reactions Flashcards
EAS Halogenation
benzene reacts with halogen to form halobenzene in presences of lewis acid catalyst
EAS nitration
benzene reacts with nitronium ion, NO2+, from HNO3/H2SO4 to give nitrobenzenes
EAS sulfonation
benzene reacts with sulfonium, HSO3+, ions in hot, concentrated H2SO4 to give benzene sulfonic acid
Friedel-Crafts Alkylation
Benzene reacts with alkyl halides in presence of lewis acid to give alkylbenzene
Friedel-Crafts Acylation
Benzene reacts with acyl halides in presence of lewis acid catalyst to give phenyl ketones
Wolff-Kishner Reduction
basic reduction of phenyl ketone to alkyl benzene with hydrazine and KOH
Clemmenson Reduction
Acidic reduction of phenyl ketone to alkyl benzene with Zn(Hg) and HCl
Benzylic Oxidation
strong oxidizing agents convert alkyl substituents into carboxylic acids in acidic conditions e.g. KMnO4, NaCr2O7.
- Must have alpha/benzylic hydrogen
Induction vs Resonance
induction: movement of electron density through sigma bonds.
Resonance: delocalisation of electron pair through conjugation
Electron withdrawing groups
- are more electronegative, positively charged or are conjugated.
- Decrease electron density in rings, reducing nucleophilicity, slowing reactions, preventing alkylation/acylation.
- Deactivating, meta-directors. E.g. C=O, NO2, SO3 (X are EWG though o-p directors)
Hyperconjugation
- partial overlap of sigma bonds with carbocation p orbital, allowing for partial delocalisation inductively.
- Stabilises carbocation, lowering activation energy, and leading to Markovnikov’s rule: the most substituted carbocation forms preferentially
Carbocation Rearrangemnet
- rearrangement to adjacent carbons if can form more substituted/stable carbocation. - 1,2-hydride shift unless no hydrogens then 1,2-alkyl shift
Hydroboration
- reaction of alkene with BH3 followed by oxidation (H2O2, OH-) to give anti-markovnikov alcohol.
- Concerted addition of BH3 where H- adds to most stable, positive carbon (most substituted)
- BH3 adds to less substituted/steric carbon
Epoxidation of alkenes
- reaction of alkene with peracid (m-CPBA) gives epoxids.
- Concerted mechanism results in syn addition.
Enamine Synthesis
- reaction of aldehyde/ketone with secondary amines.
- Similary reactivity to enolate/enols
- Can be hydrolysed back to carbonyl with acid.
Aldol Reaction
- nucleophilic addition of an enolate/enol to an aldehyde/ketone.
- Forms tertiary alcohol product
- readily dehydrates to a,b-unsaturated carbonyl (stabilized by conjugation) if heated with acid or excess base.
Claisen Condensation
- reaction of enolate/enol with ester to form beta-keto ester by substitution.
- Product more acidic than reactant, hence quench with acid.
- Beta-keto esters readily undergo decarboxylation when heated with acid.
Controlling mixed aldol/claisen
- use an aldehyde/ketone with no alpha hydrogen as electrophile
- use a strong base to form enolate completely before adding electrophile
- use a stronger electrophile to react with enolate e.g. aldehydes
- use a more acidic carbonyl that forms the enolate predominately
Michael Reaction
- addition of enolate to a,b-unsaturated ketones forming 1,5-dicarbonyl.
- The beta carbon is electrophilic due to resonance (latent polarity)
Robinson Annulation
Is a michael reaction followed by an intramolecular aldol to form a cyclohex-en-one
Decarboxylation
- beta-keto carboxylates undergo decarboxylation when heated forming an enolate.
- Under acidic conditions decarboxylation is facilitated by a proton transfer forming an enol/ketone
Wittig Reaction
- phosphonium ylide reacts with carbonyls to form alkene.
- Mechanism suspected to involve 4 member transition.
- Ylide formed by Sn2 of alkyl halide with PPh3 followed by deprotonation.
- Stabilised (conjugated, aryl substituent) ylides form the more stable trans alkene.
- Unstabilizedd ylides form cis alkenes
Sn2
2 reagent, single step substitution with stereochemical inversion
Sn2 Reactivity Factors
- less steric hinderance = more reactive (tertiary unreactive).
- Weaker leaving group bond = more reactive (I > Br > Cl).
- Stronger, unhindered nucleophile = faster reaction
Sn1
- 1 reagent start, 2 step substitution with carbocation intermediate.
- Symmetrical Trigonal planar carbocation creates racemic mixture.
- Dissociation is RDS.
- Carbocation may undergo rearrangement.
- Reactivity determined by carbocation stability (primary unreactive)
Sn1 vs Sn2
- for secondary akyl halide both are in competition.
- Increasing nucleophile concentration favours Sn2 (increases rate).
- Polar protic solvent favour Sn1 (stabilise carbocation, congest nucleophile).
- Sterically hindered nucleophilles also favour Sn1 but sterics determine whether acts as nucleophile or base
E1
- R-X spontaneously breaks to form carbocation which is deprotonated.
- Always forms most substituted alkene.
- Favoured by sterically bulky alkyl halides.
- Succeptible to carbocation rearrangement.
E2
- base abstracts proton as leaving group dissociates.
- Strongly basic, sterically hindered nucleophiles favour E2.
- Favours most substituted but abstracts proton from opposite side/antiperiplanar so always trans.
- Sterically hindered bases/no anti hydrogen can lead to less substituted alkene
Sn2 vs E2
- Secondary halides undergo substitution/elimination simultaneously.
- Sterically encumbered bases/nucleophiles favour elimination.
- Elimination is also entropically favour. High temps = E2, low temps = Sn2
Alcohol Leaving Groups
- react to Mesylate/Tosylate to form strong leaving group with same stereochemistry.
- Alternatively, react with SOCl2 to form alkyl chloride with inverted stereochemistry.
Organocopper reagents
- less nucleophilic than other organometallics (RMg, Rli),
- don’t react with carbonyls, chemeoselective.
- Formed by reacting with more electropositive organolmetalloids. Rli + Cu -> R2CuLi
Organocopper reactions
- react with alkyl halides/epoxides to from coupled product
- react with acid chlorides in substition to ketone
- react with a,b-unsaturated carbonyls to add trans at beta carbon.
Alkene Synthesis
Wittig reaction, julia olefination, Wadsworth-Emmons olefination,
Wittig Pros cons
Pros: can form both cis and trans alkenes, simple reagents.
Cons: have to change alkyl group to get selectivitys, poor atom economy.
Julia olefination
Reaction of heteroaryl sulfone with carbonyl to form trans alkene under basic conditions.
Wadworth emmons olefination
- variation of Wittig where ylide replaced by beta-oxophonate to form trans alkenes under basic conditions.
- Alkyl group must have EWG e.g. ester.
- Destabilising square intermediate can yield kinetic cis alkene e.g. adding EWG to phosphate.
Amine Synthesis
- Ammonia and alkyl halide (generally mixture, not great)
- azide reduction (primary amines)
- Gabreil Synthesis (primary)
- amide reduction (any)
- nitrile reduction (primary)
- imine reduction (primary, secondary)
- enamine reduction (tertiary)
Barton ester decarboxylation
radical removal of carboxylate group via formation of barton’s ester which is reacted with AIBN/Bu3SnH
Huckels Rules
- The molecule is cyclic (a ring of atoms)
- The molecule is planar (all atoms in the molecule lie in the same plane)
- The molecule is fully conjugated (p orbitals at every atom in the ring)
- The molecule has 4n+2 π electrons (n=0 or any positive integer)
Paul-Knorr Synthesis
prepare heterocycles by condensation between 1,4-dicarbonyl and NH3/P2O5/P2S5
Diels Alder
reaction of diene and dienophile to form cyclohexene. [4+2] cycloaddition. Concerted P orbital overlap mechanism means same stereochemistry as reactants.
Cope Rearrangement
- [3,3] sigmatropic rearrangement of a 1,5-diene. Shifts 3 atoms and 3 positions.
- Equilibrium favours lower ring/angle strain and the product with stronger bonds e.g. C=O
Oxy-Cope Rearrangement
is a cope rearrangement with a hydroxy group at the 3 position.
Tautomerisation to carbonyl strongly favours rearrangement even at mild conditions
Anionic Oxy-Cope Rearrangement
hydroxy group at 3 position is deprontonate by strong base. Rearrangement to enolate intermediate that protonates to carbonyl. Due to derpotonation reaction is non-reversible and fast
Claisen Rearrangement
[3,3]-sigmatropic rearrangement of allyl vinyl ether, i.e. heterocyle with oxygen at 3 position. Rearrangment forms a carbonyl.
Ireland-Claisen Rearrangement
claisen rearrangement but with an ester and under basic conditions with TMSCl. Deprotonation at alpha carbon leads to non-reversible rearrangement and forms a carboxylic acid. Silyl enol intermediate favours rearrangement.
Electrocylic Reactions
reversible pericyclic formation/breaking of C-C bond (number of bonds does change). Either ring closure or ring opening. Define by number of pi electrons involved e.g. 4 pi electrocyclisation
Carbene Synthesis
- diazo decomposition (loss of N2 by heat/light)
- alpha diazocarbonyl decomposition (more stable due to resonance)
- alpha elimination (base catalysed e.g CHCl3 or decarboxylation e.g. trichloroacetate)
Carbene Reactions
- cyclopropanation (concerted alkene insertion)
- simmons-smith cyclopropanation (directed by lewis bases e.g. alcohols)
- esterification of carboxylic acids (O-H insertion)
- methylation of phenols (O-H insertion, aliphatic OH unreactive as not acidic enough)
Carbene Rearrangements
1 Wolff rearrangement (C-C insertion with alpha carbonyl, homolagation)
2. Arndt-Eistert (same but add to acyl chloride first)
Nitrene
nitrogen with 6 valence electrons (though one covalent bond so uncharged).
Nitrene Synthesis
azide decomposition after reacting NaN3 with acyl chloride. Stabilized by alpha carbonyl
Curtis Rearrangement
nitrene rearrangement with alpha carbonyl (C-C insertion with N). In alcohol forms an ester, in water undergoes decarboxylation to amine.
Carbene
neutral species containing carbon with 6 valence electrons (2 covalent bonds so uncharged).
- Singlet carbene: the 2 unpaired electrons are paired and the carbon is sp2. Generally formed in solution
- triplet carbene: the 2 unpaired electrons are in separate perpendicular p orbitals with same spin.
Suzuki Miyaura Reaction
- C-C catalysed coupling between aryl halide and boronic acid
- Pd catalyst
- under basic conditions
Heck Reaction
Catalysed coupling between aryl halide and alkene under basic conditions
- intermolecular or intramolecular (more steric tolerance)
sonogashira reaction
Catalysed coupling between alkyne and aryl/vinyl halide
- Pd catalyst and Cu co-catalyst
- basic conditions
Glaser Coupling
alkyne coupling reaction
- copper halide catalyst
- basic conditions
Amine Protecting Groups
- BOC (tert-Butyloxycarbonyl)
- FMOC
- Bn
- imine (benzyl)
- Tosylate
alkyne hydration
adds alcohol to form enol which tautomerises to ketone
olefin metathesis
- exchanges olefin fragments, creating the mixed products
- often used for ring opening/closing
- Grubbs Catalyst
ozonolysis
alkene reacts with ozone to cleave into two carbonyls
dihydroxylation
catalysed reaction of alkene to vicinal diol
- OsO4 catalyst
Weinreb Amide
- Used to create ketones from acid chlorides
- formed by reacting acid chloride with NH(OMe)Me
- then react with organometallic reagent to form ketone under acidic conditions
- or reduce with LiAlH4 to aldehyde
- prevents over addition when react acid chloride straight with organometallics
