Nucleophilic Addition to the Carbon-Oxygen Double Bond | CHE 256, Study notes of Organic Chemistry

Download Nucleophilic Addition to the Carbon-Oxygen Double Bond | CHE 256 and more Study notes Organic Chemistry in PDF only on Docsity! Nucleophilic Addition to the Carbon-Oxygen Double Bond The reactivity of the carbon-oxygen double bond is determined by the polarization: C=O : : δ-δ+ Because of the permanent dipole, nucleophiles add to the electropositive carbon and electrophiles add to the electronegative oxygen. These are the most characteristic reactions of aldehydes and ketones. Two General Mechanisms for Nucleophilic Addition (1) When the reagent is a strong nucleophile (Nu:-) such as an organometallic or metal hydride reagent, addition usually occurs first to the carbon center, forming an alkoxide ion. Electrophilic addition then occurs to the oxide. (2) A second general mechanism is acid-catalyzed nucleophilic addition. This involves a weaker nucleophile adding to the carbonyl group in the presence of catalytic amounts of acid, which protonates the carbonyl oxygen. C=O : : Nu:- sp2-hybridized carbon trigonal planar C O: : : R R' Nu R R' - sp3-hybridized carbon tetrahedral E+ C O-E : : Nu R R' Addition product tetrahedral In these additions, E+ is often a proton or metal ion. First General Mechanism sp3-hybridized carbon δ+ δ- top bottom (racemic) (and enantiomer) Electronic Factors A ketone carbonyl is stabilized relative to that of an aldehyde by the presence of two electron-releasing alkyl groups. C :O:= R H C :O:= R R' δ− δ− δ+ δ+ More stable, so less reactive Less stable, so more reactive This diminishing of C O carbon charge in ketones contributes to their lower reactivity compared with that of aldehydes. Alkyl ketones are generally more reactive than aryl ketones because of greater electronic stabilization of the starting state of the latter by π- electron delocalization. C :O:= R C :O: R= : + - etc. δ+ δ− SUMMARY: Any reduction in the partial positive charge on the C O carbon decreases its reactivity in nucleophilic addition. Any increase, e.g., by the presence of a strongly electron withdrawing group like -CF3, increases reactivity. Addition Reactions of Aldehydes and Ketones Addition of Water and Alcohols: Hydrates and Acetals Hydrates: gem-Diols When aldehydes or ketones are dissolved in aqueous media, an equilibrium is established between the carbonyl compound and its hydrate. The hydrate is a geminal diol ("gem-diol"). C=O R R' + H2O K C R' R OH OH The position of equilibrium depends on the size and electronic effects of the R groups. For most ketones, K' = K[H2O] = << 1. Most ketones exist essentially 100% in the carbonyl form. Aldehydes hydrate somewhat more extensively. Bulky and/or electron-donating R groups stabilize the carbonyl compound in the above equilibrium. Electron-withdrawing groups destabilize the carbonyl compound and promote formation of the hydrate. These factors are illustrated in the table that follows. Equilibrium Constants at 25 oC for the Reaction RR'C=O + H2O RR'C(OH)2 Carbonyl compound K' = K[H2O] = [RR'C(OH)2] [RR'C=O] C=O H H 2 x 103 C=O H CH3 1.3 C=O CH3 CH3 2 x 10-3 C=O H CH3CH2 0.71 C=O H (CH3)3C 0.24 C=O H Cl3C 2.8 x 104 KETONE (Note all others are aldehydes.) LOWEST VALUE electron-withdrawing CCl3 group simplest aldehyde Hemiacetals Most acyclic hemiacetals are unstable and cannot be isolated. C O-R: R' H OH : : : But cyclic hemiacetals with 5- and 6-membered rings are stable and are widely found in carbohydrates (sugars and polysaccharides like cellulose and starch). Intramolecular hemiacetal formation: : : 4-Hydroxybutanal : + - proton transfer Cyclic hemi-acetal stable HO H O O O H : : O OH : Ketals: Acetals of Ketones Acetal (ketal) formation with ketones is generally not a favorable process: C R' R OR'' OR'' + H2O H+ C=O R' R + 2 R''OH KetalKetone H+ As in the hydration reaction, the equilibrium heavily favors the ketone. Cyclic ketals, formed from 1,2- or 1,3-diols, are an exception: C=O R' R + HOCH2CH2OH 1,2-Ethanediol (ethylene glycol) H+ H+ C R' R O-CH2 O-CH2 + H2O Cyclic ketal (stable) Cyclic acetals or ketals hydrolyze easily in aqueous acid solution: C=O R' R + HOCH2CH2OH H+ C R' R O-CH2 O-CH2 + H2O excess Acetals as Protecting Groups While acetals readily hydrolyze back to the carbonyl compound in the presence of acid as a catalyst, they are stable to bases, even strong bases. C R R' OR'' OR'' H+ H2O C=O R R' HO- H2O no reaction Acetals often are used to protect aldehyde and ketone functions from undesired reactions in the presence of strong bases during syntheses. The acetal function, a geminal (1,1) diether, is not reactive towards nucleophiles, and its hydrogens are very non-acidic. Imine-Type Carbonyl Derivatives C O= CH3 H + H2N-OH hydroxylamine -H2O C N-OH= CH3 H an oxime C O= CH3 CH3 + H2N-NH2 hydrazine -H2O C N-NH2= CH3 CH3 a hydrazone C O= C6H5 CH3 H2N-NHC6H5+ phenylhydrazine -H2O C N-NHC6H5= CH3C6H5 a phenylhydrazone O= + H2N-NH- NO2 O2N 2,4-dinitrophenylhydrazine -H2O C N-NHCNH2= HC6H5 O= a semicarbazone N-NH-= NO2 O2N a 2,4-dinitrophenyl- hydrazone C O= C6H5 H + H2N-NHCNH2 O= semicarbazide -H2O Enamines: Addition of 2o Amines C R(H) O + H2NR'R'' C R(H) N R'' H2O+ H3O+ Aldehyde or ketone 2o Amine H R' Enamine Mechanism: C C O HNR'R''+ C O - NHR'R'' + C OH NR'R'' C OH2 NR'R'' + C N R' + R'' C N R'' H3O+ -H2O H2O H3O+ + Iminium ion Amino alcoholH C H C H C C H C H Enamine Addition of Hydrogen Cyanide: Cyanohydrins Hydrogen cyanide (HCN) adds to aldehydes and unhindered ketones to produce cyanohydrins. RCH O= + H-C N RC-C N OH H RCR' O= + H-C N RC-C N OH R'(unhindered) Cyanohydrins In the reaction, a mineral acid is added to a mixture of the carbonyl compound and sodium cyanide. Too much acid slows the reaction by tying up the nucleophilic cyanide ion as HCN. The following sequence describes the mechanism of cyanohydrin formation. RCR' O= + :C N- Cyanide ion (a good nucleophile) slow RC-C N O R' H-C N RC-C N OH R' :C N+ - - Synthesis of Ylides The ylides required for the Wittig reaction may usually be made by a two-step synthesis beginning with triphenylphosphine. Step 1. Triphenylphosphine reacts with sterically unhindered alkyl halides by an SN2 mechanism yielding alkyltriphenylphosphonium halides, which are analogous to quaternary ammonium halide salts, R4N+ X-. (C6H5)3P: Nucleophile + R''CH-X R''' SN2 (C6H5)3P-CH R'' R''' + + X- Alkyltriphenylphosphonium salt Step 2. Because the phosphorus atom carries a full positive charge, protons on adjacent carbons (α-position) are relatively acidic and may be removed with an appropriate base, producing a phosphorus ylide. (C6H5)3P-C-H R'' R''' + X- + :B- (C6H5)3P-C: R'' R''' + - + BH Phosphorus ylide Example: (C6H5)3P: + CH3Br benzene (C6H5)3P-CH3 + Br- Methyltriphenylphosphonium bromide (89%) (C6H5)3P-CH3 + Br- + C6H5Li Phenyllithium (a very strong base) ether (C6H5)3P-CH2 + - + C6H6 + LiBr Phosphorus ylide Choice of Base The choice of base and solvent in the deprotonation of the phosphonium salt depends on the acidity of the α-H. When simple alkyl groups are deprotonated, very strong bases such as alkyl- and aryllithiums in ether solvents are used. When powerful electron- withdrawing groups are present, oxygen bases in alcohol solvents may be used to produce the ylide. A Resonance Description of the Phosphorous Ylide The phosphorus ylide is represented as a hybrid of the two resonance structures below. The octet rule restriction does not apply to phosphorus, a third-row element. (C6H5)3P-CH2 + -: (C6H5)3P=CH2