Preparation of 2-Hydroxy-3-Phenylpropanoic Acid
Background
In this experiment, you will perform a substitution reaction beginning with the naturallyoccurring, optically-active amino acid, L-phenylalanine and making 2-hydroxy-3phenylpropanoic acid, according to the reaction scheme below:
O
O
O
H2O
NaNO2
OH
OH
OH
acid
OH
N2
NH2
stereochemistry?
In this laboratory experiment, the amino group from a naturally-occurring amino acid,
phenylalanine, is converted into a leaving group (nitrogen) through diazotization.
Diazonium salts, such as formed in this reaction sequence, are excellent leaving groups,
allowing neutral, gaseous nitrogen to be displaced by a nucleophile. Amines can be
converted into diazonium salts by treatment with sodium nitrite under acidic conditions,
as in this experiment. Once the leaving group is formed, it can be attacked by solvent
water to form the hydroxyl compound.
Nucleophilic substitution reactions are important reactions in organic chemistry and are
generally covered in great depth early in the sophomore organic chemistry curriculum.
You have learned about two general mechanisms for substitution: the SN1 mechanism
that leads to mixed stereochemistry, and the SN2 mechanism, which gives inversion of
stereochemistry. A third possibility, is neighboring group participation, which includs
two backside displacements, leading to overall retention of stereochemistry. This
laboratory exercise is designed primarily to investigate the stereochemical outcome of
this reaction, which will allow for a determination of the mechanism of reaction. Three
possible mechanisms will give different stereochemical outcomes:
O
OH
OH
SN2
O
O
SN1
OH
OH
+/OH
NH2
O
neighboring
group participation
OH
OH
Verification of the stereochemical outcome of the reaction is readily available by
measuring the optical rotation of the product and comparing it to the known literature
value.
Procedure:
Week 1. To a 25-mL Erlenmeyer flask containing 1.65 g (10 mmol) L-phenylalanine and
a magnetic stir bar, add 10 mL of 1M H2SO4 (caution: corrosive). Magnetically stir the
solution at room temperature until homogeneous. Cool the solution to 3-5˚C in an icewater bath. Monitor the temperature with a thermometer clamped in place such that the
magnetic stir bar does not hit the thermometer. Once the solution is cool, add 5 mL of a
3.0 M NaNO2 (caution: strong oxidizing agent) solution dropwise via a disposable
pipette. The rate of the addition should be slow enough to maintain the reaction
temperature below 5 ˚C and minimize the formation of noxious brown nitrogen oxide
fumes. If a significant amount of brown fumes form, slow down the rate of addition.
The addition should take about 45 minutes. During the addition, note bubbles of N2 gas
forming. Once the addition is complete, remove the ice-water bath and allow the reaction
to stir at room temperature until the end of the lab period. Lightly cork the Erlenmeyer to
allow gas to escape, and leave the reaction in your drawer until the next lab period.
Week 2. Cool the solution to 0-5 ˚C to maximize yield, and isolate the solid product by
vacuum filtration. Wash the crystals by slurrying in 5 mL of ice-cold water in the
Büchner funnel with the vacuum released. Remove the wash solvent by vacuum
filtration. Pull air through the crystals until they are mainly dry. Spread out the crystals
on a watch glass to dry further. Analyze the product by melting point (120-121.1 ˚C), 1H
NMR (acetone-d6), and specific rotation (c = 1.4, acetone).
Report Guidelines:
Include typical results and observations as you have been learning for a synthetic lab.
For the discussion, include comments on the success of the reaction based on
experimental data. Why is the starting L-phenylalanine soluble in the reaction mixture
but the product is not? Discuss the similarities and differences between the two
structures in your answer. How high yielding was the reaction? How could it be
improved? Did you form the product that you intended to form? (Does the proton NMR
support this product—list all coupling constants and explain the splitting.) What is the
stereochemistry of the product, and how is this supported? What is the enantiomeric
excess of the reaction? Propose a mechanism for its formation. Explain how other
mechanisms are excluded based on data.