Organic Chemistry Chapter 7 PDF

Organic Chemistry Chapter 7 1  Alkyl Halides Alkyl halides: halogen atom bonded to an sp3 hybridized carbon atom. The halogen atom in halides is often denoted by the symbol “X”. Alkyl halides are classified as primary (1 degree), secondary (2 degre...

Organic Chemistry Chapter 7 1  Alkyl Halides Alkyl halides: halogen atom bonded to an sp3 hybridized carbon atom. The halogen atom in halides is often denoted by the symbol “X”. Alkyl halides are classified as primary (1 degree), secondary (2 degrees), or tertiary (3 degrees), depending on the number of carbons bonded to the carbon with the halogen atom. 2  Naming Alkyl Halides Same rules as naming alkanes: 1. find parent chain 2. Name and number the substituents 3. Alphabetize the substiuents 2-chloro-5-methylheptane. 3  Common Names of Alkyl Halides Common names are often used for simple alkyl halides ine becomes ide 4 Alkyl halides are weakly polar molecules. exhibit dipole-dipole interactions 5  Polar Carbon-Halogen Bond The halogen atom in alkyl halides creates a polar bond, making the carbon atom electron deficient. Slightly positive carbon becomes a reactive site alkyl halides. Allows for substitution (and elimination) reactions Figure 7.4 6  Nucleophilic Substitution the nucleophile substitutes for the halide Reaction of a nucleophile to the electrophilic carbon R X + Nuc:- R Nuc + X:- Nucleophiles can be negatively charged or neutral donate electron pair halide leaves bond is heterolytically cleaved The more stable the halide; better it is to accept the electron pair from the nucleophile The halide is known as a leaving group 7  Notice the nucleophile replaces the halide in these examples Negatively charged nucleophile example Neutral nucleophile example 8 These are Lewis acid-base reactions: Lewis acid accepts electron pair (alkyl halide) Lewis base donates electron pair (nucleophile) Leaving groups include oxygen and nitrogen functionalities…… 9  Leaving Group Ability The weaker the base, the better the leaving group. 10 Good Leaving Groups 11  Poor Leaving Groups Conjugate bases of weaker acids are poorer leaving groups. 12  Nucleophiles and Bases Nucleophiles and bases are structurally similar: both have a lone pair or a bond. They differ in what they attack. Bases attack protons. Nucleophiles attack other electron-deficient atoms (usually carbons). 13  Nucleophiles vs. Bases Basicity is a measure of how readily an atom donates its electron pair to a proton. It is characterized by an equilibrium constant, Ka in an acid-base reaction, making it a thermodynamic property. Nucleophilicity is a measure of how readily an atom donates its electron pair to other atoms. It is characterized by a rate constant, k, making it a kinetic property. 14  Nucleophilicity Parallels Basicity Nucleophilicity parallels basicity in three instances: For two nucleophiles with the same nucleophilic atom, the stronger base is the stronger nucleophile. The relative nucleophilicity of HO− and CH3COO−, is determined by comparing the pKa values of their conjugate acids (H2O = 15.7, and CH3COOH = 4.8). HO− is a stronger base and stronger nucleophile than CH3COO−. 15 A negatively charged nucleophile is always a stronger nucleophile than its conjugate acid. HO− is a stronger base and stronger nucleophile than H2O. Right-to-left across a row of the periodic table, nucleophilicity increases as basicity increases: 16 Nucleophilicity is affected by steric hindrance: reactivity decreases because of bulky groups at the reaction site Steric hindrance decreases nucleophilicity but not basicity. 10/27/22 up to here Next Exam: 11/17/22 Final: week of 12/12…tentative for 12/15 at regular class time 17 Be sure to understand: Nucleophiles & electrophiles Leaving group concept Mechanisms of nucleophilic substitution (following slides in this chapter) Note: Chapter deals with alkyl halides as the primary topic but these form other functional groups Again…..look at what happens in a reaction..changes in a reactant molecule compared to a product molecule 18 Nucleophilicity can be affected by the nature of the solvent (reactants usually dissolve) Since substitution reactions involve polar starting materials, polar solvents are used to dissolve them. There are two types of polar solvents: protic and aprotic. Protic solvent: contain a hydrogen bound to oxygen, nitrogen (H-bonding) water, alcohols, amines Aprotic solvent: lack an acidic hydrogen; can’t H-bond; 19 examples 20  Nucleophilicity in Polar Protic Solvents Smaller, more electronegative anions are solvated more strongly, effectively shielding them from reaction. In polar protic solvents, nucleophilicity increases down a column of the periodic table as the size of the anion increases. This is the opposite of basicity. 21  Nucleophilicity in Polar Aprotic Solvents Polar aprotic solvents solvate cations by ion-dipole interactions. Anions are not well solvated because the solvent cannot hydrogen bond to them. These anions are more reactive. nucleophilicity parallels basicity, the stronger base is the stronger nucleophile. basicity decreases as size increases down a column, nucleophilicity decreases as well. 22 Common Nucleophiles 23 Bond Breaking and Making in Nucleophilic Substitution Mechanisms But what is the order of bond making and bond breaking? In theory, there are three possibilities. Bond making and breaking occur at the same time. Bond breaking occurs first. Bond making occurs first. 24 What does this have to do with alkyl halides? Alkyl halides are the starting compounds for many syntheses Many types of compounds are used to synthesize compounds with different functional groups Polar solvents are used to allow reactions to progress Understanding nucleophilic reactions, 2 different mechanisms 25 SN2 reactions Substitution Nucleophilic bimolecular Inversion of configuration Second order reaction: rate depends on both reactants Bimolecular reaction 26  Nucleophilic Substitution Mechanisms–Concerted Theory: Bond making and bond breaking occur at the same time. The mechanism is comprised of one step. In such a bimolecular reaction, the rate depends upon the concentration of both reactants. The rate equation is second order. 27  Kinetics and Mechanisms Bromomethane and sodium acetate From kinetic data, the rate of reaction: depends on the concentration of both reactants bimolecular reaction with a one-step mechanism. SN2 mechanism 28  Reaction Mechanism mechanism of an SN2 reaction example 29 example Reference: slideshare Transition state has partial bond breaking and partial bond forming….and partial charges 30  𝐍 Kinetics 2nd order kinetics. reaction is bimolecular – both the alkyl halide and the nucleophile appear in the rate equation. 31  Energy Diagrams for 𝐍 Reactions See slide 28 32  Stereochemistry of the Reaction Backside Attack: The nucleophile approaches from the side opposite the leaving group. results in inversion of configuration at the stereocenter. 33  Inversion in 𝐍 Reactions Reference: master Organic Chem SN2 from internet. 34  Inversion in 𝐍 Reactions Reference: UCLA Chemistry and Biochemistry from internet. 35  Substrate Reactivity in 𝐍 Reactions Increase in the number of R groups on the carbon with the leaving group, the rate of an SN2 reaction decreases. Methyl and primary alkyl halides undergo SN2 reactions with ease. Secondary Alkyl halides react more slowly. Tertiary Alkyl halides do not undergo SN2 reactions due to steric effects. Bulky R groups near the reaction site make nucleophilic attack from the backside more difficult, slowing the reaction rate. 36  Steric effect on rate Reference: master Organic Chem SN2 37 Characteristics of the 𝐍 Mechanism 38  The 𝐍 Reaction in the Synthesis of Drugs Figure 7.11 39 Consider: By SN2 mechanism this reaction should be slow…. However the reaction is faster than CH3Br when water is the solvent..WHY? Another mechanism must be present…… SN1 (substitution nucleophilic unimolecular) mechanism. 40  SN1 Mechanism– Bond Breaking First mechanism has two steps Bond breaking occurs before bond making. carbocation is formed as an intermediate. first step is rate-determining. rate depends on the concentration of RX only. rate equation is first order. 41 Consider this reaction: rate of reaction depends on the concentration of only the alkyl halide. This suggests a two-step mechanism in which the rate-determining step involves the alkyl halide only. SN1 (substitution nucleophilic unimolecular) mechanism. 42  Reaction Mechanism Mechanism shows the breaking of the carbon halide bond to form a carbocation; then attack by a nucleophile to the carbocation Carbocation is the reactive intermediate. 43 Summary SN1 reactions exhibit 1st order kinetics. The reaction is unimolecular – involving only the alkyl halide. The identity and concentration of the nucleophile have no effect on the reaction rate. Therefore, the nucleophile does not appear in the rate equation: 44  Energy Diagrams for Reactions: generalization Reference: chemistry libre SN1 reactions 45 Energy Diagrams for Reactions 46  Stereochemistry of 𝐍 Reactions geometry of the carbocation intermediate dictates the stereochemistry 47  Stereochemistry of 𝐍 Reactions geometry of the carbocation intermediate dictates the stereochemistry Means nucleophile can attack from either direction to form a racemic mixture Equal amounts of the enantiomers are formed: Inversion: product configuration changes from starting material’s (inverts) Retention: product configuration stays as the starting material’s (retains) 48  Racemization in Reactions Summary: racemization. Loss of the leaving group generates a planar carbocation that is achiral. attack of the nucleophile can occur on either side to afford two products which are a pair of enantiomers. an equal amount of the two enantiomers is formed—a racemic mixture. 49  Racemization in Reactions-1 Here are two examples of racemization in the SN1 reaction. Figure 7.13 50  Example: SN1 reaction mechanism Reference: Wikipedia SN1 reaction 51  Substrate Reactivity in 𝐍 Reactions rate of reaction is affected by the type of alkyl halide tha is involved. This trend is exactly opposite to that observed in SN2 reactions.. 52 Characteristics of the 𝐍 Mechanism 53  Carbocation Stability effect of the type of alkyl halide on SN1 reaction rates can be explained by considering carbocation stability. Carbocations are classified as primary (1 degree), secondary (2 degrees), or tertiary (3 degrees), based on the number of R groups bonded to the charged carbon atom. As the number of R groups increases, carbocation stability increases. 54  Inductive Effects and Carbocation Stability carbocation stability: due inductive effects and hyperconjugation. Inductive effects: pull of electron density through σ bonds caused by electronegativity differences between atoms Any group that can donate electron density through σ bonds can stabilize a positive charge Alkyl groups are electron density donors (better than hydrogen) In general, the more alkyl groups attached to a carbocation, the more stable the cation will be. 55 Carbocation Stability 56  Hyperconjugation and Carbocation Stability Hyperconjugation is the spreading out of charge by the overlap of an empty p orbital with an adjacent σ bond. Delocalization of the positive charge on the carbocation over a larger volume, thus stabilizing it. (CH3)2CH+can be stabilized by hyperconjugation, but CH3+ cannot. 57 Hyperconjugation and Carbocation Stability Reerence: organicmystery.com 58  The Hammond Postulate Hammond postulate states that the transition state of a reaction resembles the structure of the species (reactant or product) to which it is closer in energy. Or The structure of the transition state will resemble the species that is closer to it in energy (species meaning reactants or products) 59 Transition State Energy and the Hammond Postulate What this means is 60  Endothermic Reaction Transition States the transition state resembles the products more than the reactants, so anything that stabilizes the product stabilizes the transition state also. lowering the energy of the transition state decreases Ea, which increases the reaction rate. All this means: If there are two possible products of different stability in an endothermic reaction, the transition state leading to the more stable product is lower in energy, so this reaction should occur more quickly. (figure 7.15..next slide) Note: reactions may give more than one product…. 61  Transition State Energy of an Endothermic Reaction Figure 7.15 Possible different transition states 62  Exothermic Reaction Transition States the transition state resembles the reactants more than the products. lowering the energy of the products has little or no effect on the energy of the transition state. Since Ea is unaffected, the reaction rate is unaffected. All this means: is that in an exothermic reaction, the more stable product may or may not form faster, since Ea is similar for both products. (figure 7.16, next slide) 63  Transition State Energy of an Exothermic Reaction Figure 7.16 Same transition state 64  Application of the Hammond Postulate to the 𝐍 Reaction the rate determining step is the formation of the carbocation, an endothermic process. According to the Hammond postulate, the stability of the carbocation determines the rate of its formation. Compare the two reactions: 65 Previous slide as an energy diagram Figure 7.17 66 Predicting the Mechanism of Nucleophilic Substitutions Reactions A given reaction is likely to proceed by an SN1 or an SN2 mechanism based on: The alkyl halide—CH3X, RCH2X, R2CHX or R3CX The nucleophile—strong or weak The leaving group—good or poor The solvent—protic or aprotic Up to here 10/20 67  Nature of the Alkyl Halide What type of alkyl halide is present? (summary) 68  Effect of the Nucleophile Strong nucleophiles (which usually bear a negative charge) present in high concentrations favor SN2 reactions. Weak nucleophiles, such as H2O and ROH favor SN1 reactions ( by decreasing the rate of any competing SN2 reaction.) Consider what happens when the 2o alkyl halide is treated with either the strong nucleophile HO− or the weak nucleophile H2O. (next slide..reaction of cis-1-bromo-4-methylcylclohexane) SN1 favors racemization (2 enantiomers) SN2 favors only the trans isomer 69  or an based on Nucleophile The strong nucleophile favors an SN2 mechanism. The weak nucleophile favors an SN1 mechanism. Note: loss of proton during mechanism. 70  Effect of Leaving Groups A better leaving group increases the rate of both SN1 and SN2 reactions (Summary). 71  Effect of Solvent (summary) Polar protic solvents like H2O and ROH favor SN1 reactions because the ionic intermediates (both cations and anions) are stabilized by solvation. Polar aprotic solvents favor SN2 reactions because nucleophiles are not well solvated, and therefore, are more nucleophilic. 72 Predicting 𝐍 or an 𝐍 –Summary 73  why are substitution reactions and mechanisms important Basically: How do we make organic compounds Organic synthesis is the systematic preparation of a compound from a readily available starting material by one or many steps. Nucleophilic substitution reactions are used to introduce a wide variety of functional groups into a molecule (one of many categories of reactions) 74 Example of Organic Synthesis Using Alkyl Halides to make various functionalities 75  Retrosynthesis or retro engineering a product How can we make a desired product? If a nucleophilic substitution is being used, determine what alkyl halide and what nucleophile can be used to form a specific product. Look at the product and determine what can be used to make it: need an alky group and something to make an alcohol 76 A primary halide and a strong base Note: make sure to look for all changes or things that happen between the reactants and products when writing a mechanism or a synthesis 77 Examples of organic synthesis problems 78 Examples of organic synthesis problems 79 End Chapt 7 HW: 7.6; 7.9; 7.10; 7.17; 7.20; 7.22 (NaH is a base); 7.30; 7.34 a, c; 7.34; 7.52 More Chapt 7 practice problems in another posted PDF 80