Chapter 10, Aldehyde and ketones

1 is pyridinium chlorochromate, PCC C5H5NH CrO3Cl C5H5NH CrO3Cl RCH O RCH2OH R1 CR2 H OH K2Cr2O7 R1 CR2 O Aldehydes and Ketones Preparation of Aldehydes — Oxidation of primary alcohols – The aldehyde that is the product is very easily oxidized to a carboxylic acid, RCOOH. Preparation of Ketones — Oxidation of secondary alcohols – Unlike aldehydes, ketones are not easily oxidized.2 C C R2 R1 H2SO4, HgSO4 H2O C C R2 R1 O HH C C R2 R1 HH O + H2O H2SO4, HgSO4 C C R H C C R H O HH Owing to the formation of mixtures if R1 R2, this reaction is most useful when R1 = R2 ... ...or when the alkyne has a terminal triple bond. ¹ Hydration of an alkyne – An enol initially forms in this reaction, but it tautomerizes to the more stable ketone. Terminal alkynes, following Markovnikov’s rule, give methyl ketones rather than aldehydes.3 H R CO Cl AlCl3 CO R + C O sp2 orbitals p d+ d- Friedel-Crafts acylation for aryl ketones – The aromatic ring cannot have, as a substituent, an amino group or a meta director. Structural Features of Aldehydes and Ketones Both contain the carbonyl group and only carbons or hydrogens bonded to this group. In aldehydes at least one hydrogen is joined to the carbonyl carbon (formaldehyde has two). In ketones, only carbons are bonded to the carbonyl carbon. Since the carbon has a partial positive charge it is likely to be a site that is attacked by nucleophiles. And, since the oxygen bears a partial negative charge, it is likely to be a site of electrophilic attack. Since ordinary carbanions (R:-) and hydride ions (H:-) are very poor leaving groups (unlike halide ions, X-) nucleophilic substitution does not usually occur at the carbonyl carbon of aldehydes or ketones.4 C O R2 R1 Nu:-C O R2 Nu R1:-+ Æ5 Aldehydes R C H O (Ar) O2 or CrO3 or K2Cr2O7 or KMnO4, etc. R C OH O (Ar) Tollen's test for aldehydes: R C H O (Ar) + Ag(NH3)2+ -OH RCO- + Ago (Ar) Fehling's test, Benedict's test: R C H O (not Ar) + 2 CuO RCOH O + Cu2O complexed with citrate or tartarate, in solution red precipitate Ketones RCH2 C CH2R' O RCOH O R'COH O + hot KMnO4 or hot HNO3 Vigorous conditions required for reaction. R'CH2COH O + RCH2COH O Reactions of Aldehydes and Ketones — Oxidation — Aldehydes are easily oxidized to carboxylic acids, ketones are not.6 R C O R' :Nu-d- d+ R C O R' Nud-d- becoming tetrahedral: sp2 sp3 R C O R' Nu H+ R C OH R' Nu R, R' = alkyl, aryl, H Nucleophilic Additions — :Nu or :Nu-is a generic nucleophile. Since there is an increase in crowding on going from reactant to transition state (~120o to ~109o), some steric effects might be expected. This is one reason aldehydes (less crowded) are more reactive than ketones.7 C O R' R + H+ C O R' R H C O R' R H More easily attacked by nucleophile than unprotonated carbonyl. C O H2O COH OH + acid or base catalyst Nucleophilic additions may be acid catalyzed — However, when acid catalysis is employed one should usually be careful to avoid completely converting the nucleophile to its conjugate acid (which would be much less nucleophilic). Nucleophilic Addition of Water: Hydration — The product here is known as a geminal diol. In most cases the equilibrium greatly favors the carbonyl compound. Formaldehyde and chloral (trichloroacetaldehyde) are two common exceptions.8 C O C O HO HO H O H C O HO HO H + The mechanism for this reaction under basic conditions is as follows – In this case – basic catalysis – a powerful nucleophile attacks the substrate. In acidic catalysis, as we shall see below, the nucleophile will be much weaker – water. But the substrate has been activated by protonation and is more susceptible to attack.9 C O OH H H H O H C O H C O H H O H H O H C O H H O H H O C O H H O H H + Under acidic conditions the following mechanism applies – 10 C O ROH C OH RO ROH C OR RO H2O + H H hemiacetal acetal Acetal Formation — Under acidic conditions an aldehyde or ketone will react with an alcohol to form a hemiacetal. The hemiacetal, in turn, will react with more alcohol to form an acetal.11 C O OH H R R O H C O H C O H R O H R O H C O H R O H R O C O H R O H H + hemiacetal The mechanism is as follows – OK. Now we have to get from the hemiacetal to the acetal.12 OH H R R O H R O H R O C O H R O C O H H R O C O H H R O H R O C R O H R O R O C R O H H acetal Acetals are used to “protect” the carbonyl groups of aldehydes and ketones when one wants to have some other part of the molecule react without affecting the aldehyde or ketone functional group. They can be used this way because they are fairly unreactive and the carbonyl functional group can be regenerated from the acetal. For example if you wanted to convert a ketoacid to a ketoalcohol you could do the following: (1) convert the keto group to an acetal, (2) reduce the acid with LiAlH4, and (3) regenerate the keto group from the acetal.13 R-X or Ar-X + Mg anhydrous C2H5OC2H5 or O R-Mg-X or Ar-Mg-X X = I, Br, Cl Addition of Grignard Reagents — A powerful method for synthesis of alcohols. In the Grignard Synthesis smaller molecules —> larger molecules. Formation of Grignard reagent — 14 3o alcohol ketone 2o alcohol aldehyde 1o alcohol formaldehyde R'' CR' OH R H2O H3O+ C O R' R'' + H CR' OH R H2O H3O+ C O R' H + H CH OH R H2O H3O+ C O HH + RMgX or ArMgX + Mg(OH)X R C O H H2O magnesium salt of an alcohol X R C O Mg Mg X R C O d+ d- C O R Mg X d- d+ Grignards react with aldehydes and ketones to give alcohols — A pseudo-mechanism for this reaction — 15 Synthesize 2-phenyl-2-butanol using a Grignard synthesis — The figure below shows three possible routes by which this synthesis can be accomplished. In practice, the route chosen would likely depend on the starting materials that may be at hand in the laboratory (all of these compounds could be purchased). In the scheme below, CH3MgBr could be made from CH3Br and Mg, but methyl bromide is not convenient to handle. It boils at 4oC, so it is a gas at room temperature. [Large quantities of methyl bromide are used as a soil and grain fumigant. Its use is quite controversial since it is somewhat toxic and an ozone depleting chemical. See, for example: http://www.epa.gov/docs/ozone/mbr/mbrqa.html]16 O H3CC CH3CH2MgBr +CH3CH2Br Mg anhydrous ether CH3CH2CCH3 O + MgBr Mg anhydrous ether Br C CH3CH2 O + CH3MgBr CH3 OH CH3CH2 C not commonly available17 alcohol 1 alkyl halide Grignard reagent alcohol 2 aldehyde or ketone more complicated alcohol which may become alcohol 1 or 2 in a subsequent Grignard synthesis, etc. It is possible to extend the Grignard synthesis to make quite complex alcohols from simple ones (you don’t win the Nobel prize for nothing). The basic scheme is as follows – 18 C O R' R + K+ -C N H3O+ R' COH CN R H3O+ CH3CH2CH2 COH CN H H2O heat CH3CH2CH C COOH H H2O, KOH heat CH3CH2CH2 COH COO-K+ H H2O HCl CH3CH2CH2 COH COOH H + KCl Formation of Cyanohydrins — These compounds can be hydrolyzed by base or acid to give a-hydroxyacids or a,b-unsaturated acids, respectively.19 CO + R NH2 weak acid catalyst CN Ran imine a primary amine CO + NH2OH weak acid catalyst CN OH an oxime hydroxylammin CO NO2 O2N NH2NH + weak acid catalyst NO2 O2N NH NC a 2,4-dinitrophenylhydrazone Oximes, 2,4-DNPs, and semicarbazones are used as derivatives in identifying aldehydes and ketones. Addition of Ammonia and Its Derivatives —