University Of Central Lancashire Department of Forensic and Investigative Science FZ1025 Experimental techniques in chemistry

11. Synthesis of a Heterocyclic Compound: 2-Amino-4,6-dimethylpyrimidine

INTRODUCTION The production of a number of drugs involves the synthesis of a heterocyclic compound. There are two main ways to prepare heterocyclic compounds:1. Assemble the heterocyclic ring from non-heterocyclic starting materials (as in this experiment). 2. Structurally modify an existing, readily available heterocycle. The overall reaction, shown below, is a condensation of two acyclic starting materials (precursors)

NH2 HN C NH2

.
2

O H2CO3

O NaOAc

+ CH3CCH2CCH3 2,4,-pentanedione (acetylacetone)

guanidine carbonate

CH3
6 1

N N
3

5 4

+ 3 H2O + CO2 CH3

H2N

2-amino-4,6-dimethylpyrimidine
PRE-LAB QUESTIONS 1) Using the Symyx package, draw the structures of pyridine, pyrimidine, pyrazine and pyridazine. (4 marks) 2) Why are pyridine and pyrrole both aromatic (3 marks) 3) Name and draw the structure of the reaction product between pyridine and hydrogen peroxide. (3 marks)

COSHH ASSESMENT Please read the safety information carefully before beginning the practical Chemical / Hazard Likelihood Risk (A x B) Safety Process Severity of (Likelihood x Grade 1-4 occurrenc hazard) A e Grade 1-4 B Guanidine 1 1 1 May cause irritation to skin carbonate Low 2,42 1 2 Flammable. May cause pentanedione Low irritation to skin, toxic if swallowed. Use only in a fume cupboard Sodium 1 1 1 May cause irritation to skin acetate Low Methanol 1 1 1 Flammable. Store in a well Low ventilated place. Do not breath vapour

EXPERIMENTAL

Ask for help/advice if you are unsure about any of the experimental procedures. CAUTION 2,4-Pentanedione and methanol are flammable. NO flames should be used
during this experiment. Methanol is highly TOXIC do NOT drink any. 1. Assemble a clamp and stand and a small condenser with rubber tubing (thin not thick vacuum tubing) so it can be water cooled (inlet at the bottom, outlet at the top). Take care when attaching rubber tubing and ask for assistance if necessary. 2. Place 2.7 g of guanidine carbonate and 1.5 g of sodium acetate in a 50 cm 3 conical flask with a Quickfit (ground glass) joint, add 10 cm 3 of water and swirl the contents of the flask until all the solid dissolves. 3. To this solution, working in a fume cupboard, add 3.0 cm3 of 2,4-pentanedione, in one transaction. Swirl the contents of the flask for 2 minutes, connect the conical flask to the reflux condenser (you may need an adapter if the two dont fit together) and heat the flask and contents on the hotplate at reflux for 15 minutes. Adjust the water tap until there is just a gentle flow of cooling water through the condenser. Make sure the outlet tubing is in the sink and avoid flooding. 4. After refluxing cool the flask in an ice bath and collect the solid that crystallizes by vacuum filtration using a small Buchner funnel. Then leave the vacuum on for five minutes to dry the solid product. Dispose of the filtrate to the aqueous waste container in the fume cupboard. 5. Dissolve the product in the minimum volume of hot methanol (about 5 cm3). If a large percentage of solid remains filter through a fluted filter paper into a small, clean, dry conical flask (not normally necessary). Cool the flask in an ice-bath until you judge that crystallization is complete.

6. Collect the crystals using vacuum filtration. Dry the product (in the oven at 80 C) for 10 minutes, weigh it and determine the melting point. Dispose of the filtrate to the non-chlorinated waste container in the fume cupboard. REPORT Your report should contain the following details and answers to the questions that follow:Actual yield of product (g); the theoretical yield (g) for the reaction and hence your % yield and the observed melting point range of your product. You should also submit your product in a labelled polythene bag. QUESTIONS 1) 2) 3) 4) What information can be obtained from the melting point of the compound? How could the identity and purity of the compound be determined? What is the purpose of adding sodium acetate to the reaction mixture? The amino groups in guanidine are effective nucleophiles, this involves nucleophilic addition of the amino groups of guanidine to the carbonyl groups of 2,4-pentanedione followed by elimination of water (overall a condensation reaction). The mechanism is represented below:-

NH2

C O

NH2 C O

N C OH

N C

H2O

Two such reaction steps occur in this pyrimidine synthesis, the first one is intermolecular (between two different molecules) and the second is intramolecular (within the same molecule) resulting in the product being formed following a rearrangement reaction. Suggest a reaction mechanism for the formation of 2-amino-4,6-dimethylpyrimidine.