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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Organic chemistry is required coursework for degrees in life, food, and medical sciences. To help the students discouraged by the belief that this topic cannot be mastered without significant memorization, Arrow Pushing in Organic Chemistry serves as a handy supplement for understanding the subject.
• Includes new chapters, an expanded index, and additional problem sets complete with detailed solutions
• Focuses on understanding the mechanics and logic of organic reaction mechanisms
• Introduces ionic and non-ionic reactive species and reaction mechanisms
• Teaches strategies to predict reactive species, sites of reactions, and reaction products
• Provides a solid foundation upon which organic chemistry students can advance with confidence
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Seitenzahl: 401
Veröffentlichungsjahr: 2017
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Table of Contents
Cover
Title Page
Preface
Acknowledgements
About the Author
Chapter 1: Introduction
1.1 DEFINITION OF ARROW‐PUSHING
1.2 FUNCTIONAL GROUPS
1.3 NUCLEOPHILES AND LEAVING GROUPS
1.4 SUMMARY
PROBLEMS
Chapter 2: Free Radicals
2.1 WHAT ARE FREE RADICALS?
2.2 HOW ARE FREE RADICALS FORMED?
2.3 FREE RADICAL STABILITY
2.4 WHAT TYPES OF REACTIONS INVOLVE FREE RADICALS?
2.5 SUMMARY
PROBLEMS
Chapter 3: Acids
3.1 WHAT ARE ACIDS?
3.2 WHAT IS RESONANCE?
3.3 HOW IS ACIDITY MEASURED?
3.4 RELATIVE ACIDITIES
3.5 INDUCTIVE EFFECTS
3.6 INDUCTIVE EFFECTS AND RELATIVE ACIDITIES
3.7 RELATIVE ACIDITIES OF HYDROCARBONS
3.8 SUMMARY
PROBLEMS
Chapter 4: Bases and Nucleophiles
4.1 WHAT ARE BASES?
4.2 WHAT ARE NUCLEOPHILES?
4.3 LEAVING GROUPS
4.4 SUMMARY
PROBLEMS
Chapter 5: S
N
2 Substitution Reactions
5.1 WHAT IS AN S
N
2 REACTION?
5.2 WHAT ARE LEAVING GROUPS?
5.3 WHERE CAN S
N
2 REACTIONS OCCUR?
5.4 S
N
2′ REACTIONS
5.5 SUMMARY
PROBLEMS
Chapter 6: S
N
1 Substitution Reactions
6.1 WHAT IS AN S
N
1 REACTION?
6.2 HOW ARE S
N
1 REACTIONS INITIATED?
6.3 THE CARBOCATION
6.4 CARBOCATION REARRANGEMENTS
6.5 SUMMARY
PROBLEMS
Chapter 7: Elimination Reactions
7.1 E1 ELIMINATIONS
7.2 E1cB ELIMINATIONS
7.3 E2 ELIMINATIONS
7.4 HOW DO ELIMINATION REACTIONS WORK?
7.5 E1cB ELIMINATIONS VERSUS E2 ELIMINATIONS
7.6 SUMMARY
PROBLEMS
Chapter 8: Addition Reactions
8.1 ADDITION OF HALOGENS TO DOUBLE BONDS
8.2 MARKOVNIKOV’S RULE
8.3 ADDITIONS TO CARBONYLS
8.4 SUMMARY
PROBLEMS
Chapter 9: Carbenes
9.1 WHAT ARE CARBENES?
9.2 HOW ARE CARBENES FORMED?
9.3 REACTIONS WITH CARBENES
9.4 CARBENES VERSUS CARBENOIDS
9.5 SUMMARY
PROBLEMS
Chapter 10: Pericyclic Reactions
10.1 WHAT ARE PERICYCLIC REACTIONS?
10.2 ELECTROCYCLIC REACTIONS
10.3 CYCLOADDITION REACTIONS
10.4 SIGMATROPIC REACTIONS
10.5 SUMMARY
PROBLEMS
Chapter 11: Moving Forward
11.1 FUNCTIONAL GROUP MANIPULATIONS
11.2 NAME REACTIONS
11.3 REAGENTS
11.4 FINAL COMMENTS
PROBLEMS
Appendix 1: pK
a
Values of Protons Associated with Common Functional Groups
Appendix 2: Answers and Explanations to Problems
Appendix 3: Student Reaction Glossary
Index
Periodic Table of Elements
End User License Agreement
List of Tables
Chapter 11
Table 11.1 Name reactions and reaction types useful for modification and expansion of organic structures.
Table 11.2 Reagent classes and associated properties.
List of Illustrations
Chapter 01
Scheme 1.1 Example of the Wittig reaction.
Scheme 1.2 Example of the Diels–Alder reaction.
Scheme 1.3 Example of a tin hydride dehalogenation.
Figure 1.1 Examples of chemical bonds.
Figure 1.2 Examples of chemical bonds and lone pairs.
Scheme 1.4 Illustration of homolytic cleavage.
Scheme 1.5 Illustration of heterolytic cleavage.
Scheme 1.6 Illustration of a concerted reaction (Cope rearrangement).
Scheme 1.7 Illustration of arrow‐pushing applied to the Cope rearrangement.
Scheme 1.8 Application of arrow‐pushing to homolytic cleavage using single‐barbed arrows.
Scheme 1.9 Application of arrow‐pushing to heterolytic cleavage using double‐barbed arrows.
Figure 1.3 Common organic functional groups.
Figure 1.4 How functional groups influence polarity.
Scheme 1.10 Example of a nucleophilic reaction.
Chapter 02
Figure 2.1 Tethered ball model for bond strain.
Figure 2.2 Tethered ball model for breaking bonds.
Figure 2.3 Translation of tethered ball model to anions, cations, and free radicals.
Figure 2.4 Common free radicals.
Figure 2.5 Formation of radical ions via electron transfer.
Scheme 2.1 Homolytic cleavage of
N
‐bromosuccinimide.
Figure 2.6 Common free radical initiators.
Figure 2.7 Conjugated aromatic ring systems form radical anions more readily.
Scheme 2.2 Free radicals readily pair forming covalent bonds.
Figure 2.8 Molecular structures of graphite and diamond.
Figure 2.9 Order of free radical stability.
Figure 2.10 Hydrogen atom
s
orbitals can donate electron density to adjacent centers of electron deficiency as can heteroatoms bearing lone electron pairs.
Scheme 2.3 Examples of bromination reactions.
Scheme 2.4 Arrow‐pushing mechanism for bromination of methane.
Scheme 2.5 Allylic and benzylic bromination (halogenation).
Scheme 2.6 Free radicals stabilized by conjugation can form multiple products.
Figure 2.11 Common organic polymers.
Scheme 2.7 Free radical formation of polystyrene.
Scheme 2.8 Termination of polystyrene free radical polymerization.
Scheme 2.9 Examples of oxidative functional group transformations.
Scheme 2.10 Mechanism for autoxidation of isobutane.
Chapter 03
Scheme 3.1 General representation of acid dissociation.
Figure 3.1 Solvent effects on acid dissociation.
Figure 3.2 Common polar and non‐polar organic solvents.
Scheme 3.2 Dissociation of a carboxylic acid forming a proton and a carboxylate anion.
Scheme 3.3 Resonance forms of the carboxylate anion.
Scheme 3.4 Rationalization of the carboxylate anion resonance forms using arrow‐pushing.
Scheme 3.5 Dimethyl malonate does not spontaneously liberate malonate anions.
Scheme 3.6 Potassium tert‐butoxide partially deprotonates dimethyl malonate.
Scheme 3.7 Resonance forms of the malonate anion rationalized using arrow‐pushing.
Figure 3.3 Definition of the equilibrium constant ( K
eq
).
Figure 3.4 K
a
is the K
eq
specifically related to dissociation of acids.
Figure 3.5 Definition of pH.
Figure 3.6 Definition of pK
a
.
Figure 3.7 pK
a
values are related to pH.
Figure 3.8 The Henderson–Hasselbalch equation.
Figure 3.9 In a perfect equilibrium, pK
a
= pH.
Figure 3.10 Representative functional groups with associated acidic protons.
Figure 3.11 Representative functional groups with adjacent acidic protons.
Scheme 3.8 Resonance capabilities of carboxylic acids compared to alcohols.
Figure 3.12 Common carboxylic acids and their respective pK
a
values.
Scheme 3.9 Esters can be deprotonated α to ester carbonyls.
Scheme 3.10 Rationalization of the acidity of protons α to ester carbonyls.
Scheme 3.11 Electron‐withdrawing groups increase acidity by increasing anionic stability.
Scheme 3.12 Electron‐donating groups decrease acidity by decreasing anionic stability.
Figure 3.13 Common electron‐withdrawing groups and electron‐donating groups.
Figure 3.14 pK
a
values associated with alcohols increase as alkyl branching increases.
Scheme 3.13 Amines and alcohols can both be deprotonated.
Scheme 3.14 Hydrocarbons can be deprotonated and have measurable pK
a
values.
Chapter 04
Scheme 4.1 General representation of bases reacting with acids.
Figure 4.1 Common bases used in organic chemistry.
Scheme 4.2 Equilibrium between methyl acetate and triethylamine.
Scheme 4.3 Equilibrium between methyl acetate and potassium
tert
‐butoxide.
Scheme 4.4 Equilibrium between methyl acetate and phenyllithium.
Scheme 4.5 Amine basicity is related to the nitrogen lone pair.
Scheme 4.6 Alcohol and ether oxygens can be protonated.
Scheme 4.7 Carboxylic acids and esters can be protonated.
Scheme 4.8 Aldehydes and ketones can be protonated.
Scheme 4.9 Carbonyl‐based functional groups delocalize charges through resonance.
Scheme 4.10 Protonated carbonyl‐based functional groups delocalize their positive charges.
Scheme 4.11 Protonated carbonyl‐based functional groups are susceptible to reaction with nucleophiles.
Figure 4.2 Representative nucleophiles and their corresponding acid forms.
Figure 4.3 Relationship between nucleophilicity, electronegativity, and basicity as illustrated using first row elements.
Figure 4.4 The order of increasing nucleophilicity of halide ions is influenced by polarizing influences such as solvent effects.
Figure 4.5 Solvent shells surround hard bases more closely, making them less reactive nucleophiles compared with soft bases.
Figure 4.6 Steric effects can override the influence of p
K
a
values on nucleophilicity.
Scheme 4.12 Example of a nucleophilic reaction.
Chapter 05
Scheme 5.1 Representation of an S
N
2 reaction.
Figure 5.1 Enantiomers are mirror images, not superimposable and dependent upon the tetrahedral arrangement of carbon atom substituents.
Scheme 5.2 Mechanistic explanation of S
N
2 reactions.
Scheme 5.3 S
N
2 reactions proceed when incoming nucleophiles are more nucleophilic than outgoing leaving groups.
Scheme 5.4 S
N
2 reactions do not proceed when incoming nucleophiles are less nucleophilic than outgoing leaving groups.
Figure 5.2 Chloromethane bears a partial negative charge on the electronegative chlorine atom and a partial positive charge on the carbon atom.
Figure 5.3 The carbon–chlorine bond in chloromethane is polarized.
Scheme 5.5 Understanding the direction of bond polarity allows identification of reaction site, trajectory of nucleophile, and identification of the leaving group.
Scheme 5.6 Steric bulk slows down reaction rates for S
N
2 reactions.
Scheme 5.7 Resonance forms can be used to rationalize the stability of cations adjacent to sites of bond unsaturation.
Figure 5.4 Partial charges can be delocalized through unsaturated bonds.
Scheme 5.8 Comparison of S
N
2 and S
N
2′ reactions as explained with arrow‐pushing.
Scheme 5.9 Competing S
N
2 and S
N
2′ reaction mechanisms can lead to product mixtures.
Chapter 06
Scheme 6.1 The initial phase of an S
N
1 reaction involves dissociation of a leaving group from the starting molecule generating a carbocation.
Scheme 6.2 The second phase of an S
N
1 reaction involves reaction of a carbocation with a nucleophile generating a new product.
Scheme 6.3 Solvolysis of tert‐butylbromide in methanol produces MTBE via an S
N
1 mechanism.
Scheme 6.4 Explanation of the solvolysis of tert‐butylbromide in methanol using arrow‐pushing.
Scheme 6.5 Methanol will not react with tert‐butylbromide via an S
N
2 mechanism.
Figure 6.1 Fully substituted carbon atoms present substituents in tetrahedral arrangements.
Figure 6.2 s‐Orbitals are spherical and p‐orbitals are shaped like hourglasses.
Figure 6.3 Hybrid orbitals result from combinations of s‐ and p‐orbitals.
Figure 6.4 Like substituents, lone pairs influence molecular geometry.
Figure 6.5 Different orbital hybridizations results in different molecular geometries.
Figure 6.6 sp
2
Hybridized carbocations possess trigonal planar geometries.
Scheme 6.6 The stereochemical courses of S
N
2 reactions are defined by the stereochemical configuration of the starting materials—one product is formed.
Scheme 6.7 The stereochemical identities of starting materials subjected to S
N
1 reactions are lost due to the planarity of reactive carbocations—two products are formed.
Figure 6.7 Tertiary carbocations are more stable than secondary carbocations, and secondary carbocations are more stable than primary carbocations.
Figure 6.8 Hydrogen atom s‐orbitals can donate electron density to adjacent cationic centers as can heteroatoms bearing lone electron pairs.
Figure 6.9 Heteroatoms stabilize carbocations better than hyperconjugation effects.
Figure 6.10 Allylic carbocations are more stable than secondary carbocations.
Figure 6.11 Tertiary carbocations are more stable than allylic carbocations.
Figure 6.12 Hyperconjugation occurs when a carbon–hydrogen bond lies in the same plane as a carbocation’s vacant p‐orbital.
Figure 6.13 Hyperconjugation can be viewed as formation of a “pseudo‐double bond.”
Scheme 6.8 Hyperconjugation leads to migration of hydrogen atoms through a 1,2‐hydride shift.
Scheme 6.9 Rearrangements via 1,2‐hydride shifts generate more stable carbocations from less stable carbocations.
Scheme 6.10 The pinacol rearrangement.
Scheme 6.11 The pinacol rearrangement proceeds through solvolysis‐mediated cation formation.
Scheme 6.12 1,2‐Hydride shifts will not occur when the product cation is less stable than the starting cation.
Scheme 6.13 Alkyl migrations occur when the resulting carbocation is more stable than the starting carbocation.
Scheme 6.14 Conclusion of the pinacol rearrangement involves migration of the positive charge to the adjacent oxygen atom followed by deprotonation.
Chapter 07
Figure 7.1 Hyperconjugation occurs when a carbon–hydrogen bond lies in the same plane as a carbocation’s vacant p‐orbital.
Figure 7.2 Hyperconjugation can be viewed as formation of a “pseudo double bond.”
Scheme 7.1 Dissociation of a proton through hyperconjugation completes the final stage of an E1 elimination mechanism.
Scheme 7.2 E1 mechanisms explain additional products observed during S
N
1 reactions.
Scheme 7.3 Solvolysis of 2‐bromo‐2,3‐dimethylpentane in methanol leads to formation of up to six different products via multiple mechanistic pathways.
Scheme 7.4 General representation of bases (B or B
−
) reacting with acids (HA) forming conjugate bases (A
−
).
Scheme 7.5 Formation of the conjugate base and associated resonance structure resulting from the reaction of 2‐iodomethyl dimethylmalonate with sodium hydride.
Scheme 7.6 β‐Elimination of the iodide completes the E1cB mechanism converting the 2‐iodomethyl dimethylmalonate anion to 2‐methylidene dimethyl malonate.
Scheme 7.7 Reaction of 2‐iodomethyl dimethyl malonate with a nucleophile results in predominant formation of the E1cB elimination product.
Scheme 7.8 S
N
2 substitution reactions can occur in competition with E2 elimination reactions.
Figure 7.3 Tertiary carbocations are more stable than secondary carbocations, and secondary carbocations are more stable than primary carbocations.
Figure 7.4 When a carbon–hydrogen (or carbon alkyl) bond is aligned with an empty p‐orbital, 1,2‐hydride/alkyl shifts and E1 eliminations are favorable.
Figure 7.5 When a carbon–hydrogen bond or a negatively charged orbital is aligned trans‐periplanar with a carbon leaving group bond, E2 eliminations and E1cB eliminations are favorable.
Scheme 7.9 E2 eliminations depend upon the presence of trans‐periplanar relationships.
Scheme 7.10 Mechanistic progression of E2 eliminations.
Scheme 7.11 If trans‐periplanar relationships can be established, E2 elimination products can form.
Chapter 08
Scheme 8.1 Addition of bromine to ethylene.
Scheme 8.2 Molecular bromine reacts with double bonds generating a bromonium ion and a bromide anion.
Scheme 8.3 Bromonium ions possess electrophilic carbon atoms.
Scheme 8.4 Nucleophilic reaction between a bromide anion and a bromonium ion generates 1,2‐dibromoalkanes.
Scheme 8.5 Protic acids can add across double bonds.
Scheme 8.6 Double bonds can become protonated under acidic conditions.
Scheme 8.7 Nucleophiles add to protonated olefins.
Scheme 8.8 Multiple potential products are possible from addition of protic acids across double bonds.
Scheme 8.9 Protonation of propene introduces cationic character to both primary and secondary centers.
Figure 8.1 While unsubstituted olefins are nonpolar, carbonyls are polar.
Scheme 8.10 Nucleophiles can add to carbonyls to form alcohols.
Scheme 8.11 Addition of nucleophiles to carbonyls can be reversible.
Scheme 8.12 Products resulting from addition of nucleophiles to acetone.
Scheme 8.13 Carbonyls can become protonated.
Scheme 8.14 Addition of nucleophiles to carbonyls can occur under acidic conditions.
Scheme 8.15 Addition of nucleophiles to simple carbonyls results in 1,2‐additions.
Figure 8.2 Comparison of S
N
2 and S
N
2′ reactions as explained with arrow‐pushing.
Scheme 8.16 Addition of nucleophiles to α,β‐unsaturated carbonyl groups as explained using arrow‐pushing.
Scheme 8.17 Addition of nucleophiles to α,β‐unsaturated carbonyls can result in 1,4‐additions.
Scheme 8.18 α,β‐Unsaturated carbonyl systems can be sequentially subjected to 1,4‐additions and 1,2‐additions.
Figure 8.3 Unlike most carbonyl‐based functional groups, nonconjugated esters can react with nucleophiles and retain the carbonyl unit.
Scheme 8.19 The addition–elimination mechanism illustrated with arrow‐pushing.
Figure 8.4 Functional groups capable of participating in addition–elimination reactions.
Chapter 09
Figure 9.1 Structural representations of carbenes using dot notation, inclusion of orbitals and representative illustration of neutralizing charges.
Scheme 9.1 Chloroform can be deprotonated in the presence of strong bases.
Scheme 9.2 α‐Elimination versus β‐elimination.
Figure 9.2 General representation of diazo compounds and resonance forms.
Scheme 9.3 Decomposition of diazo compounds leads to carbene formation.
Figure 9.3 Representation of carbene dimerization.
Scheme 9.4 Reaction of dichlorocarbene with the trichloromethyl anion.
Scheme 9.5 Reaction of the ethyl acetate carbene with ethyl diazoacetate.
Scheme 9.6 Example of cyclopropane formation by intramolecular S
N
2 reaction.
Figure 9.4 Hyperconjugation can be viewed as a “protonation of a double bond.”
Scheme 9.7 The carbene empty p‐orbital can directly interact with an olefin leading to cyclopropane ring formation.
Scheme 9.8 Carbene additions to olefins generate syn‐products.
Scheme 9.9 Dichlorocarbene produces different products from cis‐ and trans‐olefins.
Figure 9.5 Reaction of cis‐2‐butene with dichlorocarbene produces the same product from both top and bottom approaches of dichlorocarbene.
Figure 9.6 Reaction of trans‐2‐butene with dichlorocarbene results in formation of enantiomers.
Scheme 9.10 Cyclopropanation products are influenced by the trajectory (top vs. bottom) of the carbene and by the spatial orientation of the carbene.
Scheme 9.11 Carbene O—H insertion reactions are complementary to the Williamson Ether Synthesis.
Figure 9.7 Example base‐mediated side reactions avoided using carbene insertion reactions.
Scheme 9.12 Formation of a carbenoid on reaction of ethyl diazoacetate with rhodium(II) acetate.
Chapter 10
Figure 10.1 Cyclic transition states enable progression of pericyclic reactions.
Figure 10.2 σ‐Bonds and π‐bonds comprise molecular orbitals formed from the overlap of s‐orbitals, p‐orbitals, and combinations thereof.
Scheme 10.1 Electrocyclic conversion of cis‐1,3,5‐hexatriene to 1,3‐cyclohexadiene.
Figure 10.3 Substitution patterns can impact the rate and success of electrocyclic reactions.
Scheme 10.2 Electrocyclic reactions involving four‐membered rings, eight‐membered rings, and bicyclic ring systems.
Scheme 10.3 Stereochemical courses for electrocyclic reactions forming six‐membered and eight‐membered rings.
Scheme 10.4 Diels–Alder reaction with 1,2‐butadiene and ethylene.
Figure 10.4 Diene–dienophile orientations for Diels–Alder reaction progression.
Scheme 10.5 Diels–Alder reaction between cyclopentadiene and acrolein.
Figure 10.5 Example dienes and dienophiles useful in Diels–Alder reactions.
Scheme 10.6 Ene reaction with propylene and ethylene.
Scheme 10.7 Ene reaction between 1‐butene and acrylonitrile.
Scheme 10.8 Intramolecular ene reactions can form substituted ring systems.
Figure 10.6 Examples of dipolar molecules and dipolar functional groups.
Scheme 10.9 Examples of 1,3‐dipolar cycloadditions.
Figure 10.7 1,3‐Dipoles can approach dipolarophile in two possible orientations.
Scheme 10.10 Mechanistic pathway for ozonolysis reactions.
Scheme 10.11 Cope rearrangement of 1,5‐hexadiene.
Scheme 10.12 Cope rearrangement of 3‐methyl‐1,5‐hexadiene.
Scheme 10.13 Oxy‐Cope rearrangement of 3‐hydroxy‐1,5‐hexadiene.
Scheme 10.14 Claisen rearrangement of allyl phenyl ether.
Scheme 10.15 Multiple Claisen rearrangements can be used to generate phenol structures with multiple substitutions.
Scheme 10.16 Allyl acetate can be converted into a silyl ketene acetal precursor for the Ireland–Claisen rearrangement.
Scheme 10.17 The Ireland–Claisen rearrangement generates carboxylic acids with terminal double bonds.
Scheme 10.18 Example of the Johnson–Claisen rearrangement.
Figure 10.8 Examples of orthoesters.
Scheme 10.19 Mechanism for the Johnson–Claisen rearrangement.
Chapter 11
Scheme 11.1 Addition of bromine across a double bond.
Scheme 11.2 Markovnikov addition of hydrobromic acid across a double bond.
Figure 11.1 Functional groups available from alkyl halides via S
N
1 and S
N
2 mechanisms.
Scheme 11.3 Conversion of alcohols to ethers—the Williamson ether synthesis.
Figure 11.2 Transformations of carboxylic acids to esters and amides.
Figure 11.3 Transformations of esters to carboxylic acids and amides.
Figure 11.4 Transformations of aldehydes and ketones to imines, oximes, and enamines.
Figure 11.5 Oxidative and reductive conversions of functional groups.
Scheme 11.4 The Diels–Alder reaction.
Scheme 11.5 The Cope rearrangement.
Scheme 11.6 The Claisen rearrangement.
Scheme 11.7 The pinacol rearrangement.
Scheme 11.8 The Favorskii rearrangement.
Scheme 11.9 The aldol condensation.
Scheme 11.10 The Robinson annulation.
Scheme 11.11 Alkylation and acylation reactions adjacent to carbonyls.
Scheme 11.12 The Friedel–Crafts acylation.
Scheme 11.13 The Wittig reaction.
Scheme 11.14 The Horner–Emmons reaction.
Scheme 11.15 A cation–π cyclization.
Scheme 11.16 The Grignard reaction.
Scheme 11.17 Formation of Grignard reagents involves oxidative addition.
Scheme 11.18 The Suzuki reaction.
Scheme 11.19 Simplified Suzuki reaction mechanism.
Scheme 11.20 The Michael addition.
Guide
Cover
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Arrow‐Pushing in Organic Chemistry
An Easy Approach to Understanding Reaction Mechanisms
Second Edition
Daniel E. Levy
This edition first published 2017© 2017 John Wiley & Sons, Inc.
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Library of Congress Cataloguing‐in‐Publication Data
Names: Levy, D. E. (Daniel E.)Title: Arrow‐pushing in organic chemistry : an easy approach to understanding reaction mechanisms / Daniel E. Levy.Other titles: Arrow pushing in organic chemistryDescription: Second edition. | Hoboken, NJ : John Wiley & Sons, Inc., 2017. | Includes bibliographical references and index. | Includes index.Identifiers: LCCN 2016043334| ISBN 9781118991329 (pbk.) | ISBN 9781118991206 (epub)Subjects: LCSH: Chemistry, Organic–Textbooks. | Reaction mechanisms (Chemistry)–Textbooks.Classification: LCC QD253.2 .L48 2017 | DDC 547/.2–dc23LC record available at https://lccn.loc.gov/2016043334
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Dedicated to the memory of Henry Rapoport (1918–2002)Professor Emeritus of ChemistryUniversity of California–Berkeleya true teacher and mentor
Preface
Organic chemistry is a general requirement for most students pursuing degrees in the fields of biology, physiology, medicine, chemical engineering, biochemistry, and chemistry. Consequently, many of the students studying organic chemistry initially do so out of obligations to required curriculum rather than out of genuine interest in the subject. This is, in fact, alright and expected as almost all college students find themselves enrolling in classes in which they either have no interest or cannot foresee application of the subject to their future vocation. Alternatively, there are students who are intrigued with the potential application of organic chemistry to fields including pharmaceuticals, polymers, pesticides, food science, and energy. However, whichever group represents the individual students, there is always a common subset of each that tenuously approaches the study of organic chemistry due to rumors or preconceived notions that the subject is extremely difficult and requires extensive memorization. Having personally studied organic chemistry and tutored many students in the subject, I assure you that this is not the case.
When first presented with organic chemistry course material, one can easily be caught up in the size of the book, the encyclopedic presentation of reactions, and the self‐questioning of how one can ever decipher the subject. These students frequently compile endless sets of flash cards listing specific chemical reactions and their associated names. Like many of my classmates, I began to approach the subject in this manner. However, this strategy did not work for me as I quickly realized that memorization of reactions did not provide any deductive or predictive insight into the progression of starting materials to products and by what mechanisms the transformations occurred. In fact, the fundamental fault in the “memorization strategy” is that in order to be effective, the student must memorize not only all chemical reactions and associated reaction names but also all associated reaction mechanisms and potential competing processes. It wasn’t until I abandoned the “memorization strategy” that I began to do well in organic chemistry and develop a true appreciation for the subject and how the science benefits society.
The presumption that introductory organic chemistry entails very little memorization is valid and simplifies the subject provided the student adheres to the philosophy that the study of organic chemistry can be reduced to the study of interactions between organic acids and bases. From this perspective, organic chemistry students can learn to determine the most acidic proton in a given molecule, determine the most reactive site (for nucleophilic attack), and determine the best reactants (nucleophiles and electrophiles) and how to predict reaction products. In learning to predict these components of organic reactions, the beginning organic chemist will be able to deduce reasonable routes from starting materials to products using the basic mechanistic types involved in introductory organic chemistry. Furthermore, through an understanding of how electrons move, extrapolations from ionic or heterolytic mechanisms can be used to explain free radical and pericyclic processes. Finally, by utilizing the principles discussed in this book, the student will gain a better understanding of how to approach the more advanced reaction types discussed as the introductory organic chemistry course progresses.
The goal of this book is not to present a comprehensive treatment of organic chemistry. Furthermore, this book is not intended to be a replacement for organic chemistry texts or to serve as a stand‐alone presentation of the subject. This book is intended to supplement organic chemistry textbooks by presenting a simplified strategy to the study of the subject in the absence of extensive lists of organic reactions. Through application of the principles presented herein, including new chapters covering free radicals, carbenes, and pericyclic reactions, it is my hope that this second edition, when used as intended, will aid the beginning student in approaching organic chemistry as I did—with little memorization and much understanding.
DANIEL E. LEVY, PH.D.
Acknowledgements
I would like to express my deepest appreciation to my wife, Jennifer, and to my children, Aaron, Joshua, and Dahlia, for their patience and support while writing this book. I would also like to express special thanks to Dr. Lane Clizbe for his editorial contributions and to Professor James S. Nowick for his suggestions regarding content for the second edition.
About the Author
Daniel E. Levy received his Bachelor of Science in 1987 from the University of California at Berkeley where, under the direction of Professor Henry Rapoport, he studied the preparation of 4‐amino‐4‐deoxy sugars and novel analogs of pilocarpine. Following his undergraduate studies, Dr. Levy pursued his Ph.D. at the Massachusetts Institute of Technology. Under the direction of Professor Satoru Masamune, he studied sugar modifications of amphotericin B, the total synthesis of calyculin A, and the use of chiral isoxazolidines as chiral auxiliaries. In 1992, Dr. Levy completed his Ph.D. and has since worked on various projects involving the design and synthesis of novel organic compounds. These compounds include glycomimetic inhibitors of fucosyltransferases and cell adhesion molecules, peptidomimetic matrix metalloproteinase inhibitors, carbocyclic AMP analogs as inhibitors of type V adenylyl cyclase, heterocyclic ADP receptor antagonists, inhibitors of calmodulin‐dependent kinase, and nanoparticle delivery vehicles for siRNA‐based therapeutics. In 2010, Dr. Levy founded DEL BioPharma LLC—a consulting firm providing research and development services to emerging pharmaceutical companies.
Arrow‐Pushing in Organic Chemistry is Dr. Levy’s third book—the first edition having been published in 2008. In 1995, Dr. Levy coauthored a book entitled The Chemistry of C‐Glycosides (1995, Elsevier Sciences). Collaborating with Dr. Péter Fügedi, Dr. Levy developed and presented short courses entitled “Modern Synthetic Carbohydrate Chemistry” and “The Organic Chemistry of Sugars,” which were offered by the American Chemical Society Continuing Education Department. With Dr. Fügedi, Dr. Levy coedited his second book entitled The Organic Chemistry of Sugars (2005, CRC Press).
Chapter 1Introduction
The study of organic chemistry focuses on the chemistry of elements and materials essential for the existence of life. In addition to carbon, the most common elements present in organic molecules are hydrogen, oxygen, nitrogen, sulfur, and various halogens. Through the study of organic chemistry, our understanding of the forces binding these elements to one another and how these bonds can be manipulated are explored. In general, our ability to manipulate organic molecules is influenced by several factors that include the nature of functional groups near sites of reaction, the nature of reagents utilized in reactions, and the nature of potential leaving groups. In addition, these three factors impart further variables that influence the course of organic reactions. For example, the nature of the reagents used in given reactions can influence the reaction mechanisms and ultimately the reaction products. By recognizing the interplay between these factors and by applying principles of arrow‐pushing, which in reality represents bookkeeping of electrons, reasonable predictions of organic mechanisms and products can be realized without the burden of committing to memory the wealth of organic reactions studied in introductory courses. In this chapter, the concept of arrow‐pushing is defined in context with various reaction types, functional groups, mechanism types, reagents/nucleophiles, and leaving groups.
1.1 DEFINITION OF ARROW‐PUSHING
Organic chemistry is generally presented through a treatment of how organic chemicals are converted from starting materials to products. For example, the Wittig reaction (Scheme 1.1) is used for the conversion of aldehydes and ketones to olefins, and the Diels–Alder reaction (Scheme 1.2) is used for the formation of six‐membered ring systems and treatment of alkyl halides with reagents such as tributyltin hydride (Scheme 1.3), resulting in removal of the associated halides. However, by presenting these reactions as illustrated in Schemes 1.1, 1.2, and 1.3, no explanation is provided as to how the starting materials end up as their respective products.
Scheme 1.1Example of the Wittig reaction.
Scheme 1.2Example of the Diels–Alder reaction.
Scheme 1.3Example of a tin hydride dehalogenation.
By definition, the outcome of any chemical reaction is the result of a process resulting in the breaking and formation of chemical bonds. Referring to material covered in most general chemistry courses, bonds between atoms are defined by sets of two electrons. Specifically, a single bond between two atoms is made of two electrons, a double bond between atoms is made of two sets of two electrons, and a triple bond between atoms is made of three sets of two electrons. These types of bonds can generally be represented by Lewis structures using pairs of dots to illustrate the presence of an electron pair. In organic chemistry, these dots are most commonly replaced with lines. Figure 1.1 illustrates several types of chemical bonds using both electron dot notation and line notation. The list of bond types shown in Figure 1.1 is not intended to be exhaustive with respect to functional groups or potential combinations of atoms.
Figure 1.1Examples of chemical bonds.
While chemical bonds are represented by lines connecting atoms, electron dot notation is commonly used to represent lone pairs (nonbonding pairs) of electrons. Lone pairs are found on heteroatoms (atoms other than carbon or hydrogen) that do not require bonds with additional atoms to fill their valence shell of eight electrons. For example, atomic carbon possesses four valence electrons. In order for carbon to achieve a full complement of eight valence electrons in its outer shell, it must form four chemical bonds, leaving no electrons as lone pairs. Atomic nitrogen, on the other hand, possesses five valence electrons. In order for nitrogen to achieve a full complement of eight valence electrons, it must form three chemical bonds, leaving two electrons as a lone pair. Similarly, atomic oxygenpossesses six valence electrons. In order for oxygen to achieve a full complement of eight valence electrons, it must form two chemical bonds, leaving four electrons as two sets of lone pairs. In the examples of chemical bonds shown in Figure 1.1, lone pairs are not represented in order to focus on the bonds themselves. In Figure 1.2 the missing lone pairs are added where appropriate. Lone pairs are extremely important in understanding organic mechanisms because they frequently provide the sources of electron density necessary to drive reactions as will be discussed throughout this book.
Figure 1.2Examples of chemical bonds and lone pairs.
As organic reactions proceed through the breaking and subsequent formation of chemical bonds, it is now important to understand the various ways in which atomic bonds can be broken. In general, there are three ways in which this process can be initiated. As shown in Scheme 1.4, the first is simple separation of a single bond where one electron from the bond resides on one atom and the other electron resides on the other atom. This type of bond cleavage is known as homolytic cleavage because the electron density is equally shared between the separate fragments and no charged species are generated. It is this process that leads to free radical reactions.
Scheme 1.4Illustration of homolytic cleavage.
Unlike homolytic cleavage, heterolytic cleavage (Scheme 1.5) of a chemical bond results in one species retaining both electrons from the bond and one species retaining no electrons from the bond. In general, this also results in the formation of ionic species where the fragment retaining the electrons from the bond becomes negatively charged while the other fragment becomes positively charged. These charged species then become available to participate in ion‐based transformations governed by the electronic nature of reactants or adjacent functional groups.
Scheme 1.5Illustration of heterolytic cleavage.
Having introduced homolytic cleavage and heterolytic cleavage as the first two ways in which bonds are broken at the initiation of organic reactions, attention must be drawn to the possibility that bonds can rearrange into lower energy configurations through concerted mechanisms where bonds are simultaneously broken and formed. This third process, associated with pericyclic reactions, is illustrated in Scheme 1.6 using the Cope rearrangement and does not involve free radicals or ions as intermediates. Instead, it relies on the overlap of atomic orbitals, thus allowing the transfer of electron density that drives the conversion from starting material to product. Regardless, whether reactions rely on free radicals, ions, or concertedmechanisms, all can be explained and/or predicted using the principles of arrow‐pushing.
Scheme 1.6Illustration of a concerted reaction (Cope rearrangement).
Arrow‐pushing is a term used to define the process of using arrows to conceptually move electrons in order to describe the mechanistic steps involved in the transition of starting materials to products. An example of arrow‐pushing is illustrated in Scheme 1.7 as applied to the Cope rearrangement introduced in Scheme 1.6. As the Cope rearrangement proceeds through a concertedmechanism, the movement of electrons is shown in a single step. As will become apparent, arrow‐pushing is broadly useful to explain even very complex and multistep mechanisms. However, while arrow‐pushing is useful to explain and describe diverse mechanistic types, it is important to note that different types of arrows are used depending on the type of bond cleavage involved in a given reaction. Specifically, when homolytic cleavage is involved in the reaction mechanism, single‐barbed arrows are used to signify the movement of single electrons. Alternatively, when heterolytic cleavage or concerted steps are involved in the reaction mechanism, double‐barbed arrows are used to signify the movement of electron pairs. Schemes 1.8 and 1.9 illustrate the use of appropriate arrows applied to homolytic cleavage and heterolytic cleavage, respectively.
Scheme 1.7Illustration of arrow‐pushing applied to the Cope rearrangement.
Scheme 1.8Application of arrow‐pushing to homolytic cleavage using single‐barbed arrows.
Scheme 1.9Application of arrow‐pushing to heterolytic cleavage using double‐barbed arrows.
1.2 FUNCTIONAL GROUPS
Having presented the concept of arrow‐pushing in context of the steps that initiate chemical reactions, some factors impacting the flow of electrons leading from starting materials to products can now be explored.
As a general rule, electrons will flow from atomic centers high in electron density to atomic centers low in electron density. This dependence on polarity is similar to the way that electricity flows in an electrical circuit. If there is no difference in electrical potential between the ends of a wire, electricity will not flow. However, if a charge is applied to one end of the wire then the wire becomes polarized and electricity flows. If we imagine a simple hydrocarbon such as ethane, we can analogously relate this system to a non‐polarized wire. Both carbon atoms possess the same density of electrons and thus ethane has no polarity. However, if functionality is added to ethane through the introduction of groups bearing heteroatoms, the polarity changes and electron flow can be used to induce chemical reactions. These heteroatom‐bearing groups are known as functional groups and serve to donate or withdraw electron density.
While functional groups can be either electron donating or electron withdrawing, these properties rely upon the specific heteroatoms the functional group is composed of and the configuration of these heteroatoms relative to one another. With respect to the specific heteroatoms, electronegativity of the heteroatoms is the driving force influencing polarity. Thus, the more electronegative the atom, the greater the affinity the atom has for electrons. As a calibration for electronegativity, the Periodic Table of the Elements serves as an excellent resource. Specifically, moving from left to right and from bottom to top, electronegativity increases. For example, nitrogen is more electronegative than carbon, and oxygen is more electronegative than nitrogen. Likewise, fluorine is more electronegative than chlorine, and chlorine is more electronegative than bromine. It is important to note that the influence of electronegativity on polarity is so strong that simply replacing a carbon atom with a heteroatom is enough to impart strong changes in polarity compared to the parent structure. Figure 1.3 illustrates common organic functional groups as components of common organic molecules.
Figure 1.3Common organic functional groups.
Polarity in organic molecules is generally represented as partial positive (δ+) charges and partial negative (δ−) charges. These partial charges are induced based on the presence of heteroatoms either by themselves or in groups. These heteroatoms, as described in the previous paragraph and in Figure 1.3, define the various functional groups. Returning to the example of ethane as a nonpolar parent, Figure 1.4 illustrates how polarity changes as influenced by the introduction of heteroatoms and functional groups. As shown, heteroatoms such as nitrogen, oxygen, and halogens, due to their increased electronegativities compared to carbon, adopt partial negative charges. This causes adjacent carbon atoms to take on partial positive characteristics. As illustrated in Figure 1.4, charges on carbon atoms are not limited to positive. In fact, when a carbon atom is adjacent to a positive or partial positive center, it can adopt partial negative characteristics. This ability to control the charge characteristics of carbon atoms leads to the ability to create reactive centers with a diverse array of properties. By taking advantage of this phenomenon of induced polarity, we are able to employ a multitude of chemical transformations, allowing for the creation of exotic and useful substances relevant to fields ranging from material science to food science to agriculture to pharmaceuticals.
Figure 1.4How functional groups influence polarity.
1.3 NUCLEOPHILES AND LEAVING GROUPS
As discussed in Section 1.2, polarity is the key to the ability to initiate most chemical reactions. However, this is not the only factor influencing the ability to initiate reactions. In fact, the type of reaction on a given molecule is often dependent on the nature of the solvent and the reagents used. For example, solvent polarity can influence the reaction rate and the reaction mechanism. Furthermore, the nature of the chemical reagents used can affect the reaction mechanism and the identity of the final product. The following definitions will be key to understanding the terminology used in the following chapters.
Nucleophiles are reagents that have an affinity for positively charged species or electrophiles. In organic reactions, nucleophiles form chemical bonds at sites of partial positive charge through donation of their electrons. This generally results in the need for the starting compound to release a leaving group. An example of a nucleophilic reaction is shown in Scheme 1.10 where Nu: represents the nucleophile and L: represents the leaving group. Arrow‐pushing is used to illustrate the movement of the electron pairs.
Scheme 1.10Example of a nucleophilic reaction.
Leaving groups are the components of chemical reactions which detach from the starting material. Referring to Scheme 1.10, the leaving group, L:, ends up separate from the product while the nucleophile, Nu:, becomes incorporated into the product. Furthermore, while an initial evaluation of the material covered in an introductory organic chemistry course may seem overwhelming, the majority of the material covered can be reduced to the principles illustrated in the single reaction shown in Scheme 1.10.
1.4 SUMMARY
In this chapter, the basic principle of arrow‐pushing was introduced in the context of organic reactions driven by homolytic cleavage, heterolytic cleavage, or concerted mechanisms. Furthermore, the concept of polarity was introduced using heteroatoms and common organic functional groups. This discussion led to the definitions of nucleophiles and leaving groups in the context of simple nucleophilic reactions. Finally, by pulling these ideas together, the concept of approaching the study of mechanistic organic chemistry from a simplified perspective of understanding the principles of arrow‐pushing was introduced.
While characteristics such as homolytic cleavage, heterolytic cleavage, and concerted mechanisms were discussed, the principles of arrow‐pushing apply equally to all. However, with respect to heterolytic cleavage, an understanding of the properties of organic acids and bases is essential in order to understand underlying organic mechanisms. These concepts are introduced in Chapters 3 and 4.
PROBLEMS
Add arrow‐pushing to explain the following reactions:
Place the partial charges on the following molecules:
