CHM 301 Fall 2018 Lecture 24 1 NOTE: we will not be covering radical chemistry this semester. You will have to wait until February. The material in Chapter 12 will not be covered in lecture nor on the exams. Readings for the final exam: Chapter 9 (all except sec 9.5); Chapter 11: oxidation sections—11.3, 11.4 Chapter 10 includes a section on electrophilic addition to 1,3-dienes (10.3). This will covered in Chem 304 Chapter 11 contains a section (11.2) on reduction of alkenes, which we have discussed incidentally already. Please read it and understand it. Review: Electrophilic addition to alkenes. Three variations on the mechanism: a. Rate-determining addition of H+ to give the more stable, open cation followed by fast addition of a nucleophile. Formation of the more stable cation intermediate determines regioselectivity. b. Rate-determining addition or Br+ (as Br-X where X=Br, OH, etc) to give a bridged bromonium ion, followed by backside (SN2-like) addition of a nucleophile. Addition at the carbon which would give the more stable cation (break weakest bond in the second step). Also for Cl+ c. Concerted one-step addition, with a polar transition state and partial (+) buildup at the site of better cation stabilization. 1. Hydroboration. Both electronic (best cation site for polarized carbon in the TS), and steric effects (R2B unit is large and adds to the less substituted end, independent of electronic effects). Syn addition, both H and B from the same face of the alkene. Process by treatment with aqueous hydrogen peroxide and base, leading to a C-OH group. Formation of alcohol from alkene with regioselectivity opposite to acid-catalyzed hydration of an alkene. 2. Epoxidation. One step concerted syn mechanism with a percarboxylic acid (peracid). Forms two bonds to oxygen. Syn addition. Cis alkene gives cis epoxide. Trans alkene gives trans epoxide. Approach from less hindered face of alkene, when relevant. 3. Ozonolysis. One step concerted addition to give transient adduct which rearranges spontaneously to the ozonide. Processing with Me2S (reduction) leads to two C=O and DMSO. 4. OsO4. One step concerted syn addition to give osmate ester. Processing (no mechanism) gives a cis 1,2-diol. Approach from less hindered face of alkene, when relevant. d. Addition of carbocations to alkenes. Alkene polymerization initiated by acid. Intramolecular addition to form 5- and 6-membered rings. Steroid biosynthesis: “polyolefin cyclization”; hydride and Me shifts to give lanosterol. Squalene biosynthesis. Additional topic: Electrophilic addition to alkynes: reactivity similar to alkenes. Protonation to give the vinyl (linear) cation followed by trapping with the nucleophile. Analogous mechanisms to those for alkenes (not discussed systematically in lecture). Think about it. Text: sec 9.2CHM 301 Fall 2018 Lecture 24 2 Carbon electrophile in additions to alkenes: NATURAL PRODUCTS: Biosynthesis. sec 9.3c,d Steroid biosynthesis: Hypothesis: Poly(1,5-dienes) can fold up and cyclize to give trans-fused cyclohexane derivatives Clue: lanosterol is precursor of cholesterol Clue: squalene epoxide can give lanosterol in one step: HOHHHHcholesterolOHOHHHHtestosteroneOHHOHHHHoestradiolOOHHOHHcortisoneOHOMeHHHMeRMeMeRMeHHHMeEOHMeMesqualenesqualene epoxidesqualeneepoxidaseOMeMeMeHMeMeHHHOHHHOMeMeMeMeMeMesqualene cyclaseHOHcholesterolHHlanosterolCHM 301 Fall 2018 Lecture 24 3 Where does squalene come from? Terpenes and the rule of 5: C5 C5 C5 C5 C5 C5O POOO POOOXHXXHsqualeneXXXHXXC10XC15C20C30C30a terpenea sesquiterpenediterpenetriterpeneCHM 301 Fall 2018 Lecture 24 4 Farnesol and all things C-15: OHXlimonenenerol pyrophosphatecitranellol!OHOcamphor!OHgeraniolOcitralα-pinenecampheneOHteresantalolHOHgrandisolOHHOnepetalactone (catnip)(sex attractant forcotton boll weevil)cedreneHHcadinenelongifoleneOHXXfarnesolα-bisaboleneCHM 301 Fall 2018 Lecture 24 5 Other examples: where are the C-5 (isoprene) units? ________________________________________________________________________________ Oxidation of Alcohols to Carbonyls—a kind of elimination reaction Elimination to form C=O Is this an oxidation? Reduction/oxidation in organic chemistry: a little fuzzy text: sec 11.1 Adding electronegative atoms to carbon in place of H or C is considered an oxidation. How arrange Z group efficiently? CrO3 is one example MeMeHOMeOMeMeMeMeMevitamin E (α-tocopherol)OOHtetrahydrocannabinolHOH?O+ 2 H + 2eHOH?O+ 2 H + 2eHOZE2-likeO+ H + ZZ = good electron acceptorCrOOOCHM 301 Fall 2018 Lecture 24 6 Further variations on the theme: Clorox oxidation How does Nature do this? Alcohol dehydrogenase: HOH+CrOOOHOHCrOOOHOCrOOOHO+CrOOOHH +HOH+CrOOOORHRHprimaryalcoholHOH+CrOOOORRRRsecondary alcoholHOH+HOHClHOClO+H +ClOHClOHalcohol dehydrogenaseOHacetaldehydeCHM 301 Fall 2018 Lecture 24 7 Possible Alternate Oxidation Scheme: Strong electrophile to remove H-. Base to remove H+ Stepwise with, for example, trityl cation Ph3C+. E1-like process, with H- as the leaving group. Even more effective if remove H- and H+ in the same step. ORRHHORRH HHydride abstraction from CProton abstraction from OORRHORRHvia:ORRHX+HOHH+OH+ORRHHORRE:BE-H B-HCHM 301 Fall 2018 Lecture 24 8 Nature's oxidizing agent: NAD Sec 11.4c Bio-oxidation mechanism: consider the pyridinium ion NNMeHOOHO OHNNPOONNOONH2HO OHNONH2RHNONH2RHNONH2HH3COH++Nicotinamide Adenosine Dinucleotide+ AlcoholDehydrogenase (enzyme)OPOOCH3CH2OHnicotineNOOHnicotinic acid (niacin)NADHNRONH2HNRONH2HRHOHNRONH2HHRHO..+ H++++HCHM 301 Fall 2018 Lecture 24 9 OOHO OHNNPOONNOONH2HO OHNOH2NOPOOHMeHOH2N+HOOHO OHNNPOONNOONH2HO OHNOH2NOPOOHMeH2NHHOHEnzyme binds to the cofactor, NAD+, and to the alcohol through molecular association, blocking one face of the pyridinium ring. EtOH binds nearby and is in proximity to have a hydride abstracted by the pyridinium ring, selectively to one face of the ring. The EtOH is held in a way to allow transfer of only one of the two enantiotopic hydrogens. The enzyme can also