Aldehydes have a high and versatile reactivity serving as indispensable reagents in the organic synt — Organic Chemistry Chemistry Question
The formose reaction
Aldehydes have a high and versatile reactivity serving as indispensable reagents in the organic synthesis. Carbon atom of the carbonyl group is an electrophilic center. In the aldol condensation reactions a nucleophilic enol (or enolate) attacks the electrophilic carbonyl group of the other aldehyde (or ketone) molecule.
Fill in blank boxes in the representative aldol condensation reaction, and mark by letters E or N the respective nucleophilic and electrophilic reaction centers which take part in the process
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Model Answer
The base-catalyzed aldol condensation involves a highly reactive nucleophilic enolate-ion, which directly attacks the electrophilic carbonyl carbon of another aldehyde molecule giving β-hydroxyaldehyde (aldol).
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Such aldehydes are commonly referred to as non-enolizable. Why? Give any three examples of such aldehydes.
Model Answer
Non-enolizable are aldehydes lacking β-protons , that are those which cannot give enols or enolates. Among important non-enolizable aldehydes, besides formaldehyde are benzaldehyde PhCHO, trichloroacetic acid aldehyde (chloral) CCl3CHO, glyoxal OHC−CHO, and many others.
Suggest a method for industrial preparation of formaldehyde from coal and water in no more than 3 stages.
Model Answer
Formaldehyde is produced by a 3-step process involving a) gasification of coal by the action of steam at high temperature to give the so-called syngas, which is used as feedstock for b) methanol synthesis using copper on zinc oxide catalyst at 250 °C and a pressure of 100 atm. Methanol is catalytically dehydrogenized into formaldehyde over silver mesh at 650°.
C + H2O → CO + H2
CO + 2 H2 → CH3OH
CH3OH → CH2O + H2 (or oxidation/dehydrogenation to CH2O + H2O)
Mark in structure of the product (benzoin) the fragments coming from benzaldehyde and put the letters E and N over electrophilic and nucleophilic centers.
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Model Answer
The main trick in the mechanism of benzoin condensation is the addition of nucleophilic catalyst to carbonyl group of a non-enolizable aldehyde. Central carbon of the adduct is no more sp2-carbon, but rather sp3-carbon bearing two substituents capable of delocalization of negative charge and thus rendering a reasonable CH-acidity. After deprotonation the resulting carbanion serves as a nucleophile attacking carbonyl group of the other aldehyde molecule. Elimination of nucleophilic catalyst (here, cyanide) regenerates carbonyl group. Thus, the net result is the transfer of PhCO (or generally RCO, acyl) residue from aldehyde.
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Mark in thiazolium the CH-acidic center equivalent to that in HCN. Draw the structure of the respective carbanion and show its resonance structures that account for the enhanced CH-acidity.
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Model Answer
The analogy between cyanide and thiazolium is profound and very interesting. Apparently, both HCN and thiazolium (with regard to C-2 atom) can be considered as derivatives of formic acid. Resonance structures for thiazolium anion suggest that besides carbanionic form there is the only one other form, an electroneutral carbene! Indeed, this is a true carbene with 6-electron configuration of carbon atom, a lone pair and a vacant orbital. Recent research has shown that thiazolium anion and closely related anions of analogous heterocycles (e.g. imidazolium) are indeed stable (!) carbenes, which immediately found a lot of applications in organic chemistry and catalysis. These carbenes are nucleophilic due to two electron-rich heteroatoms connected to carbene center. Thus, it can be assumed that Nature employs a stable carbene in the transketolase catalysis. Coming back to the analogy with cyanide, we see that cyanide has a second resonance form, isocyanide with carbene-like divalent carbon.
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Alcohol addicts often suffer from an acute B1 deficiency. Why?
Model Answer
As shown above thiamine pyrophosphate, as other thiazolim salts, is very reactive towards aldehydes. In the organisms of heavy drunkards there is a lot of alcohol dehydrogenation product, acetaldehyde. This reactive aldehyde binds to thiamine thiazolium residue, thus stealing the vitamin from vital biochemical processes.
Complete this scheme to the final product.
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Model Answer
Continuation is straightforward to employ the same chemistry as in the steps already shown. Catalyst (thiazolium anion or thiazolidene, if we choose the carbene form) is regenerated at the last stage exactly as in the benzoin condensation.
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Fill in empty boxes on the simplified scheme of formose reaction below.
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Model Answer
Refer to the complete scheme showing the initiation step (induction period) and the catalytic cycle of the formose reaction with all intermediate carbohydrate structures filled in.
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Show the step(s) involved in the induction period.
Model Answer
The Umpolung in the true formose reaction is apparently furnished by CH-acidic properties of the hydrated form of formaldehyde. Due to the lack of good mesomeric stabilization CH-acidity is much lower, and the deprotonation leading to nucleophilic carbanion is much less efficient. Therefore, the reaction is very slow at the beginning. The induction period is accounted for by very low concentration of carbanion.
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Show the catalytic cycle. What compound(s) serve(s) as catalyst(s)?
Model Answer
But as soon as some glycolaldehyde is accumulated, a highly effective catalytic cycle is switched on. Within the catalytic cycle formaldehyde behaves as a normal electrophile. The catalyst compounds are carbohydrates (specifically glycolaldehyde, which launches the autocatalytic cycle).
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