Reduc&on of Organic Compounds METAL HYDRIDE REDUCING AGENTS •Reduc&on of Aldehydes and Ketones to Alcohols •Reduc&on of Acids, Esters to Alcohols •Reduc&on of Esters, Amides, etc. to Aldehydes •Reduc&on of Imines and Amides to Amines BORANE •Hydrobora&on of alkenes and alkynes •Carbonyl reduc&on HYDROGENATION •Alkene hydrogena&on •Alkyne hydrogena&on •Carbonyl hydrogena&on DISSOLVING METAL REDUCTION •Alkyne reduc&on •Selec&ve reduc&on of alkenes in cyclohexenones •Birch reduc&on LOW VALENT METAL REDUCTIONS •Forma&on of Grignard reagents •N–O, N–N bond reduc&on •Clemmensen reduc&on and Wolﬀ–Kishner reduc&on NADPH AND RELATED REDUCING AGENTS
Reduc&on is a process in which a chemical species gains electron(s). In most (but not all) organic reduc&ons, two electrons are transferred. ONen, the products contain one addi&onal proton (from the reac&on workup) for each electron transferred.
METAL HYDRIDE REDUCING AGENTS
The more OR or R groups on the metal, the lower the ac&vity
Reduc&on of Aldehydes and Ketones to Alcohols
Sodium borohydride (NaBH4), lithium aluminum hydride – LAH (LiAlH4) can reduce aldehydes and ketones to alcohols. NaBH4 is preferred due to its easy handling and gentle reac&vity compared to the more reac&ve LiAlH4.
Meerwein-‐Pondorf-‐Verley reduc&on using Al(Oi-‐Pr)3 in isopropanol (IPA)
Chemoselec&vity in reduc&on of aldehydes, ketones and enones
Reduc&on of Acids, Esters to Alcohols Esters to alcohols: LiAlH4, LiBH4
-‐ -‐ -‐
Although the aldehyde is an intermediate in the reduc&on of esters to alcohols, it is impossible to isolate it (even when using a sub-‐stoichiometric amount of reducing agent), as the aldehyde is much more reac&ve than the star&ng ester and gets reduced immediately. Acids to alcohols: Less reac&ve metal hydrides as NaBH4 cannot reduce carboxylic acids due to the forma&on of carboxylates between carboxylic acids and counter ions. In this case only the much stronger LiAlH4 or borane can be used. LiBH4 : The Li+ ca&on is a stronger Lewis acid than the Na+ ca&on. Li+ coordina&on with the carbonyl group enhances the electrophilicity of the carbonyl carbon, thereby facilita&ng hydride transfer. Lithium borohydride is a more powerful reducing agent than sodium borohydride: it reduces esters to primary alcohols but is unreac&ve towards a m ides.
Hydride consup&on in LiAlH4 Reduc&ons
Reduc&on of Esters, Amides, etc. to Aldehydes Diisobutylaluminum hydride – DIBAL or DIBAL-‐H
Unlike other metal hydrides, DIBAL acts as a Lewis acid that coordinates to Lewis base (O of C=O) before it is ac&vated and transfers hydride. Choice of solvent is crucial (usually hexane, toluene), as coordina&ng solvents like THF destabilize the tetrahedral intermediate and cause over-‐reduc&on.
Reduc&on of esters/carboxylic acids to aldehydes via Weinreb’s amide forma&on
The formed tetrahedral intermediate is stabilized by chela&ng the metal center of the hydride reducing agent. This prevents further reduc&on un&l the aqueous workup, in which excess reducing agent is decomposed, and the aldehyde is revealed.
Reduc&on of Imines and Amides to Amines
-‐ Imines to amines: The C=N double bonds react with nucleophile in a same way as C=O double bonds. Therefore, reducing reagents that can reduce aldehydes or ketones to alcohols can be used in reducing imines to amines such as LiAlH4, NaBH4, NaCNBH3 in acidic condi&ons. -‐The advantage of NaCNBH3 as a selec&ve reducing agent for imines is that it tolerates other carbonyl groups which would be also reduced by LiAlH4 or NaBH4. -‐ Amides to amines: Again, LiAlH4 is a good reagent for this transforma&on. Borane (BH3) is also a good alterna&ve to LiAlH4 for reducing amides in the presence of esters (BH3 does not reduce esters)
Boron has three electrons in the valence shell, which form three conven&onal bonds with other atoms in a planar structure leaving a vacant 2p orbital. This orbital is able to accept a lone pair from a Lewis base or from a nucleophile. Borane exists as a mixture of dimer (B2H6) and monomer (BH3). Diborane, B2H6, is a gas and is diﬃcult to handle. However, borane complexed with donors such as THF or dimethylsulﬁde are commercially available and have become valuable reagents for the reduc&on of various func&onal groups. BH3·∙ SMe, is soluble in and unreac&ve toward a wide variety of apro&c solvents such as THF, Et2O, CH2Cl2,and hydrocarbons.
Hydrobora&on of alkenes and alkynes
Hydrobora&on is regioselec)ve (an&-‐Markovnikov) and stereoselec)ve (syn-‐addi&on across the alkenes)
Unlike borohydrides, borane is not an ion. It behaves as a Lewis acid and reacts best with the most electrophilic carbonyl groups. Consequently, it reduces electron-‐rich carbonyl groups such as carboxylic acid and amide fastest. Electron-‐poor carbonyl groups such as acyl chlorides and esters will not be aﬀected.
Selec&vity in BH3 ·∙ THF Reduc&ons
HYDROGENATION Cataly&c hydrogena&on is chemoselec&ve for the C=C double bonds over C=O double bonds.
The mechanism of the hydrogena&on of C=C double bonds starts with the coordina&on of the double bonds on to the catalyst surface.
-‐ Reduc&on of alkynes to Z-‐alkenes: Lindlar’s catalyst (Pd, CaCO3, Pb(OAc)2) is a palladium catalyst (Pd/CaCO3) poisoned by lead. The lead lowers the ac&vity of the catalyst. Consequently, it will hydrogenate alkynes to alkenes rather than alkenes to alkanes. -‐ Reduc&on of alkynes to E-‐alkenes: Na in NH3 (liquid) (discussed below)
Carbonyl hydrogena&on -‐ Cataly&c asymmetric hydrogena&on (Noyori – Nobel prize in Chemistry 2001)
Concept of asymmetric catalysis -‐ Enan&omeric ra&o is directly propor&onal to the rela&ve rate of the enan&omeric products. -‐ Enan&omeric ra&o is governed by diﬀeren&al ac&va&on parameters (∆∆G‡, ∆∆H‡ and ∆∆S‡). -‐ R and S are chosen below arbitrarily.
Some useful number to think about in enan&oselec&ve catalysis: -‐ ∆∆G‡ of 1.38 kcal/mol is needed to achieve 80% ee at room temp -‐ ∆∆G‡ of ~2.0 kcal/mol is needed to achieve 90% ee at room temp -‐ ∆∆G‡ of 2.60 kcal/mol is needed to achieve 98% ee at room temp -‐ ∆∆G‡ of 2.73 kcal/mol is needed to achieve 99% ee at room temp -‐ ∆∆G‡ of 1.80 kcal/mol is needed to achieve 98% ee at -‐78°C
DISSOLVING METAL REDUCTION Alkyne reduc&on
Stereoselec&ve – trans product is favored
Selec&ve reduc&on of alkenes in cyclohexenones Similar to reduc&ons of alkynes, also stereoselec&ve
Changing the workup in a reduc&on of anisole can lead to cyclohexenones.
Dependent on subs&tu&on of anisole, diﬀerent substa&on pamerns obtained
LOW VALENT METAL REDUCTIONS Forma&on of Grignard reagents Very basic and strong nucleophile
N–O, N–N bond reduc&on
Reduc&on of the N–O bond oNen proceeds to the free amine under strong acidic condi&ons This is not always the case and the reac&on can be stopped at an intermediate stage by using neutralcondi&on.
Nitro compounds with α hydrogen can be reduced to the corresponding oximes in ace&c acid.
Similarly N–N bonds can be reduced.
Clemmensen reduc&on Does not tolerate acid sensi&ve func&onali&es
A related reac&on to Clemmensen reduc&on is called the Wolﬀ–Kishner reduc&on
NADPH AND RELATED REDUCING AGENTS Similar to hydride reducing agents we have covered. Coupled with enzymes, have the added beneﬁt of absolute stereoselec&vity NADH and NADPH
FAD Reduc&on of molecular oxygen reduc&on leads to forma&on of epoxides
Ascorbic acid as hydride donor Mild reducing reagent. Used biologically to protect against stray oxidants and reducing important intermediates (peroxides and Fe3+)
Biological CO2 reduc&ons (CO2 ﬁxa&on)
Conversion of CO2 to small organic compounds is achieved in the Calvin cycle, an important step in photosynthesis. The enzyme RuBisCo (Ribulose-‐1,5-‐bisphosphate carboxylase oxygenase) catalyzes the CO2 ﬁxa&on.
Industrial/Cataly&c CO2 ﬁxa&on
Synthesis of hydrobenzoic acid by Kolbe-‐Schmidt reac&on
Similarly other carbon nucleophiles can be used