Use the lecture and precept coverage as a guide, unless otherwise instructed. The following reading list is just designed to alert you to the sections of the text which overlap with lecture topics. The coverage can be quite different in depth and detail. When in doubt, send me an email. MFS

Miscellaneous [molecular association, acidity/basicity]

Chapter 12: All. Allenes (12.1-12.3) not covered in lecture, but read it)

Chapter 13: but not 13.11b and 13.12 (read it anyway)

Chapter 14: 14.3-14-12 There is a lot of detail in this chapter, and the level of coverage in lecture will be less. Use your judgement.

3/1/99

Chapter 16. All. We will touch on all of these topics in lecture, although the depth on each topic will vary and may not be reflected in the coverage in the book.

Chapter 17. The chemistry of alcohols has been discussed and used in various contexts already. You should read 17.1-17.11, 17.14 and verify that it is familiar or at least reasonable based on what we already know. I hope to spend some time in lecture on the sulfur analog, Sec 17.12-17.13, but this chapter of the book will pass by quickly.

Chapter 18. This chapter is based on a fundamental reaction of ketones and aldehydes, the aldol reaction. It comes in numerous variations, and the various sections of the chapter are examples of the variations. We will emphasize the basic mechanism and will not talk about every different variation. Nevertheless, reading about them will solidify your understanding of the mechanism. Basic mechanism: 18.1-18.3. We will not be emphasizing 18.6c, 18.6d, 18.7, synthesis. Look carefully at p. 942 and be sure you understand each reaction.

Chapter 19. This is another important chapter with quite a bit of new material and lots of relevance to biological processes. Our lectures will touch on all the concepts here, although some details or examples will not be discussed.

Chapter 20.Again, there are a couple of new general reactions here and many examples. Everything in the chapter should make sense to you after you have mastered the concepts, and I suggest reading everything. We will not be covering 20.14, 20.13 20.15.

Chapter 21: 21.1, 21.2, 21.3, 21.4 (old stuff), 21.5 (old stuff), 21.6, 21.7, 21.8

Chapter 22: not covered

Chapter 23: most not covered. Read Sec 23.5a, 23.5b, 23.5c

Chapter 24: 24.1, 24.2a,24.2b,24.3,24.5

Chapter 25: We have already talked about epoxides: review 25.1. Extension to 4-membered rings is obvious and will not appear in lecture: 25.2. We already covered 25.3, 25.4; 25.4 are simple extensions; note syntheses in 25.5g,h; 25.6d, 25.8b, 25.8c. We will later talk about penicillin (25.9).

Chapter 26 All (we will go deeper than the book, with other handouts)

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Brush up on reversible additions to C=O: 1,2/,4-add, addition-elimin (acylation) p 763-769; 774-787, 808-810; Aldol type reaction p 900-906; add of cyanide p 773; Michael rxn p 918-921; RCO2H: acidity, p 958-962; esters, 963-972; amides, 973-976; acyl derivatives: p 1003-1004; esters, p1022-1024; amides: 1028-1030; ester enolates: 1036-1042. Spectroscopy: UV (conjugation detector), IR (-OH, C=O, NH stretch), NMR generally (coupling of adjacent C-H = 7 Hz; pattern of coupling; approx chem shift effects of -OH, -NH-, -C=O groups on adjacent H). Aldehyde CH chem shift.

Condensation polymers: nylon (demonstration), polyesters. Mech of formation. Fatty acid structure and props, triglycerides, phospholipids p 992-993 [handout]. Amines and related: p 1080-1093, 1096, 1099[handout: "amino acids, peptides, proteins"]. amine bonding and structure, inverting pyramidal, basicity related to hybridization, delocalization (again), basicity/acidity of imidazole; aromatic diazonium salts as equivalent of phenyl cation, diazo cpn synthesis; diazomethane, bonding and rxns with acids to make esters, nitrenes--rearrangements [Hoffmann, Curtius] of carboxylic acids to one carbon-shorter amines + CO2. Text: p 1220-1225. Wolff rearrangement of diazoketones (from acid chloride and diazomethane) via a carbene. Amino acids: text: 1346-1369, 1372-1380. Structure of a-aminoacids; stereogenic center, varying side chains, think about each of the 20 essential AAs and imagine the molecular association, acid/base chemistry, and nucleophile reactivity of the side chains. Have a sense of relative acidity and basicity. Zwitterion and essential acid/base features of the amino acids themselves (before amide bond formation). Isoelectric point; electrophoresis--what does it do? how does it work? Ninhydrin visualization--chemical mechanism. Chemical synthesis of AAs: Racemic: Cyanide addition, hydrolysis. Mechanism? Phthalimide as nucelophile in SN2; hydrazine removal--mechanisms. Asymmetric synthesis--produce one enantiomer selectively. Resolve by making salt wiht asymmetric amine, crystallize to separate, neutralize to recover aminoacid. Enzyme induces reaction with one enantiomer selectively--enzymatic resolution. Make chiral precursor: Protecting group idea. BOC and CBZ for amino [how put on and take off?] Ester (various) for carboxy group [how put on and take off?]. Two ideas for chiral precursor. Both depend on making ester enolate. Add a nitrogen electrophile in one case and carbon electrophile (the R group) in the second case. The enolate has two sides or faces; asymmetry favors reaction from one side. Remove the chiral directing group. Biosynthesis of AA: Key idea is 1,3-shift of H in an imine intermediate formed from an a-ketoester. Pyridoxamine as the key cofactor. Acid and base on the enzyme to make things happen. Deprotonation activated by adding electrons to the pyridine ring of the cofactor; re-protonation at a different site, from one "side", by re-forming the pyridinium ion. [This would be a reasonable exam question, had we not already talked about it--given the pieces, the products, and some hints, work out a mechanism]. Enzyme inhibitor: mechanism of enzyme inhibition by gabaculine; closely related to AA biosynthesis. Why does it inactivate the enzyme? What is the mechanism of formation of the final product? Methods of breaking down proteins: nucleophilic aromatic substitution [Sec 14.13 for general discussion], Sangers reagent. React [mechanism?] with terminal NH2 group to give non-basic amino group; completely hydrolyze polypeptide, isolate special AA with the dinitrophenyl group (yellow), and assign as the N-terminus of the protein. Note: Nucleolphilic side chains will also be converted to dinitrophenyl derivatives. Edman degradation [mechanism?] can systematically cleave off the amino terminal AA and convert it to a special heterocycle which can be analyzed. Stepwise sequencing of the polypeptide chain. Synthesis of polypeptides: BOC protection of the free amino group. Couple amino group on one AA with carboxy group on the other AA using DCC [mechanism?]. BUT; for convenience, do it all using solid phase synthesis techniques; easily remove byproducts and reagents by simple filtration. Formation of cross-linked polystyrene, addition of ClCH2- group, attach of the first AA via carboxylate SN2 on the benzylic chloride group. De-protect amino group, and add third amino acid [free carboxy and protected amino/, add DCC--tripeptide attached to polystrene. Cleave the ester bond to the polystyrene and release the tripeptide. 3D structure of proteins: Primary structure--amino acid sequence and disulfide bonds (cross linking of the chain). Secondary structure: (1) a-helix, with backbone amide N-H associating with backbone carbonyl O to give a helix. Side chains pointing out perpendicular (approx) to the axis of the helix, not involved in the formation of the helix. (2) b-sheet : side-by-side association between backbone amide N-H associating with backbone carbonyl O on adjacent chain. fairly planar ribbon with some "pleating" or folding. Side chains not involved in the association responsible for the sheet; pointed up and down perpendicular to the plane of the sheet. (3) random coil. Less regular, but specific, structure for the polypeptide. Tertiary structure: specific side chain interactions influencing conformation (folding) of the chain: ionic interactions, hydrophobic, H-bonding. Quarternary structure: Association of two or more independent protein chains. Mechanism of action of trypsin/chymotripsin. [Handout: Trypsin] Selectivity in binding to substrate protein different for the two enzymes. Mechanism of catalysis: role of serine to make acyl-enzyme intermediate; histidine, aspartate side chains in cascade proton transfer to activate. Further activation of water to cleave intermediate ester. Dissociation of products. Carbohydrates [handout: carbohydrates ] to be continued.

Thiols, sulfides, and disulfides [p 856-858, 1364-1366]. RS- as nucleophile; oxidation to RSSR; reduction back to RSH. Role of disulfide in protein primary structure.

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Review Sheet for the Final Exam [Not including the material on the review sheet for the 3rd exam]

Review molecular association: van der Waals, dipole/dipole, H-binding, charge attraction. Use to rationalize bp and solubility. self-association compared to solvent/solute interactions. Summary: Like dissolves Like. For solute with weak interactions and solvent with weak interactions (non-polar), entropy drives the tendency to dissolve. For polar solutes and solvents, the new solvent/solute interactions compensate for lost interactions and the solute dissolves. Acidity/basicity: rationalize with inductive, resonance, hybridization, steric(?), bond dissociation. Amines, amide anions, ammonium ions. Focus on the effect of structure or solvent, etc., on the high energy partner in the equilibrium (first approximation). Aniline, pyridine, etc. Delocalization: the allyl system (later for ketone enolate, amide resonance, etc--very general). Conjugation and polyenes: constructing MOs, narrowing of gap as add more p orbitals to polyene system, UV spectra in general. Useful for pi-pi* and n-pi* absorption which usually means at least two double bonds in conjugation. For a conjugated ketone, the n-pi* is of lower E (longer wavelength) compared to pi-pi*--why? Natural coloring agents--carotene, retinal, vision. Biosynthesis of isoprenes. Simple cases. Sesquiterpenes, terpenes, initiate cation formation by ionization of allylic phosphate or protonation of a double bond. Cyclize by addition to alkene unit to make 5 or 6-membered ring, generate new cation. Me shifts, alkyl shifts, H shifts from carbon adjacent to cation. Only the simplest cases. Aromaticity and benzene. nemonic for generating MOs for regular cyclic conjugated polyenes. Why cyclopentadienyl anion very stabilized compared to cyclopentadienyl cation? Other variations: review 3,4,5,6,7, and 8 membered rings. When stabilized and when not? Strain of planar ring in some cases. NMR chemical shifts for benzene and other "aromatics". Upfield shift of "inside" hydrogens. Heteroaromatics. The benzyl system, analogous to allyl. Resonance structures for benzyl anion (and cation, and radical). Electrophilic aromatic substitution: addition of electrophiles to benzene to give cyclohexadienyl cation, then loss of H+. Substituent effects on rate and position of substitution: strongly activating and o,p-directing; weak activating and o,p-directing; weak deactivating and o,p directing; strong deactivating and m directing, text table 14.1. Electrophiles: halogen, nitrosonium, sulfonium, Friedel-Crafts alkylation and acylation (AlCl3 catalyst). Carbonyl compounds: bonding and structure of ketones and aldehydes. Substituent effects on stability of C=O pi bond. Polar resonance structure. IR C=O stretch rationalized by resonance and inductive effects. NMR chemical shifts: aldehyde C-H far downfield; C-H adjacent to C=O in ketone somewhat downfield. 1,2-addition to C=O. Weak nucleophiles add reversibly; Keq depends on stability of C=O. Can be favorable (unstable C=O as in simple aldehydes and those with destabilizing substituents) or very unfavorable (normal for simple ketone, aromatic aldehydes, etc). Steric hindrance disfavors 1,2-addition. Water is the prototype. Accelerated by acid [protonation of carbonyl oxygen] and base [increase concentration of hydroxide anion]. Product is the hydrate; usually unstable. Especially in acid and base. Alcohols give hemiacetals, and, in acid, the acetal. Hemiacetals are unstable to acid and base; acetals are unstable to acid and stable to base. HCN addition. Intramolecular favored [sugars, later]. Exchange of O in carbonyl group by reversible addition of water. Nitrogen nucleophiles lead to N analogs of C=O, imines. Formed by addition, elimination of water. Imines equilibrate with enamine (like enols); very electron rich alkene.Carbon nucleophiles: simple alkyl-Li and MgBr derivatives. How formed? Very reactive nucleophiles and bases. Add irreversibly 1,2- to carbonyl groups. Alcohol synthesis. LiAlH4 and NaBH4 are prototypes of hydride delivery agents--good nucleophile, not very basic. Oxidation of alcohols to ketones and aldehydes: general mechanism like E2. How set up? CrO3, HOCl, NAD+, Mechanism of NAD oxidation; NADH reductions. Pyridinium ion as electron sink Stereospecific addition of H- to C=O to give stereogenic center as one enantiomer using asymmetry of enzyme. Enolate anions: enol/keto equilibrium, enol usually less stable. Exceptions? Exchange of protons adjacent to C=O via enol or enolate. Aldol reaction, accelerated by acid and base. Initial "aldol" can undergo elimination of -OH to give an "enone", a conjugated ketone, especially in acid. Crossed aldol successful in carefully defined cases. 1,4-Addition: Michael reaction. Weaker nucleophiles give reversible 1,2-addition by kinetic control, but can give a slower process and more stable product by 1,4-addition. Why more stable? Reactive nucleophiles like LiAlH4 and Me-MgBr give 1,2-addition and cannot reverse; tend not to give 1,4-addition.

robinson annulation is a useful combination of Michael reaction and aldol addition/elimination. Cyanide and thiamine anion can initiate special process by initial 1,2-addition, followed by second proton abstraction and second nucleophile addition to another carbonyl. Think hard about thiamine! It illustrates a number of general features. Thiamine and imines employed by Nature in retro-aldol and aldol reactions: transketolase enzyme.
Acyl derivatives. Carboxylic acids: acidity, ester formation by acid catalysis with an alcohol. Formation of acid chlorides with thionyl chloride. Precursor of other acyl derivatives by addition/elimination. Addition/elimination is a VERY important mechanism. Amide formation, ester formation. Anhydrides are also activated acyl derivatives. Stabilized nucleophiles tend to give addition/elimination. Very reactive nucleophiles give 1,2-addition, elimination, and a second 1,2-addition to the intermediate ketone (aldehyde): LiAlH4, R-MgBr., R-Li. Reactions of nitriles in analogy with acyl derivatives. Enolate anions of acyl derivatives such as esters. Claisen condensation (like aldol, with elimination). Product has acidic proton, deprotonates under basic conditions. Polymerization via addition/elimination: polyamides, polyesters, nylon demonstration, Kevlar. Homopolymers, alternating copolymers. Elimination reactions of special mechanisms: Wittig reaction by elimination of P-O. Phosphonium ion-stabilized anion adds to ketone or aldehyde, then elimination from intermediate. Tends to give cis double bond; analyze initial addition to the aldehyde, then syn elimination. Also: syn elimination of H by acetate pyrolysis, amine oxide elimination. Fatty acids. non-polar tail line up to form membranes (phospholipids bilayers); cis double bonds in chain decrease regularity in packing, reduce mp and membrane stability (triglycerides for energy storage).

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H-bonding pattern for DNA code. Structures of the nucleic acids: ribose with N-glycoside to a "base", and a phosphate linking the units into a polymer. Function of mRNA, tRNA: deliver amino acids adjacent to one another for linking by enzyme-catalyzed amide bond formation. Bacterial cell wall synthesis; penicillin mimicking D-ala-D-ala side chain. Amide bond formation to complete crosslinking of cell wall via thioester attachment to the transpeptidase enzyme. Penicillin attaches to same thiol unit, by addition/elimination reaction at the strained, reactive carbonyl in the 4-membered ring. Irreversible, removes enzyme from action. Catalytic antibodies. See problem on Last Problem set (from final exam, the last time I gave 303; same coverage).

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Last Updated January 26, 1999
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