5.4.3 Organic synthesis

1. 5.4.3 Organic synthesis

2. a. give examples to illustrate the importance of organic synthesis in research for the production of useful products. • Organic synthesis involves the replication and modification of naturally occurring compounds, as well as the creation of new ones. • The dominant reason for conducting organic synthesis, is that it can be used to make a profit. This factor is rarely mentioned as this motivation is very difficult to make us look like wonderful altruistic and principled beings engaged in a valiant worthy pursuit. The marketing and advertising branches of society would would find it extremely difficult to employ their usual quiver of tools and tricks, in fact it would probably have very few arrows to shoot in the direction of the consumer. So secondary (or lower) motivations are talked about instead. Secondary motivations sound much better, they whitewash the unflattering primary motivation and consequently help make us believe we are fantastic and such good people. Secondary motivation is something the marketing/advertising people love. They can induce a warm and fuzzy feeling inside us. E.g. making new drugs to “help the sick” or “making some new useful component for device” etc. If cancer or malaria rates are high, the chances are there’ll be a lot of work being done because the chance of great profit looms. If cancer rates are low, or there is some rare disease which only a handful of people suffer from, expect little if any progress in organic synthesis to be done to help those people. The fact that almost 1/7 people in the world go to sleep hungry each day and virtually nobody helps them, is because they are poor and there’s no money to be made by helping them. It’s the same thing with synthesis. And because profit is the main motivator, greed eventually makes its presence felt: More money can be made by treating symptoms rather than providing a cure for them, or making a low quality component with a life-span to cover the warranty period only instead of making a quality durable component. These things offer far greater potential for profit. The secondary factors are generally the ones the examiners would expect you to write. • The primary factor for replicating naturally occurring organic compounds or modifying them or making new ones is that it will be cheaper, hence more profitable. • Some useful naturally occurring compounds (e.g. the pain reliever salicilin found in the bark of the willow tree and in parts of the body of otters) are present in small amounts and/or take a long time for natural processes to make them. Hence it is advantageous to make then synthetically. Artificial compounds like cis-platin have also proven useful hence it is productive to replicate (manufacture) organic compounds. • It is also useful to modify organic structures into new forms, the active ingredient in salicilin was said to cause stomach irritation. The modified structure synthetically is supposedly reported to cause less irritation. You (the student) are free to differ

3. b. explain why sensitive methods of chemical analysis are important when planning and monitoring organic syntheses ‘Sensitive methods’ of detection and analysis ensure products can be distinguished/identified from the reactants. Sensitive techniques include NMR, HPLC, GC, IR, Look for number of peaks, characteristic chemical shifts, splitting patterns and integration heights, for HPLC, number of peaks, retention factor of peaks (resolvable using solvents of different polarity) and use of standards (usually keep some of the reactants for this purpose). GC is similar but ensure compound is sufficiently thermally stable, so as not to decompose. IR look for peaks in the functional group region (<1500 cm-1). Bpt and mpt also can be used as can chemical tests for ions like Ba2+ functional groups like C=O.

4. c. deduce the empirical formulae, molecular formulae and structural formulae from data drawn from combustion analysis, elemental percentage composition, characteristic reactions of functional groups, infrared spectra, mass spectra and nuclear magnetic resonance. • The above have been covered in much detail in my AS and A2 classes.

5. d. use knowledge of organic chemistry contained in this specifications to solve problems such as: • i. predicting the properties of unfamiliar compounds containing one or more of the functional groups included in the specification, and explain these predictions • Molecules containing OH’s behave like alcohols, compounds containing halogen atoms behave like halogenalkanes. Compounds containing a mixture of functional groups have properties of their individual groups. If functional groups are on the same carbon then a new functional group forms, e.g. C=O bonded to OH, gives carboxylic acid. C=O with NH2 (on the carbonyl carbon) gives amide etc. • ii. planning reaction schemes of up to four steps, recalling familiar reactions and using unfamiliar reactions given sufficient information • Create “spider diagrams” showing how all functional groups relate to each other by conversion. Creating them is more helpful than just looking at them in the book. Choose a simple molecule then choose another, try and use your reactions to change them. May need one or two reactions off syllabus but will help reinforce the ones actually on the syllabus as they are likely to be used • .

6. iii. selecting suitable practical procedures for carrying out reactions involving compounds with functional groups included in the specification • I.e. refluxing, distillation, steam distillation, solvent extraction, removing water using anhydrous MgSO4 or Na2SO4 etc. vacuum filtration, gravity filtration… • iv. identifying appropriate control measures to reduce risk during a synthesis based upon data of hazards • Choose less reactive species, use lower quantities, minimize solvent use and recycle solvent use (or replace them altogether with these new ‘ionic liquids’) • v. understanding why, in the synthesis of stereo-specific drugs, it is important to understand the mechanism of the reaction and how this can help to plan the synthesis • Stereoisomers (geometric [cis-platin] and optical [thalidomide] ) can have radically different biological effects, some disastrous. Should choose mechanisms that do NOT give racemic mixtures in cases where one enantiomer is biologically damaging. E.g. SN2 mechanisms will not give racemic mixtures. In certain circumstances, SN1 reactions and Addition reactions may also produce racemic mixtures,

7. e. explain why the pharmaceutical industry has adopted combinatorial chemistry in drug research, including passing reactants over reagents on polymer supports

8. Combinational Chemistry • Collection of techniques which allow for the synthesis of multiple compounds at the same time rapid synthesis (compared to traditional synthesis methods). Specific sequences of molecular constituents/parts can created e.g. proteins, specific multi monomer polymers. E.g. one end of some kind of monomer is attached to a bead. Different monomers are attached to a different bead (e.g each bead has an alcohol with a different chain length bonded to it). All beads are then mixed together with a compound that will react with the functional group present in the monomers (e.g. a difunctional carboxylic acid). The beads are then removed by filtration and washed. The molecule sticks to the bead. All beads can then be separated and each bead put into a specific difunctional alcohol, creating a second ester linkage. Beads are removed again, washed and then ALL put into the same difunctional carboxylic again. This process is repeated again and again and a so a number of specific polyesters can be created at the same time with great efficiency. This way sequence of monomers can be precisely controlled as can the chain length. This can be done for any polymer, such as polyamides, polyesters, polypeptides (proteins) etc. See the diagram after the next text slide.

9. (combinational chem contd.) • Waste/excess reagent can be washed away and beads retained. Beads may have many reaction sites on them. • When finished and separated, molecule is cleaved from the bead to yield the final product. • Purification/isolation steps is largely made redundant.. • Leads to much greater efficiency in : organic synthesis, drug discovery, aiding catalyst design, and material sciences.

10. (to mix) and divide into batches (to mix) and divide into batches Many beads of one type • http://chem3513-2007.pbworks.com/w/page/15648417/Combinatorial%20Chemistry

11. http://chem3513-2007.pbworks.com/w/page/15648417/Combinatorial%20Chemistryhttp://chem3513-2007.pbworks.com/w/page/15648417/Combinatorial%20Chemistry

12. These columns of test tubes are prepared first. Resulting matrix of products This row sequence of alcohols isthen added to the test tubes

13. Refluxing • Allows of for higher temps to be used, without loss of solvent or reactant, hence reaction rate increases. • SHOW OPEN SYSTEM and NO BUNSEN

14. Distillation • When thermometer reading const, a single substance is coming off.Open at end only! (& not near thermometer / entrance to condenser) Open at end only! • If bpt = 81oC, collect fraction from +/- 1oC of the bpt

15. Steam Distillation • Steam distillation: Use when normal distillation could cause compound to decompose. Allows distillation (compound and water vapor droplets) to “distill” off at a lower temperature. • Need to remove water at end (e.g. use separating funnel and do liquid-liquid extraction {sometimes solvent extraction} on water layer) After, DRY product (e.g. anhydrous MgSO4)

16. Steam Distillation (contd) • Used for natural oils / hydrophobic molecules / complex esters etc. Example is limonene from orange peel.

17. Steam distillation 1 (simple set-up) • Open system at end only. http://thegeekgroup.org/forums/topic/steam-distillation-of-catnip-to-produce-nepetalactone/

18. Steam distillation 2 (slightly more complicated set-up)

19. Steam distillation VIDEO – Limonene • http://www.youtube.com/watch?v=1OfLPQ-29Iw

20. Recrystalization (of solids) • If product (solid) mixed with liquid (e.g. 2,4-DNP derivative) use vacuum filtration. • Dissolve in minimum amount of hot solvent., i.e. while under heat, add hot solvent until solid just dissolves. Good solvent = dissolves solid when hot but not when cold.Do gravity filtration when hot using fluted filter paper and a preheatedstemless funnel. • Allow to cool SLOWLY. Once cooled cool in ice • Do vacuum filtration. Wash solid with a few drops of ice-cold solvent. • Allow solid to dry in a desiccator. The liquid produced after filtering a solid in a liquid is called filtrate.

21. Note: “Suitable solvent” has poor solubility for the solute(substance to be dissolved) when cold, and high solubility for solute when hot. • Video of Recrystalisation = • Organic Chemistry Lab: Recrystallization http://www.youtube.com/watch?v=XK0MZk3Q4jk

22. Solvent (liquid-liquid) extraction • A compound has an appreciable difference in solubility between two immiscible (i.e. cannot mix – get two separate liquid layers) solvents (one often being water, the other usually organic solvent e.g. diethylether). • Organic compound usually more soluble in non-water solvent. • Use Separating funnel (straight or round) • Add roughly equal amount of solvent and (usually water based) mixture into sep funnel. • Stopper and shake, opening tap when inverted (hold stopper in place) to allow gas pressure build up to escape. Drain off water layer. Keep organic layer. • Wash the water layer with more organic solvent. • Can add salt to make water later more polar forcing the compound out of the water even more. • Combine all organic layers. Add anhydrous MgSO4 to remove traces of water. Filter and evaporate organic solvent leaving product behind.

23. Solvent extrction This technique is also useful at removing ionic and polar impurities from a reaction product if water and non-polar solvents are used. The polar and ionic impurities will enter the aqueous layer. http://www.tutorbene.com/index.aspx?PageID=92

24. YouTube video on liquid-liquid extraction: Liquid-liquid extraction (or separation) http://www.youtube.com/watch?v=vcwfhDhLiQUand Organic Chemistry Lab Demo: Extractions (part 1) http://www.youtube.com/watch?v=CyIA8NhMUl4&feature=relatedOrganic Chemistry Lab Demo: Extraction techniques sourcs of confustion (emulsions) (i.e. part 2) http://www.youtube.com/watch?v=CyIA8NhMUl4