Download Preparation of 2-Hydroxy-3-Phenylpropanoic Acid Background In

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
acid
NH2
OH
OH
N2
OH
stereochemistry?
In this laboratory experiment, the amino group from a naturally-occurring amino acid,
phenylalanine, is converted into a leaving group (nitrogen) through diazotization. While
not one of the typical leaving groups discussed in beginning organic chemistry such as
halides or sulfonate esters, a diazonium salt such as formed in this reaction sequence is an
excellent leaving group, 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 S N 1 mechanism
that leads to missed stereochemistry, and the S N 2 mechanism, which gives inversion of
stereochemistry. A third possibility, discussed in Brown and Foote Chapter 9.9, is
neighboring group participation, which included two backside displacements, leading to
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, which is +26.9o for the R enantiomer of 2-hydroxy-3-phenylpropanoic acid .
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 H 2 SO 4 (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 NaNO 2 (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 N 2 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-d 6 ), and specific rotation (c = 1.4, acetone).
Notebook 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, and include the implications for the stereochemistry of the compound
formed. Propose a mechanism for its formation.
Formal report guidelines
Introduction: For the introduction, discuss substitution reactions in general, and cite a
recent paper (2009-2010) from the primary literature that uses a substitution reaction in
synthesis. Discuss the diazonim leaving group and give a figure with a mechanism. For
diazonium formation.
Results/Discussion: Answer these questions within the discussion section, using
appropriate data to support your answers.
1. Discussion of the reaction. 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?
2. Discussion of the product. 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?
3. Discussion of the mechanism. Propose a mechanism that would lead to the
stereochemistry in the product you isolated. Draw a figure with the mechanism,
and explain it in a paragraph. Are there any inconsistencies?
Make a photocopy of the lab notebook and attach it to the hardcopy of the formal
report you turn in.