Organic Chemistry I: Reactions and Overview Cheat Sheet, Cheat Sheet of Organic Chemistry

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Organic Chemistry I: Reactions and Overview Andrew Rosen Editor: Raghav Malik January 13, 2013 Contents I Library of Synthetic Reactions 3 II Organic Trends and Essentials 4 1 The Basics: Bonding and Molecular Structure 4 1.1 Resonance Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2 Families of Carbon Compounds 4 2.1 Strength of London Dispersion Forces (Polarizability) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2 Degree of Unsaturation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3 An Introduction to Organic Reactions and Their Mechanisms 4 3.1 Comparing Acid Strengths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4 Nomenclature and Conformations of Alkanes and Cycloalkanes 5 4.1 Ring Flipping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5 Stereochemistry 5 5.1 Naming Enantiomers via the -R and -S System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.2 Stereochemistry Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6 Ionic Reactions - Overview 6 6.1 General Nucleophilic Substitution Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6.2 Carbocation Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6.3 Factors Aecting the Rates of SN1 and SN2 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6.4 Elimination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 6.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 7 Alkenes and Alkynes I - Overview 8 7.1 The E-Z System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 7.2 Relative Stabilities of Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 7.3 Factors Aecting Elimination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 7.4 Acid-Catalyzed Dehydration of Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1 III Reaction Mechanisms 9 8 Ionic Reactions - Mechanisms 9 8.1 The SN2 Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 8.2 The SN1 Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 8.3 The E2 Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 8.4 The E1 Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 9 Alkenes and Alkynes I - Mechanisms 11 9.1 Acid-Catalyzed Dehydration of Secondary or Tertiary Alcohols: An E1 Reaction . . . . . . . . . . . . . . . . 11 9.2 Acid-Catalyzed Dehydration of Primary Alcohols: An E2 Reaction . . . . . . . . . . . . . . . . . . . . . . . . 12 9.3 Synthesis of Alkynes from Vic-Dihalides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 9.4 Substitution of the Acetylenic Hydrogen Atom of a Terminal Alkyne . . . . . . . . . . . . . . . . . . . . . . . 12 9.5 Deprotonation Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 9.6 Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 10 Alkenes and Alkynes II - Mechanisms 13 10.1 Addition of H−X to an Alkene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 10.2 Acid-Catalyzed Hydration of an Alkene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 10.3 Mercuration-Demercuration and Hydroboration-Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 10.4 Summary of H−X and H−OH Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 10.5 Electrophilic Addition of Bromine and Chlorine to Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 10.6 Halohydrin Formation from an Alkene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 10.7 Oxidative Cleavage of Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 10.8 OsO4 Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 10.9 Summary for Dihalide, Dihydroxy, and Carbene Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 10.10 Electrophilic Addition of Bromine and Chlorine to Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 10.11 Addition of Hydrogen Halides to Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 10.12 Oxidative Cleavage of Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 11 Alcohols and Ethers - Mechanisms 16 11.1 Alcohols with H−X . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 11.2 Alcohols with PBr3 or SOCl2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 11.3 Leaving Group Derivatives of Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 11.4 Converting OH to LG Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 11.5 Synthesis of Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 11.6 Protecting Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 11.7 Ether Reactions Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 11.8 Epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 11.9 Epoxide Reaction Summary with Example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 12 Alcohols from Carbonyl Compounds - Mechanisms 19 12.1 Alcohols by Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 12.2 Oxidation of Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 12.3 Alcohols from Grignard Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 13 Radical Reactions - Mechanisms 20 13.1 Bromination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 13.2 Chlorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 2 ARIO Explained: • Atom: Look at what atom the charge is on for the conjugate base.  For atoms in the same row, we consider electronegativity. The further to the right on the periodic table an atom is, the more electronegative it is. If a conjugate base's negative charge is on a more electronegative atom, it is more stable, and thus the parent acid is stronger.  For atoms in the same column, we consider an atom's ability to stabilize a charge. The further down on the periodic table an atom is, the better it is at stabilizing a charge. If a conjugate base's negative charge is more stabilized on an atom further down a group, it is a more stable molecule, and thus the parent acid is stronger. • Resonance Stabilization: Look at resonance structures. The more distributed the charge of the conjugate base is, the stronger the parent acid is. • Inductive Eect: Look for inductive eect. If there are many electronegative atoms near the conjugate base's negative charge, electron density is pulled toward these atoms. This creates more stable anions and thus more acidic parent molecules. However, if there are many alkyl groups, this is a process called hyperconjugation, and the parent acid is actually less stable. • Orbital: Look at the orbital where the negative charge for the conjugate base is. More s character of a bond with hydrogen makes it more acidic. 4 Nomenclature and Conformations of Alkanes and Cycloalkanes 4.1 Ring Flipping • The axial groups become equatorial and vice versa  When doing a ring ip, whether a group is up or down does not change • Chair Conformation 1: Chair Conformation 2 (after ring ip): • When performing a chair ip, each atom is rotated one spot in the clockwise direction • A molecule is more stable when steric hindrance is minimized and bulky substituents are equatorial as opposed to axial 5 Stereochemistry 5.1 Naming Enantiomers via the -R and -S System 1. Each of the four groups attached to the chirality center is assigned a priority of 1, 2, 3, or 4. Priority is assigned on the basis of the atomic number of the atom that is directly attached to the chirality center. The group with the highest atomic number gets the highest priority and vice versa. 2. When a priority cannot be assigned on the basis of atomic number of the atoms, then the next set of atoms in the unassigned groups is examined. This process is continued until a decision can be made at the rst point of dierence. 5 (a) Step 1: Step 2: 3. If the 4th atom is a dashed wedge (downward): Analyze if the numbers (1→ 2→ 3→ 4) go clockwise or counterclock- wise. Clockwise indicates that the molecule is R, while counterclockwise indicates the molecule is S. 4. If the 4th atom is a solid wedge (upward): Analyze this intermediate molecule to see if the numbers go clockwise or counterclockwise. Clockwise indicates that the original molecule is S, while counterclockwise indicates the molecule is R. 5.2 Stereochemistry Examples 6 Ionic Reactions - Overview 6.1 General Nucleophilic Substitution Reactions • A deprotonation step is required to complete the reaction when the nucelophile was a neutral atom that bore a proton Example showing deprotonation4: 6.2 Carbocation Stability • Order of Carbocation Stability: 3◦ > 2◦ > 1◦ > Methyl 6.3 Factors Aecting the Rates of SN1 and SN2 Reactions • Simple alkyl halides show the following trend for order of reactivity in SN2 reactions:  Methyl > primary > secondary (tertiary-unreactive) 4Deprotonation is normally seen as H3O + in water, but when there is a dierent solvent in excess it will be dierent 6 • The rates of SN2 reactions (not SN1) depend on both the concentration and identity of the attacking nucleophile • In a selection of nucleophiles in which the nucleophilic atom is the same, nucleophilicities parallel basicities:  RO− > HO−  RCO−2 > ROH > H2O • Nucleophiles parallel basicity when comparing atoms in the same period • Nucleophiles do not parallel basicity and, instead, parallel size when comparing atoms of the same group • The best leaving groups are weak bases after they depart • Polar aprotic solvents favor SN2 and polar protic solvents favor SN1  Most of the solvents with abbreviated names are polar aprotic 6.4 Elimination Reactions • Higher temperatures increase the rates of elimination reactions • A product with a more substituted double bond is more stable and thus more favorable • If tert-butoxide is used, sterics must be considered to nd out which hydrogen it takes through the E2 reaction 6.5 Summary • Note: It is debatable, but secondary molecules can have SN1 or E1 in polar protic solvents 7 8.2 The SN1 Reaction • An SN1 reaction will cause racemization if enantiomers are possible products 8.3 The E2 Reaction • There must be an anti-coplanar nature 10 8.4 The E1 Reaction • E1 reactions almost always accompany SN1 reactions to some extent 9 Alkenes and Alkynes I - Mechanisms 9.1 Acid-Catalyzed Dehydration of Secondary or Tertiary Alcohols: An E1 Reaction 11 9.2 Acid-Catalyzed Dehydration of Primary Alcohols: An E2 Reaction 9.3 Synthesis of Alkynes from Vic-Dihalides • Alkynes can be synthesized from alkanes via compounds called vicinal dihalides, which are compounds bearing the halogens on adjacent carbons  It requires the use of NH−2 , which can frequently be found as NaNH2 with NH4Cl 9.4 Substitution of the Acetylenic Hydrogen Atom of a Terminal Alkyne • A primary halide and a strong base must be used 9.5 Deprotonation Reagents There are two good reactant choices: 1. NaNH2 and liquid NH3 2. LDA 12 10.6 Halohydrin Formation from an Alkene • A halohydrin is produced when the halogenation of an alkene is carried out in an aqueous solution as opposed to a non-nucleophilic solvent • If the alkene is unsymmetrical, there is anti-Markovnikov addition 10.7 Oxidative Cleavage of Alkenes • O3 or KMnO4 can perform oxidative cleavage of alkenes with syn additions (useful for adding multiple hydroxyl groups) • Hot, basic KMnO4 cleaves the double bond of an alkene. Disubstituted alkene carbons are oxidatively cleaved to ketones, monosubstituted alkene carbons are cleaved to carboxylic acids, and unsubstituted alkene carbons are oxidized to carbon dioxide. • Using ozone - ozonolysis - is the best method to cleave alkenes and can open up cycloalkenes, as in the following example. The reagents are O3,CH2Cl2 and then Me2S 10.8 OsO4 Reaction • For details of this reaction, see the table below • It is important to keep the backbone the same to ensure proper stereochemistry. An example is shown below: 15 10.9 Summary for Dihalide, Dihydroxy, and Carbene Additions 10.10 Electrophilic Addition of Bromine and Chlorine to Alkynes • Alkynes show the same kind of halo-addition as alkenes (anti-addition) • Addition may occur once or twice depending upon the molar equivalents of the halogen reagent 10.11 Addition of Hydrogen Halides to Alkynes • Alkynes react with one molar equivalent of HX to form haloalkenes and with two molar equivalents to form geminal dihalides via Markovnikov's Rule • Anti-Markovnikov addition occurs when peroxides are present 10.12 Oxidative Cleavage of Alkynes • Oxidative cleavage of alkynes with ozone will yield two carboxylic acids 11 Alcohols and Ethers - Mechanisms 11.1 Alcohols with H−X • Racemic mixtures are produced if enantiomers are possible • Rearrangements are present • Methanol and 1◦ alcohols go through an SN2 mechanism. 2◦ and 3◦ alcohols go through an SN1 mechanism 16 11.2 Alcohols with PBr3 or SOCl2 • Converts a 1◦ or 2◦ alcohol to a leaving group without rearrangements • Inversion of conguration occurs since the reaction is SN2 11.3 Leaving Group Derivatives of Alcohols • Using either pyridine or DMAP, sulfonate esters can be prepared from combining an alcohol with a chlorinated sulfonate derivative • There is retention of conguration with this reaction 11.4 Converting OH to LG Summary 11.5 Synthesis of Ethers • Alcohols can dehydrate to form alkenes, as mentioned in Section 7. Also, 1◦ alcohols can dehydrate to form ethers by the following mechanism: • Acid-catalyzed dehydration is not useful for preparing unsymmetrical ethers from dierent 1◦ alcohols because the reaction leads to a mixture of products (ROR, ROR′, and R′OR′) • Alkoxymercuration-demercuration is a method for synthesizing ethers directly from alkenes, like in the example below, and parallels oxymercuration-demercuration 17