-trig/tet etc.

X = size of ring

exo = alkene outwith ring of TS

endo = alkene within ring of TS

tet = sp3 atom attacked (alkane)

trig = sp2 atom attacked (alkene)

dig = sp atom attacked (alkyne)

what is the preferred angle of attack on alkenes?

110°

what kind of cyclisation is favoured by radicals?

exo radical cyclisation

what size of ring is favoured by radical cyclisation?

5 > 6 > 3/4 > 7/8

describe the size of the ring with angle of attack

5: exo cyclisation close to preferred angle of attack

at ring size increases, the endo TS angle increases and approaches preferred angle of attack

increasing ring size = increasing proportion of endo product

describe radical clocks

ring opening reactions = rate well known

can set up reaction which have oxidation and cyclisation possible:

oxidation product observed = oxidation faster than cyclisation

cyclisation product observed = cyclisation faster than oxidation

can alter the speed of cyclisation by altering the ring size (size of ring):

ring strain ∝ speed of radical clock

describe an application of radical cyclisation

formation of large rings

what can disfavour a reaction towards radical cyclisation

= unfavourable angle

= favours reduction of radical intermediate instead

how can radical cyclisation be favoured?

using radical reagents with no available H atom

i.e. (Bu3Sn)2 not HSnBu3

what are sequential/tandem radical reactions?

before radical termination, a radical can undergo multiple reaction steps

i.e.

describe metal-mediated radical reactions

= radical reaction initiated by single electron transfer from metal

describe the pinacol coupling reaction

= synthesis of 1,2 diols

= Na OR Mg

what is the application of benzophenone pinacol coupling

sodium radical salt = absence of water = blue

radical alcohol = presence of water = colourless

= indicator of water

describe pinacol coupling with Ti and Zn

Ti = low VE = Lewis acid via single electron transfer with Zn

describe carbenes

neutral sp2 carbons with 2 non-bonding electrons

two types:

• singlet = non-bonding electron pair in sp2 orbital

= empty orbital = Lewis acid

• triplet = 1 electron in sp2 orbital, 1 electron in p orbital

what controls carbenes tending to singlet/triplet states

• steric effects/bond angles

small groups = small dihedral angle (between R) = singlet favoured

large groups = large dihedral = triplet favoured

• solvent

polar solvent = stabilises singlet state by resonance

• substituents

EDG/∏-donors (lone pairs N, O, P, S) = stabilise empty orbital by resonance = singlet favoured

how can carbenes be generated?

• generation from diazo compounds R2C=N=N

• generation from tosylhydrazones = Bamford-Stevens reaction

• a-eliminaation from 1,1-dihaloalkanes

describe carbene generation from diazo compounds

• most common

• thermally OR photolytically

driving force = loss of small, stable molecule

what is a stable form of diazo compounds

α-diazo-carbonyl

describe carbene generation from tosylhydrazones (Bamford-Stevens reaction)

ketone → tosylhydrazone → diazo → carbene

draw the entire Bamford-Stevens reaction (carbene generation)

what is an alternative SM for Bamford-Stevens reactions?

diazirines

define a carbenoid

= metal complexed carbenes

= more stable

describe carbene generation by a-elimination from 1,1-dihaloalkanes

describe carbene generation from chloroform

what are the different reactions of carbenes

• cycloproponation

• carbene insertion into single bonds

• carbene rearrangement reactions

what is the most common carbene configuration

singlet

describe carbene cycloproponation

= insertion into an alkene

singlet carbene = stereospecific syn addition major

triplet carbene = non-stereospecific (diradical) addition

describe singlet carbene cycloproponation

spins matched = fast

describe triplet carbene cycloproponation

spin flip required = slow

bond rotation possible before spin flip

describe the Simmons-Smith reaction (carbenoid cycloproponation)

what is the product of this reaction

= formation of carbenoid

= carbenoid cycloproponation (Simmons-Smith)

what kind of alkenes are favoured by Simmon-Smith reactions?

electron rich