Reductions

Reductions with LiAlH4 (LAH)

Reduces esters, acids ketones, aldehydes, etc. to alcohols

Reduces amides, nitriles to primary amines

Rate effects: Highest is LiAlH4 > LiAl(OR)H3, and so on, decreasing reactivity with more alkoxy groups, but higher selectivity

DiBAL-H Reduction

Diisobutyl Aluminum Hydride

Reduces ester to aldehyde or alcohol

Reduces nitrile to aldehyde or amine

REDAL-H

NaAlH2(OCH2CH2OMe)2

Same reactivity as LiAlH4

Reduces ester/acid, aldehyde, ketone to alcohol

Reduces amide, nitrile to primary amine

Reduces p--toluenesulfonamides to free amines

Alane Reduction

Reduces ester/acid, aldehyde, ketone to alcohol

Reduces amide, nitrile to primary amine

Tolerates halide functional group

Diborane reduction

Reduces ester/acid, aldehyde, ketone to alcohol

Reduces amide, ntirile to primary amine

Sodium Borohydride reduction

Mild reducing agent

Reduces aldehydes, ketones to alcohols

Sodium cyanoborohydride reduction

Used for reductive amination

Lithium Borohydride reduction

More reactive than NaBH4, as Li activates oxygen

Reduces esters, aldehydies, ketones to alcohol

Luche Reduction

Regioselective for 1,2 reduction of alpha-beta unsaturated ketones

CeCl3 acts as LA

Sodium Trialkoxyborohydride(Internal H- delivery)

NaBH(OAc)3/Me4NBH(OAc)3

Requires chiral OH directing group

Gives rise to 1,3 anti-selectivity

Via Chair transition state, anti product minimizes A 1,3 interactions

Narasaka-Evans Reduction (external H- delivery)

Requires chiral OH directing group

Uses catechol boranes + external hydride source

Gives rise to 1,3 syn-selectivity

L/K-selectride reduction

Reduces ester/acid, aldehyde, ketone to alcohol

Reduces amide, nitrile to primary amine

Large, bulky hydride sources

Preferential for 1,4 reduction. Resulting enolate can be trapped with electrophiles

LiBHEt3 (Super Hydride Reduction)

Reduces Ester/acid to alcohol 

Reduces amide, nitrile to primary amine

Reduces HALOGENS and can OPEN EPOXIDES

VERY powerful reducing agent (stronger than LiAlH4)

Burgi-Dunitz Angles

Angles for nucleophilic attack at carbonyl

sp2 (carbonyl): 105 degrees

sp3 (SN2): 180 degrees

sp: 120 degrees

Baldwin’s Rules

Rules for ring formation

Broken bound outside cycle: “exo”

Broken bond inside cycle": “endo”

Based on ring size: 

Favored:

Tet (sp3):

3 to 7: exo-tet favored

Trig (sp2):

3 to 7 exo-trig are favored

6 to 7 endo-trig are favored

Dig (sp)

3 to 7 endo-dig are favored

5 to 7 endo-dig are favored 

Disfavored:

Tet (sp3):

5 to 6: endo-tet disfavored

Trig (sp2):

3 to 5 endo-trig are disfavored

Dig (sp):

3 to 4 exo-dig are disfavored

Felkin-Ahn Model

Put carbonyl 90 degrees in Newman projection, attack between Rm and Rs

Electronegative atom:

When there is an alpha electronegative atom/group, when electronegative atom is perpendicular to carbonyl, most reactive confomer. EN ATOMS REPLACE RL

Larger R groups (substituent on carbonyl) increases preference for Felkin pdt

Cram model

Same and Felkin-ahn, but chiral directing groups lock conformer via chelation. Attack occurs via least hindered site.

Good chelators: Mg, Zn, Li, Ti, Sn, Al

Bad chelators: Na, K, BF3

O-sub can invert stereochemistry (large groups can give Felkin-Ahn pdt)

1,2 Cram Chelation: Anti

1,3 Carm Chelation: Syn

Reduction of cyclohexanones

Small hydride: Axial Attack. Why? Torsional strain overcomes axial sterics

Large hydride: Equatorial attack. Why? Axial sterics overpower torsional strain

Reduction of bicyclic systems

Nu will choose convex face (open face) due to less steric interactions

Enantioselective Reductions

Chiral moeities in molecule, BINOL + LiAlH —> BINAL

Alpine-Borane Reduction

Enantioselective Reduction of Borane

Derived from Hydroboration of alpha-pinene

DIP-Chloride

B-chlorodiisopinocampheylborane

Highly enantioselective

Corey-Itsuno/Corey-Bakshi-Shibata (CBS) Reduction

Enantioselective reduction of ketones, aldehydes

Chiral catalyst prepared from proline

Meerwein-Pondorf-Verley (MPV) Reduction

Reversible Reduction using Al(OiPr)3 

Thermodynamic product is obtained

Axial delivery preferred

Noyori Transfer Hydrogenation

Ru chiral catalyst

Isopropanol as Hydride source

Enantioselective reduction of Ketones, aldehydes

Can also have Formic acid/triethylamine as hydride source 

In a Beta-keto ester, ketone is reduced preferentially 

Least Hindered Catalytic Hydrogenation

Cis-delivery from least hindered face of olefin

Reactivity:

Pd > Rh > Pt > Ni > Ru

alkyne > terminal olefin > single sub > double > triple

Lindlar’s catalyst gives cis olefins (Pd(BaSO4), H2) from alkynes

Birch conditions gives trans

Common catalysts: Pd/C, Pd(OH)2 (Pearlmann’s cat), PtO2 (Adams’ cat) for imines to amines, Rainey Ni for sulfide groups,

Wilkinson’s Catalyst

Most hindered face hydrogenation (minor complex reacts fast)

Hydrogenation of Allylic and Homoallylic Alcohols

1. Draw conforamation of allylic alcohol with alcohol perpendicular to alkene (Felkin-Ahn like)

2. Determine favored conformation based on sterics

3. Favored conformation determines reduction stereoselectivity

For CH2OH groups (i.e non-OH group), perform same process

Ionic Reduction

Requires good LG, forms carbenium. Hydride transfer affords hydrogenated product.

Can also have Lewis acid plus hydride transfer. 

Diimide Reduction

[HN=NH reagent

Cis-delivery of H2 on least hindered face

Trans>Cis olefin rate 

Carbonyls, nitro, nitrile, sulfoxide, disulfide all tolerated

ONLY olefin reduction? Diimide is probably the way to go

SET Reductions

Birch conditions (Li/NH3, ether solvent)

Most thermodynamically stable product is given

Trans-fused decalins are made, as hydrogenation typically gives cis-fused 

Hydroboration

Anti-Markovnikov selectivity

Can oxidize to Anti-Markovnikov alcohol

4-membered sigma-metathesis transition state

Larger borane = better regioselectivity

Increased rate: 

Higher substitution on olefin

More olefin strain

Decreased rate: 

Steric bulk on olefin

Regioselectivity based on electronic factors:

EDG stabilizes positive charge, gives better selectivity

EWG destabilizes positive charge, gives worse selectivity

TMS stabilizes positive charge (beta-silicon effect), but can give worse selectivity. 

Hydroboration Diastereoselectivity (Endocylic olefins)

Diastereoselectivity

(Endocyclic olefins):

Least-hindered face is attacked

Bulkier boranes give better diastereoselectivity

Attack occurs at least substituted carbon

Inductive effect: Methoxy group destabilizes positive charge up at adjacent carbon, 1,2 product is favored (as opposed to 1,3)

Larger boranes give better stereoselectivity but reduced regioselectivity

(Exocylic):

Small borane = axial

Large borane = equatorial 

Hydroboration Diastereoselectivity (Acyclic)

(Acyclic olefins): 

1. Draw reactive conformations of olefin

2. RL (large sub) perpendicular to olefin

3. Borane approaches from opposite face

For 1,1 disubstituted olefins: Diastereoselectivity is driven by A1,2 strain

For dialkylboranes, the diastereoselectivity is driven by interactions between R groups on boron and Rm (medium size sub on alpha carbon). Dialkyl interactions is less favored than A1,2 for dialkylboranes. 

Remember, place RL 90 degrees to double bond (2 configurations, one with RL up and one down). Let borane attack from opposite face. Whatever you get, that is the major product.