1. 1 The objectives of the 4 th Handout are to know about: PHCM 331 – Organic and Medicinal/Pharmaceutical Chemistry I Handout # 4 Winter 2015 / 2016 Some Oxidation reactions; Syn Hydroxylation & Oxidative cleavage of alkenes. Cyclization Reactions; Carbene Addition, Epoxide Formation,. Ring opening reactions, Hydrogenation, Halogenation, and Hydrohalogenation Stereospecific Reactions; Dihydroxylation (cis) & (trans), and Halogenation (trans) Scientific terminologies; hydroxylation, Cleavage, Carbene, and Epoxides. Reactions of Acetylide Anion; method to increase carbon chain length of alkynes. Mechanism of NBS Allylic Substitution Reactions and some examples Diels Alder Reaction

2. 2 1.6.7 NBS allylic substitution Selective Radical Bromination-Allylic Substitution The position next to the double bond is called allylic. e.g. Resonance Picture p-Orbital Picture Allylic free radicals are stabilized by resonance.

3. 3 Allylic > 3  > 2  > 1  > CH 3 Stability of Intermediates 33 However, excess bromine leads to competing addition reaction.

4. 4 Competing side reaction can be prevented by using N-Bromosuccenamide (NBS) is used to produce Br atoms in very small concentration. N-Bromosuccinimide (NBS) e.g. However i.e. two intermediates exist. WHY? Homework !

5. General Examples: Indicate the structure of the products that would be produced from the following reactions.

6. 1.6.8Some Oxidation Reactions (Addition of Oxygen) 1.6.8.1 Syn Hydroxylation of Alkenes (Addition of 2 Hydroxyl Groups) Why Syn? Mechanism: e.g. cis-1,2-Dihydroxycyclopentane 6 Or OsO4

7. 1.6.8.2 Oxidative Cleavage of Alkenes (Ozonolysis) Double bond,  and  bonds, are cleaved and replaced by oxygen. This method is used for making aldehydes &/or ketones i.e. i.e. 7

8. 1.6.9Cyclization Reactions 1.6.9.1 Carbene Addition A carbene is an unusual carbon-containing species. It has a carbon with a lone pair of electrons i.e. two electrons- short than ordinary carbon atom. As a result, carbene has an empty p orbital. This empty orbital makes the carbene highly reactive. The simplest carbene, methylene (:CH 2 ) is generated by heating “diazomethane”. The reaction proceeds as follows: As expected, carbenes are strong electrophiles 8

9. Hence, carbenes react strongly with alkenes even without the formation of intermediates. It proceeds via a free radical mechanism. 1.6.9.2 Epoxide Formation (Using Peracids) / No Water 9

10. 1.6.10Ring Opening Reactions (diatomic molecules) 1.6.10.1Hydrogenation 1.6.10.2Halogenation 1.6.10.3 Hydrohalogenation 10

11. 1.6.11Stereospecific Reactions (cis/trans) Reactions that lead to a specific arrangement of atoms in the products. 1.6.11.1 Dihydroxylation (KMnO 4 ) cis-1,2-Dihydroxycyclopentane 1.6.11.2 Dihydroxylation permethanoic (performic acid) in Water 1.6.11.3 Halogenation 11

12. 1.6.12Reactions of Acetylide Anions A method to increase the chain length of an alkyne. How to make acetylide ion (anion) ? It is similar to Na + HO  H  1 / 2 H 2 + NaOH Acetylene reacts with Na as follows: + Na 12

13. The acetylide reacts readily with alkyl halides e.g. methyl chloride. Problem:Starting from Propyne make 2-Butyne Step 1: Step 2: 13 p.s. The base NH 2 Na is usually used instead of Na

14. 14 1.6.13 Diels Alder Reaction When energy is supplied to a mixture of a1,3-diene and simple alkene (a dienophile), a ring-forming reaction takes place to produce a cyclohexene. The mechanism begins with the arrow formation as shown below. It points out which bonds are broken and shows where the new bonds are made in the forward reaction. As shown in the following orbital diagram the Diels-Alder reaction begins with the overlap of the pi systems of the alkene and the diene.

15. 15 That is to say, the two reaction partners approach in parallel planes and as the bonds form, the end carbons of both the diene and alkene rehybridize from sp 2 to sp 3. It is possible to estimate the thermo chemistry in the Diels-Alder reaction by comparing the bonds made and broken in the reaction. Three pi bonds in the starting material are converted into one pi bond and the two sigma bonds in the product. 3 pi bonds x 66 =198 kcal/mol  1 pi bond x 66 + 2 sigma bonds x170=236 kcal/mol

16. 16 As shown in the previous figures, the Diels-Alder reaction requires the s-cis form of the diene component. However, it is the s-trans arrangement that is the more stable one, by approximately 3 kcal/mol. The question that may arise, as equilibrium favours the s-trans form strongly, why is the Diels-Alder reaction observed at all? Even though there is little s-cis form at equilibrium, reaction with the dienophile disturbs the equilibrium between the s-trans and the s-cis form by depleting the s-cis partner. Reestablishment of equilibrium generates more s-cis molecules, which can react in turn. Eventually, all the diene can be converted into the Diels-Alder product, even though at any moment there is very little of the active s-cis form present. When there is no possibility of any s-cis form there can be no Diels-Alder reaction.

17. 17 For example, although 1,2-dimethylenecyclohexane reacts normally with the dienophiles, 3-methylenecyclohexene does not. The product of this reaction would contain a double bond far too strained to be formed. It should be noted that, according to experimental results, Diels-Alder reaction proceeds in one-step (concerted) reaction. As is so often the case, the mechanistic question of the timing of new bond formation could be answered with a stereochemical experiment.

18. 18 A 1-step reaction must preserve stereochemical relationships present in the original alkene. For example, in a concerted reaction, a cis alkene must give a cis disubstituted cyclohexene. If the reaction is concerted, with the two new sigma bonds formed simultaneously, there can be no change in the stereochemical relationship of groups on the alkene as shown below.