If R2 is larger than R3, the anti chelate, with R1 and R2 trans in a six-atom ring, is expected to be the more stable form. Ketones were also used. This reaction is a mixed aldol condensation of an aldehyde and a ketone. Diastereomers are possible for 80 and 81, increasing the actual number of products. Subsequent reaction with an aldehyde that has no α-hydrogen atoms (benzaldehyde) leads to two aldol products (84 and 85) if there is no self-condensation of 2-methylpentan-3-one. Both of these ketones are symmetrical, and there is no opportunity for additional enolates, which would further complicate the reaction (see below). Note: Crossed aldol condensation with a double active enolate and an aldehyde. In the presence of a strong base, two different molecules of aldehyde or ketone combine to form a β-hydroxyaldehyde or a β-hydroxyketone. This process is called a retro-aldol reaction: Let’s first visualize what comes from where in the aldol product. Therefore, there are two possible aldol products, 3-hydroxy-1,3-diphenylbutan-1-one and 3-hydroxy-1,3-diphenylpropan-1-one. The enolate ion (carbanion) is the actual nucleophilic reagent. Let’s now put a complete mechanism for the aldol reaction: Looking at the mechanism, you may wonder why the enolate is shown in a resonance structure with the negative charge on the carbon atom rather than on the oxygen. The simplest aldol condensations use one type of aldehyde or ketone. The enolate derived from 3-pentanone (see 127) exists in equilibrium with the ketone under these conditions, and benzaldehyde is present. This reaction is most generally known as aldol condensation. The problem with this approach is clear when we recognize that enolate 127 can also react with unenolized 3-pentanone to produce the self-condensation aldol product (132), and hydrolysis gives 133. Cyclization occurs if the α carbon atom and the second carbonyl carbon atom can bond to form a five- or six-membered ring. Aldolisation crois e L'aldolisation crois e (en anglais : mixed (crossed) aldol condensation) met en jeu deux compos s carbonyl s (ald hyde ou c tone) diff rents. When reacted with an aldehyde with no α-hydrogens (benzaldehyde), two aldol products are formed (138 and 139) if there is no self-condensation of 43. In our catalytic tests, the main reaction products were mesityl oxides (MO’s) and isophorone (IP). 1.5.B, 6.6.Bsecs. Nonetheless, the reaction continues to a stable product because the subsequent step has a much more favorable equilibrium constant. Enolate 127 can react with benzaldehyde to give the aldolate product 128, and hydrolysis gives the alcohol as a mixture of diastereomers 129 and 130. Crossed aldol reactions are possible with weak bases such as hydroxide or an alkoxide when one carbonyl reactant does not have an a hydrogen. The ketone carbonyl is less reactive for two reasons. Some examples are shown below, and in most cases, under the conditions used, beta - elimination of water occurs. In general, these are called crossed aldol reactions and there are a few scenarios that need to be addressed separately. Note: Robinson annulation: Michael addition of a (cyclic) ketone enolate to an alpha,beta unsaturated ketone. Over all the samples the reaction rate diminished as a function of time-on-stream as shown in Fig. The pKa of 3-pentanone and cyclopentanone are close. Fig. Note: Another Robinson annulation with different reactants illustrates how different ring sizes and substituents can be prepared on the product. This is called a crossed aldol condensation. Note that this is directly analogous to malonic ester synthesis. Aldol condensation reactions can be done under acidic conditions. Syn:anti ratios increased with increasing size of R and ranged from 30:67 (R = Me) to 17:83 (R = Pri) (equation 32). Equilibration of stereochemistry was fastest with X = OMe (complete equilibration in 1 h) and slowest with X = Cl (complete equilibration in 5 h). This C–C bond-forming strategy could facilitate challenging molecule synthesis in chemical, biological, and medicinal research. All three substrates gave approximately the same equilibrium syn:anti ratio of 30:70. The aldol condensation provides a simple route to α,β-unsaturated ketones possessing further unsaturation. Note: Aldehydes may be deprotonated with base to yield enolates, but aldehydes are also good electrophiles resulting in the likely aldol addition of an enolate to an aldehyde to form a beta hydroxy carbonyl. This procedure is useful as it allows the iterative synthesis of polyenals (Equation (22)). In another example, taken from the synthesis of siphonarin B by Patterson and coworkers,116 aldehyde 149 was condensed with ketone 150 in the presence of Sn(OTf)2 to give a 92% yield of 151. In addition to the formation of 80 and 81, enolate anion 79 can condense with either the unenolized pentan-3-one (to produce 82) or with unenolized cyclopentanone (to produce 83), giving a total of four aldol products in this reaction. In Skrirsihna and Ramasastry's synthesis of (+)-2β-hydroxysolanascone,118 intramolecular aldol condensation of 158 with piperidine as the base gave a 90% yield of 159. Under the acidic conditions of the workup, that double bond moved into conjugation to give the final product 167. HOEt, 25 o C Note: Crossed aldol condensation with a double active enolate and an aldehyde. This is most often seen with an unsaturated aldehyde condensing with a ketone such as acetone, under basic conditions to give the (E) product (Equation (130)) <43CB676, 43OS(23)78, 49JCS737, 51JA719>. There are countless synthetic examples of the aldol condensation. The presence of MES in low concentrations on Al-rich samples is indicative of an acid-catalyzed reaction pathway [6]. The starting products depicted in the illustration are symmetric ketones. Pure MgO was the most active catalyst whereas Al2O3 showed the lowest activity. This overall reaction is known as a Robinson annulation. This enolate could condense with a second molecule of dione to give an aldolate product, but intramolecular attack of the second carbonyl group is much faster and leads to the cyclic aldolate product 156, which gives 157 upon hydrolysis. Initial product selectivity as a function of composition on MgyAlOx catalysts (T = 473 K, X0Acetone = 12-14 %), Kenneth A. Savin, in Writing Reaction Mechanisms in Organic Chemistry (Third Edition), 2014. Fe(acac)3 was identified as an essential co-catalyst in preventing vinyl Au protodeauration and facilitating nucleophilic additions. Crossed Aldol Condensations: An aldol reaction that starts with two different carbonyl compounds is called a crossed aldol reaction. Alkylation of 2-aminoselenazoline (33) with thiopheneacetyl bromide (34) occurs on the ring nitrogen (Scheme 3). When the β-hydroxy carbonyl is heated up in the presence of a base, an elimination reaction, called E1CB, occurs and a ɑ, β-unsaturated carbonyl compound is formed: Reaction of the enol with the protonated aldehyde via an intramolecular aldol cyclization (also see Sec. Aldol condensation is more of a problem where the enolate is unhindered and the process is generally inefficient for methyl ketones, although some improvement is possible by inverse addition of the enolate to MoOPH. In work by MacMillan and Northrup,113 L-proline was used as a chiral base. Under these conditions, cyclopentanone reacts to yield enolate anion 79. Under equilibrium conditions, both enolate anions (127 and 134) will be formed, and will be available for reaction. If 2-methylpentan-3-one were to react with sodium ethoxide under thermodynamic conditions in the presence of an unsymmetrical ketone (e.g., butan-2-one), both the kinetic and thermodynamic enolate anions of both ketones can be formed.