Massachusetts Institute of Technology Organic Chemistry 5.

12
May 2, 2008 Prof. Timothy F. Jamison

Exam 4 Study Guide

Exam 4 will emphasize Unit 4 (Chapters 15 and 16) and part of Unit 5 (Chapter 17) and the corresponding material covered in the lectures. Nevertheless, since organic chemistry is a cumulative subject, success on Exam 4 also will necessarily require mastery of the material in Units 1, 2, and 3.

The following tables will be provided as an "appendix" for you to refer to during the exam: Destabilizing Interactions in Acyclic Molecules (McMurry Table 3.5) Cyclohexane 1,3-Diaxial Interactions (McMurry Table 4.1) Table of Free Energies and Equilibrium Constants (Lecture 7) Electronegativities (McMurry Figure 2.2) Useful Bond Dissociation Energies (expanded version from Lecture 16)

Some Other Important Things You Need to Know (In addition to the topics listed in the Study Guides for Exams 1, 2, and 3)
I. General Themes Reaction knowledge base reagents, solvents, other reaction conditions for a transformation. Predict the product reactivity, stereochemical course; apply basic principles to new situations Predict the major product/faster reaction selectivity (relative reaction rates) Propose a synthesis use knowledge base of reactions, as well as your understanding of reactivity, selectivity, stereochemical course, and other requirements to design and evaluate synthesis of a target molecule. Aromaticity Is a species aromatic, antiaromatic, neither? How does aromaticity affect reactivity?

II. Summary of Individual Topics Covered Between Exams 3 and 4 A. Benzene and Aromatic Compounds B. Electrophilic Aromatic Substitution 1. CX bond formation (X = Cl, Br, I) 2. CC bond formation (Friedel-Crafts Acylation and Alkylation) C. Nucleophilic Aromatic Substitution D. Benzyne E. Oxidation and Reduction Reactions of Aromatic Compounds F. Strategies for Synthesizing Aromatic Compounds G. Synthesis and Reactions of Alcohols

III. Detailed Outline of Topics Covered in Unit III A. Benzene and Aromatic Compounds Benzene is not 1,3,5-cyclohexatriene - Approx. 36 kcal/mol more stable than predicted (resonance energy) - Planar - Non-alternating bond lengths (all 1.39 ) - Reactivity patterns different from those of alkenes Hckel 4n+2 rule - Aromatic compounds: 1. Are cyclic 2. Are planar 3. Have one p orbital at every atom in the ring (e.g., C, N, O) 4. Have 4n+2 electrons (n = 0, 1, 2, ) - Anti-Aromatic Compouds: 1. Are cyclic 2. Are not necessarily planar (e.g., cyclobutadiene: yes; cyclooctatetraene: no) 3. Have one p orbital at every atom in the ring (e.g., C, N, O) 4. Have 4n electrons (n = 1, 2, 3, ) - Otherwise a compound is neither aromatic nor anti-aromatic - Charged species and resonance forms can be aromatic or anti-aromatic - Heteroaromatic and Polycyclic Aromatic Compounds carefully count the electrons! B. Electrophilic Aromatic Substitution (EAS) Recurring mechanistic theme: Rearomatization Know Mechanism of EAS and Reaction Conditions (e.g., Br2, FeBr3 or HNO3/H2SO4) Synthesis of Aryl Halides, Nitro Arenes Friedel-Crafts Acylation Friedel-Crafts Alkylation Ortho, Meta, Para terminology Substituent Effects Know the trends and the mechanistic explanation for them - Activators direct o/p (e.g., OR, NEt2, CH3, et al.) - Halogens deactivate (inductively electron-withdrawing), but direct o/p - Meta-directors are deactivating, and include NO2, CN, CO2R, et al. If more than 1 substituent, strongest _activator_ determines major product, but mixtures possible. C. Nucleophilic Aromatic Substitution NO2 group and leaving group (usually halide) must be ortho or para to one another Nucleophile is usually HO, RO Addition-elimination mechanism (NOT SN2) D. Benzyne Under forcing conditions H2N or RO can deprotonate ortho to halogen Halide (X) leaves Resonance form is benzyne Very electrophilic, reacts with another H2N or RO, deprotonates H3N or ROH Overall substitution, but not regiospecific nucleophile may or may not end up where X was!

E. Oxidation and Reduction Reactions of Aromatic Compounds Benzylic positions (e.g, PhCH3) are activated (weak CH and CX) bonds Aromatic ring can stabilize charge or unpaired electron at benzylic C (delocalization) Reactions: 1. Free-Radical Bromination (seen previously) 2. Oxidation of Benzylic CH to Benzoic acid (need at least one benzylic CH) 3. Reduction of Benzylic Positions to Methylene (CH2) Oxidation State with H2, Pd/C: a. Halides b. Alcohols, Ethers 4. Reduction of Aromatic Ring H2, Pt or Rh/C catalyst (Pd/C not effective catalyst) F. Strategies for Synthesis of Substituted Aromatic Rings Interconversion of Functional Groups Can Change Directing Effect! 1. Reduction of NO2 (meta) to NH2 (o/p) using H2, Pd/C 2. Oxidation of NH2 (o/p) to NO2 (meta) using RCO3H 3. Reduction of C(O)R (ketone) (meta) to CH2R (o/p) using H2, Pd/C 4. Oxidation of CH2R (o/p) to CO2H meta using KMnO4 or CrO3 Temporary Blocking Group 1. Criteria a. Conditions for installation and removal must be compatible with other groups. b. Blocking Group must not exert undesired directing effect. 2. Example: SO3H Installation: SO3/H2SO4; Removal: H2SO4/H2O Use Steric Hindrance to Your Advantage Ortho substitution disfavored: 1. Between two groups 2. Next to a large group (e.g., t-Bu)

G. Synthesis and Reactions of Alcohols Alcohols are Polar Protic Solvents pKa of R-OH: alkyl: 15-18; aryl (phenol): 10; sensitive to electronic nature of fxl groups (e.g., F) Previously Covered (review, incl. scope, regioselectivity, stereochemical course, etc.): 1. Synthesis of Alcohols a. Hydroboration of alkenes b. Dihydroxylation of alkenes 2. Reactions of Alcohols a. Conversion to Alkyl Halides (ROH to RX, X = Cl, Br, I) b. Conversion to Alkyl Tosylates (ROH to ROSO2R, R = CH3, p-tol, CF3) c. SN1 and E1 reactions review trends, Zaitsevs Rule Interconversion of Alcohols and Carbonyl Groups A. Reduction of Carbonyl Groups to Alcohols 1. LiAlH4/THF RCHO, RCO2R, and RCO2H to RCH2OH; ketone to 2 alcohol 2. NaBH4/EtOH RCHO to RCH2OH; ketone to 2 alcohol; RCO2R NR 3. i-Bu2AlH/toluene RCHO to RCH2OH; ketone to 2 alcohol; RCO2R to RCHO B. Carbonyl Addition 4. RMgX (Grignard Reagents)/THF or ether a. RCHO to RCH(OH)R b. RC(O)R (ketone) to R(R)(R)COH (3 alcohol) c. RCO2R to R2(R)COH (3 alcohol) C. Oxidation of Alcohols to Carbonyl Groups

5. CrO3/H2SO4/acetone Jones Oxidation a. RCH2OH, RCHO to RCO2H b. RCH(OH)R (2 alcohol) to RC(O)R (ketone) c. R3COH (3 alcohol) NR 6. Pyridinium Chlorochromate (PCC) Oxidation a. RCH2OH to RCHO b. RCH(OH)R (2 alcohol) to R(CO)R (ketone) c. RCHO and R3COH (3 alcohol) NR Protecting Groups 1. Enable Reactions in Presence of Incompatible Functional Groups 2. Criteria a. Conditions for installation and removal must be compatible with other groups. b. Must be stable to all reactions in synthetic sequence prior to removal 3. Example: R3Si (trialkylsilyl) ethers for protection of hydroxyl groups (alcohols) a. Install with R3SiCl, Et3N, CH2Cl2 b. Conduct reaction of other group (e.g., RMgX + ketone) c. Remove R3Si with Bu4N+ F (TBAF), THF (Si-F bond stronger than Si-O) Note: The tables and charts on EAS on the back pages of the handouts of Lectures 26 and 27 (same on both handouts) will not be provided for you on the exam. In the material on the Lecture 26 and 27 handouts, you will need to know: Definitions of ortho, meta, para Which functional groups are deactivating, which are activating, and why. Which are o/p-directors, which are m-directors, and why. In the material on the Lecture 26 and 27 handouts, you do not need to know: Quantitative values for net dipole moments (but knowing the trends may help) Rates of nitration (table at the bottom of the page)