The Benzoin Condensation

The reaction of two moles of benzaldehyde to form a new carbon-carbon bond is known as the
benzoin condensation. It is catalyzed by two rather different catalysts – cyanide ion and the
vitamin thiamine – which on close examination, seem to function in a very similar manner.
2
benzaldehyde
bp 178 C
O
thiamine
or CN-
O
C
HC
OH
benzoin
mp 135 C
Consider first the cyanide (CN - ) ion reaction, which is very similar to the reaction which you will
perform in lab. The cyanide ion attacks the carbonyl oxygen to form a stable cyanohydrin,
mandelonitrile, a liquid of bp 170° C:
O
CN-
O -
C N
H 2 O
OH
mandelonitrile
Under the basic conditions of the reaction, mandelonitrile loses a proton, then rearranges by
hydride shift, to give a resonance-stabilized carbanion:
OH
C N
OH-
O -
CH
C N C -
proton
transfer
OH
C N
C N
In the last step, the alkoxide ion is protonated by water, and the subsequent OH - ion deprotonates
the carbon. (It may seems unusual that a carbon can be deprotonated so easily, but notice that the
carbanion is highly resonance stabilized).
This carbanion, a nucleophile, attacks another molecule of benzaldehyde at the carbonyl.
Eventually CN - is eliminated as a leaving group; this reaction is somewhat similar to a Gringard
reaction.
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Although the benzoin condensation proceeds rapidly and produces benzoin in high yield when
catalyzed by cyanide, we will not perform the reaction with this catalyst. Cyanide is extremely
toxic and accidental exposure to even small amounts can have serious consequences. Cyanide is
not readily absorbed through the skin, but any small cut or break in the skin can lead to accidental
exposure. In solid form, it may also be inhaled in the form of dust or small particles.
A number of biochemical reactions bear a close resemblance to the benzoin condensation but are
not catalyzed by the highly toxic cyanide ion. In the 1960s it was found that that vitamin B1,
thiamine hydrochloride, in the form of the coenzyme thiamine pyrophosphate, can function in a
manner completely analogous to cyanide ion in promoting reactions like the benzoin
condensation. The resonance stabilized conjugate base of the thiazolium ion, thiamine, and the
resonance stabilized carbanion that it forms are the key to the reaction. Like the cyanide ion, the
thiazolium ion has just the right balance of nucleophilicity, ability to stabilize the intermediate
anion, and good leaving group qualities.
H3C N NH2
N
H
S
CH 2
N +
Cl -
CH 3
OH
HO -
H3C N NH2
N
C -
S
CH 2
N +
Cl -
thiamine hydrochloride thiamine (a nucleophile)
Note that one of the carbons in the 5-membered ring is a carbanion; this will attack benzaldehyde
in much the same way cyanide does, resulting in a carbanion at the benzyl position of
benzaldehyde. It is thiamine we will use as a catalyst for the benzoin condensation. We will
form the thiamine in situ by adding thiamine hydrochloride and NaOH to our reaction mixture.
The importance of thiamine is evident in that it is a vitamin, an essential substance that must be
provided in the diet to prevent beriberi, a nervous system disease.
CH 3
OH
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Procedure
Do NOT work in pairs or groups for this lab – everyone should work independently!
Place 2.6 grams of thiamine hydrochloride* in a 125 mL Erlenmeyer flask, dissolve it in 8 mL of
water, and add 30 mL of 95% ethanol. Cool the mixture in an ice bath. Add 5 mL of 3 M NaOH
dropwise, with stirring. Keep the mixture cool during this process; the temperature should not
exceed 20°C. You will notice the formation of a yellow color as the thiamine hydrochloride is
deprotonated to form the yellow compound thiamine.
* note: thiamine hydrochloride may be labeled as “Vitamin B1 Hydrochloride”
To the yellow solution, add 15 mL pure* benzaldehyde and cover the flask with aluminum foil.
Heat the mixture, in a warm water bath, at approximately 60°C for 45 minutes. (The
concentration of the thiamine will increase during this heating process, giving the mixture a
darker yellow or orange color). The progress of the reaction can be monitored by TLC.
Alternatively, the reaction mixture can be stored at room temperature for at least 24 hours.
* note: Benzaldehyde, when stored for long periods, may slowly oxidize in air to form
benzoic acid. If the benzaldehyde appears yellow, or if crystals of benzoic acid are
evident, the benzaldehyde should be shaken in a separatory funnel with equal volumes of
5% sodium carbonate until the evolution of CO2 (bubbling or fizzing) no longer occurs.
The upper layer (benzaldehyde) can then be dried with calcium chloride or magnesium
sulfate and used. This purification process is not necessary if the benzaldehyde is clear
and free of crystals!
*note: your instructor may have this experiment as a two-week lab. If you are going to
let the reaction mixture sit overnight for the reaction to complete, this will be the point at
which you stop!
Cool the mixture in an ice bath. If crystallization does not occur, withdraw a drop of solution on
a stirring rod and rub it against the inside surface of the flask to induce crystallization. Collect
the product by vacuum filtration and wash it free of the yellow mother liquor with distilled or
de-ionized water. Weigh the crude product. Determine the melting point of the crude product.
The benzoin should be colorless and of sufficient purity (mp 134-135°C) to use in subsequent
reactions; usual yield is 10 – 12 grams.
Cleaning Up
Your instructor will collect the synthesized benzoin for use in next week’s experiment. Place the
benzoin in an open beaker, labeled with the contents and your name. You may wish to weigh the
labeled beaker first. Wait until the second week to weigh your sample and measure the
melting point; this will give a chance for the crystals to dry completely.
All reaction by-products and filtrates can be washed down the sink, diluting with water.
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Post-Lab Questions
1. A procedure is provided to remove benzoic acid, if present, from the benzaldehyde.
a. Why might the presence of benzoic acid be deleterious to the reaction? Fully explain
your answer – be specific!
b. How does treatment with sodium carbonate remove the benzoic acid? Show the
balanced reaction which would occur in that step.
2. Calculate the theoretical yield and % yield of your crude benzoin product. To receive credit,
you must show your work for both calculations; the density of benzaldehyde is 1.045 g/mL.
3. How many π-electrons are in the thiazoline ring (the 5-membered ring) of thiamine
hydrochloride? of thiamine? Are these rings anti-aromatic, non-aromatic, or aromatic?
4. Show a detailed mechanism for the reaction of the thiamine carbanion with benzaldehyde.
The reaction will be similar to nucleophilic attacks at carbonyls that you have previously studied
(ie., a Grignard reaction); you may wish to refer to your textbook. (hint: when thiamine reacts
with benzaldehyde, it forms a carbanion very similar in structure to the carbanion of
mandelonitrile, shown on the first page of this handout).
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Data / Observations Page Benzoin Condensation
Name ____________________________________________________________
Starting materials:
Mass of Erlenmeyer Flask: _____________________ grams
Mass of Erlenmeyer Flask + thiamine HCl: _____________________ grams
Mass of thiamine HCl: _____________________ grams
Product:
Mass of container: _____________________ grams
Mass of container + Benzoin _____________________ grams
Mass of Benzoin (product): _____________________ grams
melting point of product: _____________________ °C
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Pre-Lab Questions Benzoin Condensation
Name __________________________________________________
1. What purpose does the NaOH serve in the thiamine catalyzed benzoin condensation?
2. A carbanion is formed when mandelonitrile reacts with NaOH and then undergoes a proton
transfer; the resulting carbanion is described in the discussion as “resonance stabilized”. Draw
the resonance forms of the carbanion; there are several of them. (hint: the negative charge can be
shared with nitrogen, and with the aromatic ring).
3. Calculate the theoretical yield of benzoin, in grams, assuming you begin with 15.0 mL of
benzaldehyde. The density of benzaldehyde is 1.045 g/mL. (You should record this value before
you hand in the pre-lab!). You must show your work to receive credit on this problem.
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