Aldol Addition of Butanal

Step 1 The base, in this case hydroxide ion, converts a portion of butanal to its enolate by abstracting a proton from the a carbon. 

Step 2 The enolate acts as a nucleophile and adds to the carbonyl group. 

Step 3 The alkoxide product of step 2 abstracts a proton from water to give the aldol and regenerate the hydroxide catalyst. 

Write the structure of the aldol addition product of each of the following. 

Sample Solution (a) A good way to correctly identify the aldol addition product of any aldehyde is to work through the process mechanistically. Remember that the first step is enolate formation and that this must involve proton abstraction from the a carbon. 

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The aldol addition of butanal is shown in Mechanism 20.1. The enolate is formed in the first step by deprotonation of the a carbon. At this point, the reaction mixture contains both the aldehyde and its enolate. The carbonyl group of the aldehyde is electrophilic the enolate is nucleophilic. This complementary reactivity leads to nucleophilic addition of the enolate to the carbonyl group (step 2). This is the step in which the new carbon-carbon bond forms to give the alkoxide ion corresponding to the aldol. Proton transfer from the solvent (water) completes the process (step 3). The product of the aldol addition of butanal contains two chirality centers however, it is racemic because the reactants are achiral. 

Formation of aldehydes by the reaction of alkene, CO and H2 catalysed by Co2(CO)8 was discovered by Rolen in 1938 [25]. This is the 1,2-addition of H and CHO to alkenes, and hence called hydroformylation or the oxo reaction. Production of butanal, (33) from propylene as a main product is an important industrial process. Aldol condensation of butanal, followed by hydrogenation affords 2-ethyl-1-hexanol (34), which is converted to phthalate, and used as a plasticizer of poly(vinyl chloride). 

Combination of achiral enolates vith achiral aldehydes mediated by chiral ligands at the enolate counter-ion opens another route to non-racemic aldol adducts. Again, this concept has been extremely fruitful for boron, tin, titanium, zirconium and other metal enolates. It has, ho vever not been applied very frequently to alkaline and earth alkaline metals. The main, inherent, dra vback in the use of these metals is that the reaction of the corresponding enolate, vhich is not complexed by the chiral ligand, competes vith that of the complexed enolate. Because the former reaction path vay inevitably leads to formation of the racemic product, the chiral ligand must be applied in at least stoichiometric amounts. Thus, any catalytic variant is excluded per se. Among the few approaches based on lithium enolates, early vork revealed that the aldol addition of a variety of lithium enolates in the presence of (S,S)-l,4-(bisdimethylamino)-2,3-dimethoxy butane or (S,S)-1,2,3,4-tetramethoxybutane provides only moderate induced stereoselectivity, typical ee values being 20% [177]. Chelation of the ketone enolate 104 by the chiral lithium amide 103 is more efficient - the j5-hydroxyl ketone syn-105 is obtained in 68% ee and no anti adduct is formed (Eq. (47)) [178]. 

To illustrate how aldol condensation may be coupled to functional group modifi cation consider the synthesis of 2 ethyl 1 3 hexanediol a compound used as an insect repellent This 1 3 diol is prepared by reduction of the aldol addition product of butanal... 

Reaction of aliphatic aldehydes with alkali acetylides in liquid ammonia gives the carbinols in very small amounts, even when the aldehyde is added to a strongly cooled solution of lithium acetylide. The predominant reaction presumably is formation of the enolate and the aldol condensation product As shown on p. 21, a suspension of LiOCH in THF can be obtained by gradually replacing the ammonia of an ammoniacal solution of the acetylide by THF. The lithium acetylide obtained in this way probably thanks its stability to the complexed ammonia. In the procedure described below, butanal is added to the suspension to give the acetylenic carbinol in a reasonable yield. Since this compound is rather volatile, it is essential to remove the greater part of the THF, before the hydrolysis is carried out. The main solvent which then has to be removed in the isolation procedure is the diethyl ether, used for the extractions. During the addition of the aldehyde, acetylene is introduced to suppress the formation of the diol RCH(OH)C=CCH(OH)R. 

Again, the exact details of the last step are uncertain. For butanol, 4-hep-tanone was the major product, butanal was a significant product and smaller amounts of Cg aldol products were present. It was proposed that Ce02 converted the alcohol to the acid, while aldol condensation took place on the more basic MgO. Water addition increased the amount of butanal formed, and also the amount of aldol product. 

The self-condensation of butanal involves a single compound, but it is also possible to convert one ketone or aldehyde to an enolate anion, and it wiU react with a different ketone or aldehyde. This is called a mixed aldol condensation. If acetone (2) is treated with aqueous NaOH in the presence of another carbonyl molecule, such as benzaldehyde (25), enolate (26) is formed in situ. This enolate anion may react with itself (with another molecule of 2 in a selfcondensation reaction), but it may also react with aldehyde 25 via acyl addition to give alkoxide 28. Mild hydrolysis gives the mixed aldol product, 26. There is a competition for the reaction of 27 with either 2 or 25, so at least two products are possible in the reaction 28 and the self-condensation product. Note... 

Ex situ formation of (33) followed by addition to a mixture of CHCI3 and aldehyde (aliphatic or aromatic) in DMF at low temperature leads to deprotonation of CHCI3 but not of the aldehyde, and formation of the trichlorocarbinol takes place without formation of side products by aldol condensation, Scheme 21 [99]. The reaction could also be carried out (75-86% yield for butanal) using polymeric amides as a PB and with similar conditions [74]. 

In addition, other work showed that 3-hydroxy-4,5-dimethyl-2(5H)-furanone can be formed thanks to a Maillard reaction of hexoses and pentoses in the presence of cysteine 20). Due to the non-linear structure of Sotolon, its formation cannot simply be explained directly from sugar cyclization during tire Maillard reaction, like other furanones such as Furaneol. Hence, it is likely tliat Sotolon results from rearrangement of Amadori products of low molecular weight like butan-2,3-dione (diacetyl) and hydroxyacetaldehyde, via an aldol condensation (Figure 6). 

The reaction between amino group (-NH2) and a carbonyl group (C=0) elsewhere in the same molecule has been used in the synthesis of many heterocyclic compounds. For example as shown in Equation 9.53, substituted quinolines can be produced by acid-catalyzed cyclization of the appropriate aminoketones (formed during the Friedlander synthesis, in this instance between propanone and ortho-aminobenzaldehyde, in an aldol-type reaction with loss of water this chapter, vide infra), and even more than one reaction can be induced to occur. Thus, in Equation 9.54,1,2-benzenediamine (ort/io-aminoaniline) undergoes acid-catalyzed addition to 2,3-butane-dione to produce 2,3-dimethyl-13-benzopyrazine (23-dime thy Iquinoxaline). ... 

For example, consider the reaction of the enolate of cyclohexanone with 1-butanal (Eq. 11.15). Here, the nucleophile is first created by treatment with a strong base, followed by addition to the electrophile. Under proper conditions, no enolate from 1-butanal is formed, and a single product is isolated (ignoring stereoisomers). This is referred to as a mixed aldol reaction. 

In the addition step of an aldol condensation, a new carbon—carbon bond forms between the a-carbon atom of one carbonyl compound and the carbonyl of the other. The addition product has just one carbon atom between the aldehyde and alcohol carbon atoms. The aldol product derived from butanal illustrates this relationship. 

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