Aldehydes and Ketones Nomenclature - form text. The best way to think of an aldehyde or ketone (or just about any carbonyl compound) is with a slight positive charge on carbon, and a slight negative charge on oxygen: ROR'!+ !- Just about all of the chemistry of carbonyl compounds is explained by the oxygen being slightly nucleophilic (thus easily protonated) and the carbon being strongly electrophilic. Remember this! Preparation: Aldehydes: 1) Oxidation of a primary alcohol with PCC 2) Ozonolysis of an alkene REVIEW IT! 3) Reduction of an Acyl Halide. Acyl halides can be reduced with a special reagent – lithium tri(t-butoxy)aluminum hydride, LiAl(Ot-Bu)3H : ROClOLiAl( )3HROH Your text states that aldehydes can be easily prepared from esters with DIBAH (diisobutylaluminum hydride). Typically, it is easier to reduce all the way to a primary alcohol (you need 2 equivalents of DIBAH for this), then re-oxidize: ROOR'AlH(Diisobutyl aluminum hydride,or DIBAH, or DIBAL-H)ROHPCCROH Ketones 1) Oxidation of secondary alcohols – usually be the Swern oxidation, or with PCC 2) Ozonolysis of an alkene. 3) Friedel-Crafts Acylation. Below is the preparation of a ketone sequentially from a primary alcohol (through an intermediate aldehyde):OHPCCOLiOHPCCO Some ketones can also be prepared from acyl halides and organo-copper reagents (called lithium dialkylcuprates), as shown below: LiCuBrCu+ LiBrLiCuLi2Lithium dialkylcuprateOR ClOR Further oxidation of aldehydes and ketones: As you might imagine, most ketones are inert to all but the harshest oxidative conditions, and thus there is no synthetic utility in trying to oxidize them. However, aldehydes can generally be oxidized to carboxylic acids under relatively mild conditions: OR HAg2O / H2ONH4OH / EtOHOR OH Reactivity of Aldehydes and Ketones. These carbonyl compounds generally have two reaction pathways – they react with strong nucleophiles (generally, strong nucleophiles have a formal negative charge) under neutral, generally anhydrous conditions, or with weak nucleophiles (those with lone pairs, but no charge) under mild acid catalysis. If you take a good look at the nucleophile and reaction conditions, you’ll be able to figure out which way it will go... Reactivity – aldehydes are much more reactive than ketones. ‘nuff said. Addition of water or alcohols (to from a hydrate or alcoholate (ketal)). Ketones and aldehydes in aqueous or alcoholic media frequently react with the medium to form hydrates (or alcoholates). The extent to which this occurs correlates to many things, including the electrophilicity of the carbonyl carbon. While acetophenone exists mostly as the ketone, trichloroacetaldehyde (chloral) exists almost entirely as the hydrate (if exposed to water): OH2OOHO OHVery littleOHClClClH2OHClClClOHClClClHO OHVery littleSimilar things happen in neutral alcoholic medium - take chloroacetaldehyde in methanol, for example: OHClHClHOOMeMeOH Why do these hydrates form better w/ e--withdrawing substituents? Remember the first figure shown in these notes..... The mechanism for these additions is relatively straightforward: OHClHClHO OMeMeOHOMe HHClOOHMeProton-transfer This is the mechanism for the reaction in neutral media. The mechanism in basic media is left as an exercise for the reader (i.e. you!). In acidic alcoholic media, the reaction behaves like the Energizer™ Bunny - it just keeps going and going, until a completely new product is formed. It is called an acetal: OHClHClHO OMeMeOHH3O+HClMeOOMe The mechanism is quite straightforward: OHClHClO OMeMeOHH3O+HClMeO OMeHOHHOHClHOMe HHClHO OHMeOH HHHOHHHClO OMeHHOMe HHClOMeHClMeOOMeHOHH Basically, a series of protonation, nucleophile attack, deprotonation steps. Big Note: Acetal formation CANNOT occur under basic catalysis. Convince yourself that this is true...if you can’t, come see me.Remember that these reactions are all in equilibrium - it can be forced to the acetal by doing it under anhydrous conditions (or by distilling off the water), or forced back to the ketone/aldehyde by the addition of excess water (making it the perfect protecting group!): HOHEtO OEtHEtO OEtBrBrHEtO OEtHO HEtOH / H+BenzeneBr2KOHH2O / H+REtO OEt1) BuLi2) Alkylation, etc. In general, simple alcohols like methanol and ethanol are not used in the formation of acetals (particularly from less-reactive ketones!) The main reason is entropy - you’ve got to get three molecules together to form one - that’s not so good! The very common way around this is to use a glycol - ethylene or propylene glycol – to form a cyclic acetal: OTMS TMSOHHOH+ / benzeneTMS TMSOO As you would expect for ethers, acetals are stable to base and most nucleophiles, such as Grignard reagents and alkyllithiums. They revert back to the carbonyl compound on exposure to aqueous acid. Enamines: Just as with alcohols, amines can add to ketones and aldehydes. Primary amines add to give imines, while secondary amines give enamines (pronounced ene-amines). The reactions are generally catalyzed by a small amount of acid, and need to be buffered to a pH of ~4.5. An Imine (in this case, the amine is hydrazine, and the product is called a hydrazone): NROH2N NH2NRNNH2trace H+EtOH The mechanism (shown here for cyclobutanone) is pretty straightforward: OH2N NH2O NHHNH2protontransferHO NHNH2HOHHH2O NHNH2NNH2HHOHNNH2In the case of secondary amines, we have a lack of protons that can easily be removed from the amine – the mechanism thus requires that the offending positive charge be neutralized by removing a proton from the alkyl group: Overall: N HON OO NHprotontransferHO NHOHHH2O NNHOHNHNNo proton on amine to remove!-> remove proton from former ketone...HH De-Oxygenation reactions. There are two general reactions for the complete de-oxygenation of ketones and aldehydes. The general scheme for de-oxygenation is: OR R'R' can = HDe-OxygenateR R' The two methods are the Wolff-Kishner (runs under basic conditions) and the Clemmensen (under acidic conditions). Below find an example for each one:Wolff-Kishner:OH2NNH2 KOH HEAT!NNH2Clemmensen:OZn(Hg)HClHeat The Greatest Double Bond Forming Reaction Ever Invented: The Wittig Reaction This reaction is what I would call “cute” chemistry. One of the cool thing about Wittig reactions is that they just about always work. The most general scheme,