Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020) Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020) Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020) Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020) Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020)
Copyright © 2020 by Youcef Abdessalem Hammou All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, without written permission from the author youcefjosefred@hotmail.com giuseppeyoucef15@gmail.com Content I Solvents I Definition I Solvent Classification I Apolar Solvents I 2 Polar Solvents Protic Solvents Aprotic Solvents I II Solubility Reactants 10 II Substrate 10 II 1 Carbocation 11 Definition and Structure 11 Stability 11 II Carbanion 15 Definition and Structure 15 Stability 16 II Free-radical Carbon 18 Definition and Structure 18 Stability 19 II Carbene 20 Definition and Structure 20 Singlet Carbenes 20 Triplet Carbene 21 Stability 22 II Leaving Groups 24 II Nucleofuges 24 II 2 Electrofuges 26 II Nucleophiles 27 II Types of Nucleophiles 27 Neutral Nucleophiles 27 Charged Nucleophiles 27 II II III Nucleophilicity 28 Electrophiles 29 Reaction Mechanisms 30 III Substitution Reactions 30 III 1 Free-radical Substitution Reactions 30 Alkanes Halogenation 30 Allylic and Benzylic Halogenation 38 III Nucleophilic Substitution Reactions 43 Nucleophilic Aliphatic Substitution Reactions 43 Nucleophilic Aromatic Substitution Reactions 63 Nucleophilic Substitution of Carboxylic acids and their Derivatives 71 III Electrophilic Substitution Reactions 78 Electrophilic Aromatic Substitution Reactions SEAr 78 III Elimination Reactions 100 III α Elimination Reactions 100 Formation of Carbenes 100 III 2 β Elimination Reactions 101 Regiochemistry and Stereochemistry 105 Regiochemistry and Stereochemistry 112 III γ Elimination Reactions 116 Freund Reaction 116 III Competition between SN1, SN2, E1, and E2 117 III Addition Reactions 121 III Nucleophilic Addition Reactions 121 Nucleophilic Addition Reactions to Aldehydes and Ketones 121 III Electrophilic Addition Reactions 129 General mechanisms 129 Regeochemistry and Stereochemistry 129 Dihalogenation Reaction 129 Halogenation Reaction 135 Hypohalogenation Reaction 139 Hydrohalogenation Reaction 143 Acid Catalyzed Hydration 156 Oxymercuration-Demercuration Hydration 165 Hydroboration Oxidation 169 III Concerted Addition Reactions 174 Addition of Carbenes 174 Epoxidation 177 Hydrogenations Reaction 179 III 4 III Free-radical Addition Reaction 186 Oxidation Reactions 191 III Alkenes 191 Ozonolysis 191 Oxidation with Osmium tetroxide 192 Oxidation with Potassium Permanganate 194 Acid Catalyzed Oxidation of Peroxides 197 III Alcohols 199 Jones Oxidation 199 With K2Cr2O7 (Na2Cr2O7) ; H2SO4 201 Oxidation with Chromium-Based Reagents 202 Oxidation with Sodium Hypochlorite NaOCl 203 Swern Oxidation 208 III Reduction Reactions 210 III Reduction of Alkenes and Alkynes 210 III Reduction of Benzene 210 Catalytic Hydrogenation 210 Birch Reduction 211 III Reduction of Carbonyl Compounds 217 With NaBH4 and LiBH4 217 With LiAlH4 219 With DIBAL 223 Clemmensen Reduction (Aldehydes and Ketones) 224 Wolff–Kishner Reduction (Aldehydes and Ketones) 225 Rosenmund Reduction 227 Mozingo Reduction 227 Luche Reduction 228 IV Selection of Named Reactions 230 IV Grignard Reaction 230 IV Aldol Reaction 233 IV Michael Reaction 236 IV Knoevenagel Reaction 239 IV Claisen Reaction 242 IV Robinson Annulation 245 IV Diels-Alder Reaction 247 IV Beckmann Rearrangement 252 IV Wurtz Reaction 254 IV 10 Witting Reaction 256 I Solvents I Definition By definition, a solvent is a chemical substance that can be solid, liquid, or gas in which reactants “solutes” dissolve resulting in a miscible mixture known as “solution” Furthermore, the amount of a solute that can be dissolved in a specific volume of a solvent is subjected to several factor including temperature, pressure, and stirring As a result, we can distinguish four types of solutions: Diluted solutions that contain very low amount of solute Concentrated solutions that contain the maximum amount of solute that can be dissolved at standard conditions Saturated solutions contain more than the maximum amount of solute In this case, the solution is exposed to high temperature in order to dissolve more molecules of the solute Supersaturated solution, which contain more dissolved solute than required for a saturated solution This type of solutions can be prepared by heating a saturated solution while adding more solute, then cooling it gently I Solvent Classification In chemistry, solvents can be classified in several categories depending upon their chemical and physical properties For instance, they are divided into two classes “polar solvents, and apolar solvents” based on their polarity I Apolar Solvents The vast majority of organic solvents are considered apolar solvents; they have either a frail dipole-dipole moments “polarizable inert solvents”, or not at all “inert solvents” These solvents are mostly used when dissolving non-polar species I 2 Polar Solvents Polar solvents are chemical substances that exhibit dipole-dipole moments, in other word, they have a positive side, which represents the least electronegative atom(s), and a negative side where there is the most electronegative atom or group of at oms Moreover, polar solvent s are further subdivided into two sub -classes “protic, and aprotic” based on whether they can form intermolecular hydrogen bonds among themselves or not Protic Solvents Protic solvents are characterized by their ability to form intermolecular hydrogen bonds among themselves These solvents should therefore possess certain functional group such as OH, SH, or NH2 Protic solvents are also referred to as amphiprotic solvents due to their ability to donate or accept hydrogen prot on depending upon the medium in which they are The term amphoteric is derived from the Greek word ἀμφότεροι [amphoteroi], which means "both" while protic refers to protons H+ Aprotic Solvents Aprotic solvents, on the other hand, cannot fo rm intermolecular hydrogen bonds among themselves ; however, they can be hydrogen -bonds acceptors HBA , also known as protophilic solvents, such as THF, and DMF, or hydrogen-bonds donors HBD “protogenic” such as acetone I Solubility As the famous aphorism says “likes dissolve likes”, substances tend to dissolve in solvents that have similar polarity with them As a result, polar solutes d issolve in polar solvents whereas apolar solutes dissolve in non -polar solvents This phenomenon is called solvation and it can be explained through the intermolecular forces between solvent -solute molec ules and the change of entropy For polar compounds, dipole-dipole and ion -dipole forces and in case of protic solvent, hydrogen bonds facilitate the solvation of solute in the solvent Dissolution of polar solutes in polar solvents On the other hand, apolar compounds dissolve in apolar solvents due to the entropy change since these substances have only frail London forces, which are too weak to form a solution alone Dissolution of apolar solutes in apolar solvents Unlike bromine and chlorine, fluorine reacts vigorously with methane that even in the dark and at room temperature, fluorination must be carefully controlled Th e reason behind this is that fluorine has a higher reactivity than all the other halogens due to its higher electronegativity and small size Iodine, on the other hand, does not react with methane because of its higher stability Selectivity F Cl Br I Reactivity When performing a halogenation reaction, different products may be obtained with different yields This depends upon the selectivity of the halogen involved and the number of available hydrogen atomsthat can be replaced Reactivity and selectivity are inversely proportional, the more reactive a reagent, the less selective Bromine has a higher selectivity than chlorine As result, it tends to add to the most substituted carbon atom In contrast, chlorine is less selective that all potential products are produced with significant amount In theory, it is possible to predict the yield of all possible isomers using the following formula: Pi % = 100 n Hi R i ∑i n Hi R i Pi: Yield of product i Nhi: Number of hydrogen atoms of type i Ri: Reactivity factor for type i i: Sum of all types Table : Reactivity factors for chlorine and bromine Hydrogen Primary H Secondary H Tertiary H Cl 3.9 5.2 Br 82 1640 35 Example Comparison between dimethylcyclopentane monochlorination and monobromination of Dimethylcyclopentane is a symmetrical molecule that contains6 primary hydrogen atoms, secondary hydrogen atoms, and tertiary hydrogen atoms At the propagation step, a hydrogen atom would be abstracted from the substrate, which leads to the formation of a radical carbon intermediate In this case, there would be three potential radical carbon intermediate where the most stable is the one formed when abstracting a tertiary hydrogen atom On the other hand, primary radical carbon intermedia te are the least stable and ther efore, the probability of chlorine to add on this carbon is the lowest For primary hydrogens Pi % = 100 61 = 3.35% 61 + 63.9 + 25.2 For secondary hydrogens Pi % = 100 63.9 = 41.34 % 61 + 63.9 + 25.2 For tertiary hydrogens Pi % = 100 25.2 = 55.12 % 61 + 63.9 + 25.2 36 Products 1-(chloromethyl)-3-methylcyclopentane Yield: 3.35 % 2-chloro-1,3dimethylcyclopentane (1R)-1-chloro-2,4dimethylcyclopentane (1S)-1-chloro-2,4dimethylcyclopentane Yield: 41.34 % (1S)-1-chloro-1,3dimethylcyclopentane (1R)-1-chloro-1,3dimethylcyclopentane Yield: 55.12 % Notice that both stereoisomers form when the halogen adds to a chiral carbon The reason behind this is that free radical carbons have a planar geometry, which permits the addition of halogens on either sides and therefore, both stereoisomers may form In case of monobromination, -bromo-1,3-dimethylcyclopentane would predominate over the other isomers (95.21%) since bromine preferentially adds to the most substituted free radical carbon The other products might be observed but they would have an insignificant yields “0.019% and 4.46%.” 37 Products 1-(bromomethyl)-3-methylcyclopentane Yield: 0.019 % 2-bromo-1,3dimethylcyclopentane (1R)-1-bromo-2,4dimethylcyclopentane (1S)-1-bromo-2,4dimethylcyclopentane Yield: 4.76 % (1S)-1-bromo-1,3dimethylcyclopentane (1R)-1-bromo-1,3dimethylcyclopentane Yield: 95.21 % Allylic and Benzylic Halogenation Unlike saturated hydrocarbons, allylic compounds may follow different pathways depending upon reaction conditions At high concentration of halogens, allylic compounds undergo electrophilic addition (page 132) rather than free radical substitution reaction However, when the concentration of halogens is controlled and kept low, free radical s ubstitution reaction takes place whereby the allylic hydrogen atom gets replaced by the halogen 38 Allylic positions Benzylic position N-halosuccinimides are halogen source reagents typically used in allylic and benzylic halogenation reactions in order to avoid electrophilic addition to the double bond In this reaction, a stoichiometric amount of N-halosuccinimide is required along with a small amount of the corresponding hydrogen halide to produce a low concentration of the corresponding dihalide making free radical substitution reaction possible 39 NCS N-Chlorosuccinimide NBS N-Bromosuccinimide NIS N-Iodosuccinimide Mechanism Allylic bromination reaction is also known as Wohl-Ziegler reaction, which consists in converting olefins into olefin bromide s The reac tion mechanism is similar to regular alkanes halogenation except that Wohl-Ziegler reaction requires NBS to keep bromine concentration adequate for allylic substitution Production of dibromine This is a reversible reaction where NBS reacts with HBr to produce dibromine and succinimide This process is repeated whenever new HBr is available Initiation Under UV light or at high temperature, the dibromine formed would bromine free radicals upon homolytic fission of the covalent bond give two 40 Propagation and Termination When free radical carbon forms on the allylic position, resonance becomes possible and as a result, bromine can add on either radical allylic carbon atoms Moreover, although this reaction may produce four compounds , only one product would be predominant over the others because bromine preferentially adds to the most substituted allylic radical 41 Under UV radiation, at high temperature, or with radical initiators, benzylic compounds undergo free radical substitution reactions on the benzylic position when they are treated with NCS and HCl in CCl4 Nevertheless, this reaction is also possible with Cl2 and UV light 42 III Nucleophilic Substitution Reactions Nucleophilic substitution reactions are one of the fundamental chemical reactions in organic chemistry They are characterized by the replacement of a nucleofuge with a nucleophile Nu : Nucleophile E : Electrophile LG : Leaving Group, nucleofuge Furthermore, depending upon the substrate type, nucleophilicsubstitution reactions are classified into two main categories; nucleophilic aliphatic substitutions, and aromatic nucleophilic substitutions Nucleophilic Aliphatic Substitution Reactions Nucleophilic aliphatic reactions are subdivided into two types of r eactions: unimolecular nucleophilic substitution reaction, and bimolecular nucleophilic substitution reaction Although both reactions involve the same process “the displacement of leaving group”, each type requires specific conditions in order to proceed Unimolecular Nucleophilic Substitution Reactions SN1 SN1 Mechanism SN1 reaction proceeds in two steps and involves a carbocation intermediate Step One The first step is a slow process characterized by the heterolytic fission of the CLG bond, which leads to the formation of a planar carbocation This step may or may not be reversible 43 Step Two The second step, on the otherhand, is a fast process wherebythe nucleophile attacks the planar carbocation from either sides creating a new covalent bond with it If this carbocation is formed from a chiral carbon, the reaction will give a mixture of two stereoisomers This particular propriety makes SN1 reaction a non-stereoselective reaction Example 1: If the substrate contains only one chiral center, S N1 reaction would lead to an enantiomeric mixture “racemic mixture”, which is optically inactive Step one Formation of carbocation intermediate 44 Step two Attack of the nucleophile Example 2: If the substrate contains more than one chiral center, the reaction outcome would be a diastereoisomeric mixture In this case, the mixture obtained is optically active 45 Carbocation Rearrangement (hydride, methyl, and aryl shifts) As mentioned before, carbocations tend to acquire a more stable state by delocalizing the positive charge to a more substituted carbon atom via 1,2-shift In this example, the secondary carbocation intermediate can rearrange into a tertiary carbocation via hydride shit, which will then get captured by the nucleophile “MeOH” 46 Because of carbocation rearrangement , the reaction outcome would be four isomers However, one stereoisomer ic mixture would pr edominate over the other making this reaction a regioselective reaction SN1cA (Conjugate Acid) Mechanism Unimolecular substitution can also proceed through an S N1cA, mechanism also known as A1 mechanism, which differ from S N1 only in the first step where an acid-base interaction occur s This particular reaction occurs with alcohols and ethers “bases” where the oxygen ge ts protonated in order to form a better leaving group “conjugate acid” Example A good example for SN1cA reactions is reactions ofa tertiary alcohol with hydrogen halide In this case, the hydroxy group of the alcohol abstracts a hydrogen proton 47 from the hydrogen halide moleculeto form an oxonium ion“conjugate base” Once protonation is done, the leaving group “water” departs from the substrate creating, this way, a carbocation intermediate Next, the reaction proceeds according to S N1 mechanism where the nucleophilic halide attacks the carbocation from either sides SN1’ (Allylic Substitution) Mechanism When the nucleofuge is attached to an allylic carbon atom, the substrate undergoes nucleophilic substitution reaction via an S N1’ mechanism In such a case, the carbocation intermediate formed is stabilized by resonance where the positive charge is distributed between the two carbons α and γ 48 At this point, the nucleophile can attack α carbon via SN1 mechanism or γ carbon via SN1’ mechanism Reactions that involves SN1’ mechanism are nonstereoselective because both stereoisomers form Nevertheless, they are regioselective since the nucleophile preferentially attacks the most substituted allylic carbocation Kinetics Unimolecular substitution reactions follow the first order kinetics where the reaction rate depends solely on the substrate concentration As menti oned earlier, in unimolecular substitution reactions, nucleophiles not intervene in the first step, which determine the overall rate of reaction As a result, increasing or decreasing the concentration of the nucleophile will not change the velocity of reaction Rate = K[Substrate] 49 ... Leaving Group, nucleofuge 29 III Reaction Mechanisms III Substitution Reactions In organic chemistry, substitution reactions are reactions where substituents get replaced by other species These re actions... 2 β Elimination Reactions 101 Regiochemistry and Stereochemistry 105 Regiochemistry and Stereochemistry 112 III γ Elimination Reactions 116 Freund Reaction 116... Selection of Named Reactions 230 IV Grignard Reaction 230 IV Aldol Reaction 233 IV Michael Reaction 236 IV Knoevenagel Reaction 239 IV Claisen Reaction