Nucleophilic Addition to Carbonyls (Aldehydes & Ketones)

Question 1

typical nucelophilic addition to carbonyl reaction scheme

Answer 1

1. nucleophilic addition to carbonyl group

2. protonation of resulting anion

Question 2

carbonyl electrostatics

Answer 2

large dipole

based on electrostatic attraction alone we’d expect electron rich nucleophile to attack the ∂+ C of C=O

Question 3

carbonyl bonding

Answer 3

C and O are sp2 hybridised
thus O l.p.s are perpendicular to π system and reside in sp2 HAOs
largest coefficient in π* is on the C
so strongest interaction w/ nucleophile is with carbon

Question 4

carbonyl angle of attack

Answer 4

typically observed ~107°

• ideal attack angle = >90° to C=O giving maximum orbital overlap as π* is slightly splayed out
• REPULSION between filled π bonding orbital electron density and Nu electron density forces Nu to attack at even more obtuse angle

Question 5

carbonyl reactions to memorise

Answer 5

Hydride - NaBH4
Organometallics - C-metal
Water/Alcohols –> hydrates, hemiacetals and acetals

Question 6

carbonyl + hydride theory

what is source of hydride and why?

Answer 6

while H- exists in NaH (sodium hydride), 1s and π* = rubbish orbital match:
- v. small
- high charge density
so H- only ever acts as BASE: 1s and σ* of H-X much better interaction

so best (& mildest) source of hydride = SODIUM BOROHYDRIDE (B-Hσ much better matched to π* than 1s)

Question 7

carbonyl + hydride theory

what protonates anion?
what happens to BH3?

Answer 7

protonation: HX is usually a reaction solvent molecule e.g. MeOH

BH3:
sp2 hybridised
v. electron deficient
has empty p orbital
        thus Lewis acid:

reacts w/ oxyanion just created or a molecule of solvent
–> tetravalent boron anion which can transfer a second hydride to another starting carbonyl molecule

THUS CAN USE <1 EQUIV. BOROHYDRIDE FOR REACTION TO TAKE PLACE (technically 1/4 moles of NaBH4 but painstaking and inefficient and NaBH4 inexpensive so rarely minimise amount used)

Question 8

organometallics discussed in IA

C-metal bond is…

why are carbonyl+organometallics successful?

Answer 8

organomagnesium compounds (Grignard reagents)
organolithium compounds

…covalent with ionic character

Li and Mg much less electronegative than C
∂- R-Li ∂+
∂- R-MgBr ∂+
so source of C-

Question 9

Grignard synthesis

Answer 9

alkyl, aryl or vinyl (attached to double bond) halides (Br, Cl or I) with magnesium TURNINGS
- MAGNESIUM INSERTION into C-Hal bond

CH3-Br ——(Mg, Et2O)—–> CH3-MgBr

Et2O = diethyl ether = commonly called ether = non-reactive solvent

Question 10

organolithium compound synthesis

Answer 10

alkyl, aryl or vinyl (attached to double bond) halides (Br, Cl or I) with 2 EQUIV. LITHIUM —> 1 EQUIV. organolithium + 1 EQUIV. LiHalide salt

e.g. CH3-Br —–(2xLi, ether(solvent))—-> CH3-Li + LiBr
aka LITHIUM HALOGEN EXCHANGE (Li-Hal exchange)

Question 11

alkynyl organometallic synthesis

Answer 11

1. using ALKYL organolithium/grignard
2. using STRONG NITROGEN BASE, commonly sodium amide to make —≡≡≡(-)Na(+) + NH3(g)
   commonly made by 2Na + 2NH3 —> 2NaNH2 + H2

Question 12

reactions of organometallic key things to remember

Answer 12

organometallic are INCOMPATIBLE with water so done in 2 steps for carbonyl nucleophilic addition e.g.:
1. MeMgBr, 2. H2O

Question 13

not all aldehydes and ketones form significant amounts of hydrate…

Answer 13

significant [ ]s of hydrate usually only formed from ALDEHYDES:

as we increase size of R group attached to C=O, hydrate becomes harder to form:

• moving from 120° to 109.5°
• larger R group = more STERIC CLASH in product than reactant so harder to form hydrate
• RING STRAIN FACTORS: hydrate formation favourable when ring strain is released (with DECREASED BOND ANGLE)
• electronic effects (beyond IA)

kinetic arguments (difficult initial attack as H2O = more statically hindered w/ R size, if R = EWG, faster C=O attack and increased ∂+ on C) can’t be used as we are discussing an equilibrium (thermodynamic result)

Question 14

carbonyls+alcohols catalysis

Answer 14

• acid catalysts make carbonyl more electrophilic
• base catalysts make nucleophile more nucleophilic

increases rate of eqbm, not position of eqbm

Question 15

acetal formation

Answer 15

every step of acetal formation is reversible
to push acetal through to completion, use excess alcohol and/or remove H2O byproduct from reaction mixture e.g. by distillation
CAN ONLY BE CATALYSED BY ACID - OH needs to be good leaving group for this reaction which can’t happen under basic conditions
protonation of hemiacetal makes OH a good leaving group