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EUROPEAN UNION EUROPEAN SOCIAL FUND THE DEVELOPMENT OF THE POTENTIAL AND ACADEMIC PROGRAMMES OF WROCŁAW UNIVERSITY OF TECHNOLOGY Medicinal Chemistry Artur Mucha and Renata Siedlecka Multistep Organic Synthesis Practical Course Wrocław, 2010 Project co-financed by European Union within European Social Fund EUROPEAN UNION EUROPEAN SOCIAL FUND THE DEVELOPMENT OF THE POTENTIAL AND ACADEMIC PROGRAMMES OF WROCŁAW UNIVERSITY OF TECHNOLOGY Introduction Most of organic syntheses are dedicated to the creation of large, multifunctional molecules, having desired properties. Simple and easily accessible substrates are transformed into more complicated compounds, which can be used as pharmaceuticals, food additives, herbicides or polymers. During the Organic Chemistry course students are familiarized with many groups of compounds and their properties, but still it is not so easy to plan and perform synthesis of complex molecules. “Multistep Organic Synthesis” laboratory should enhance students’ knowledge and skills in two aspects: • how to design an efficient synthesis, • how to carry out all the planned experiments step by step. Bearing this in mind, this manuscript contains a short theoretical part devoted to selected basic ideas to be considered when planning the synthesis, descriptions of some more often used experimental techniques and methods, and finally a selection of recommended experiments starting from fundamental to the advanced one. The teachers are free to modify each student program individually using this selection and their own suggested procedures. Project co-financed by European Union within European Social Fund 2 EUROPEAN UNION EUROPEAN SOCIAL FUND THE DEVELOPMENT OF THE POTENTIAL AND ACADEMIC PROGRAMMES OF WROCŁAW UNIVERSITY OF TECHNOLOGY The contents 1. Safety in the Chemical Laboratory 4 2. How to Design an Efficient Synthesis 5 3. Laboratory Equipment and Techniques 8 3.1. Assembling the selected apparatus 9 3.1.1. Carrying out the reaction 9 3.1.2. Separation via destillation (purification) 11 3.2. Preparation of anhydrous solvents 16 3.3. Handling organolithium reagents (pyrophoric liquids) 18 3.4. Thin-layer chromatography (TLC) 21 3.5. The specific rotation, polarimetry 24 4. Writing a Lab Report 26 5. Experiments 30 5.1. One step procedures 30 5.1.1 Acetylsalicylic acid (Aspirin) 30 5.1.2 5,5-Dimethylcyclohexane-1,3-dione (Dimedone) 31 5.2. Two steps procedures 32 5.2.1 2,4-Dinitrophenylhydrazine 32 5.2.2 N-Phosphonomethylglycine (Glyphosate) 34 5.2.3 Incadronate (Antiosteoporotic agent) 36 5.2.4 α-Diethylamino-2,6-dimethylacetanilide (Lidocaine) 37 5.2.5 9-Formylanthracene 39 5.2.6 1,3-Diphenyl-2-propen-1-ol 40 5.3. Three steps procedures 42 5.3.1 (R)-(-)-Carvone 42 5.3.2 Nicotinic acid amide (Vitamin PP) 44 5.3.3 1-(α-Aminobenzyl)-2-naphthol (Betti base) 46 5.3.4 p-Hydroxyacetanilide (Paracetamol) 48 5.3.5 (4R,5R)-2,2-Dimethyl-α,α,α',α'-tetra(naphth-2-yl)-1,3-dioxolane- 4,5-dimethanol (TADDOL derivative) 50 5.4. Four steps procedures 53 5.4.1 N-(tert-Butoxycarbonyl)-β-iodoalanine methyl ester 53 5.4.2 Methyl -benzylacrylate 57 5.4.3 N-(Benzyloxycarbonyl)-L-vinylglycine methyl ester / L-vinylglycine 60 Project co-financed by European Union within European Social Fund 3 EUROPEAN UNION EUROPEAN SOCIAL FUND THE DEVELOPMENT OF THE POTENTIAL AND ACADEMIC PROGRAMMES OF WROCŁAW UNIVERSITY OF TECHNOLOGY 1. Safety in the Chemical Laboratory The chemistry laboratory is a dangerous environment because chemists regularly use hazardous materials. However, with sensible precautions the laboratory is probably no more dangerous than your home, where you usually have contact with drugs, bleach, herbicides, insecticides, natural gas, electrical equipment, kitchen knives and so on. It is easy to familiarize yourselves with good laboratory practice and to minimize this way the dangers of organic chemistry. Essential rules for laboratory safety: 1. Be prepared – study carefully the procedure before starting the experiment; you should know which chemicals you are going to use, what properties they have an how to deal with them (check the Material Safety Data Sheets); you should also know about the techniques you are to use; think through the next step you are going to perform before starting it. 2. Wear approved protective clothing (goggles, apron, gloves) – tie back long hair and loose items of clothing to avoid dropping them into a reagent or getting near flame. 3. Check where there are the precautionary measures in your lab – locate the nearest eye wash, fire extinguisher, spray shower, fire blanket, emergency exit. 4. Do not put anything in your mouth while in laboratory, including food, drinks and pipettes. 5. Minimize your contact with any chemicals (by skin or inhalation) – keep the bottles closed, work in a fume hood whenever it is possible. 6. Be sure that you have proper chemicals for your reaction – check labels carefully, use exact amounts you need and don’t leave the substances in unmarked flasks/containers. 7. Keep things clean – laboratory bench surface and glassware; clean also means dry – water can disturb your reaction; wash and put unused apparatus away; wipe up or take care of spills on the bench or on the floor. 8. Be careful while assembling glass and using electrical apparatus; check if all the connections are tight and stable; when dealing with electricity make sure that your hands are dry and there is no other possibility of contact with water. 9. Do not work alone; you may need assistance or help. 10. Pay attention to proper waste disposal – only a few (water soluble materials) may be disposed of to the sink, other wastes should go into special containers (follow their labels). Project co-financed by European Union within European Social Fund 4 EUROPEAN UNION EUROPEAN SOCIAL FUND THE DEVELOPMENT OF THE POTENTIAL AND ACADEMIC PROGRAMMES OF WROCŁAW UNIVERSITY OF TECHNOLOGY 2. How to Design an Efficient Synthesis Looking i.e. at the most popular prescription drugs and their number of functional groups, it is common to have at least a dozen individual transformations, whereby the product of one reaction is then used as the starting material for the next reaction. Before starting the experiments it is necessary to carefully think over the strategy. You should choose an inexpensive, readily available starting material and to predict how many and what kind of transformations to apply in order to get the target molecule. If you do not have any ready procedure, prepare yourself for rather long literature study. Several rules should be followed while planning the step by step synthesis. Two factors are of major importance: synthetic efficiency and selectivity of each individual step. Criteria for evaluating synthetic efficiency: 1. Number of steps – should be minimized. 2. Yield for each step – should be maximized (high-yielding reactions should be chosen). 3. Reaction conditions – difficult conditions (temperature, pressure), toxic materials, intricate equipment are not desirable. 4. Ease of purification – simple work-up procedures that can be performed on a large scale are preferred. 5. Total cost – reagents and materials used should be cheap and easy handled; waste disposal also becomes very important. Overall synthetic yield is defined as the product of all the individual yields (expressed as decimals) multiplied by 100%. One problem, which becomes apparent is that the yield of the final product will be limited by the lowest yielding individual reaction. Therefore, each reaction in the sequence must be high yielding. Table 1. Dependence of the overall yield versus number of steps in multistep procedures. Number Yield depending on step (%) of steps 99 90 75 50 1 99 90 75 50 2 98 81 56 25 3 97 73 42 12 4 96 66 32 6 5 95 53 18 3 Project co-financed by European Union within European Social Fund 5 EUROPEAN UNION EUROPEAN SOCIAL FUND THE DEVELOPMENT OF THE POTENTIAL AND ACADEMIC PROGRAMMES OF WROCŁAW UNIVERSITY OF TECHNOLOGY For example: a two-step synthesis with a 50% yield per step is not as efficient as a five-step synthesis with a 90% yield per step (see Table 1). To modify the synthetic efficiency, instead of linear synthesis, one can perform convergent synthesis. Different ways of achieving the same number of steps can result in very different overall final product yield. Linear synthesis – when the product of one reaction is then used as the starting material for the next step and so on. 50% 50% 50% 50% A B C D 50% E F 320 g starting material 10 g product Total yield in this synthesis goes down strongly with increasing the number of steps even when the individual step yield is “not so bad”. Convergent synthesis – if the target molecule can be divided into two or more fragments (building blocks), which can be synthesized independently (in parallel). 50% 50% A B C 50% G 50% 50% D E F 80 g starting material 10 g product (40 g A + 40 g D) With the same number of steps and the same yield per step, the total yield is much better in this case (all calculations assume similar molecular weight of substrates and product). In the professional world of organic synthesis, most molecules are polyfunctional. Furthermore some functional groups may be similar to one another and may have similar reactivity. One of the most important challenges for organic chemist is the ability to transform one functional group within a molecule without affecting other groups, or to produce one particular functionality replacing another. This ability is called the selectivity of a particular reaction. Project co-financed by European Union within European Social Fund 6 EUROPEAN UNION EUROPEAN SOCIAL FUND THE DEVELOPMENT OF THE POTENTIAL AND ACADEMIC PROGRAMMES OF WROCŁAW UNIVERSITY OF TECHNOLOGY Types of selectivity: 1. Chemoselectivity – the ability of a reagent to react with one molecule or functional group over other similar molecules or groups in the same system.