By James Ashenhurst
Book Review: “Arrow Pushing in Organic Chemistry” by Daniel E. Levy
Last updated: March 27th, 2019
One common refrain of educators (and others) who teach organic chemistry is “don’t memorize! understand what’s going on”. For someone who is new to studying the subject, understanding what that phrase actually means is not always clear. People who want a clearer idea of what “understanding” versus memorization actually means in practice can refer to Arrow Pushing in Organic Chemistry – An Easy Approach to Understanding Reaction Mechanisms by Daniel E. Levy (Wiley, 2008). The essential premise of this book is that most reactions in organic chemistry can be reduced to the study of interactions between organic acids and bases. This includes the skills of analyzing molecules to determine the most acidic proton in a molecule, the most reactive sites, the best reactants (nucleophiles and electrophiles) and predicting products. What Dr. Levy has set out to do in this book is to lay out a strategy for understanding organic chemistry based on the general principles of electron flow.
Levy begins the book by saying that when he was learning organic chemistry, he followed what everyone else did: made an endless list of flash cards listing specific chemical reactions and their names. However he found that:
…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…. it was not 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. “
What is Arrow Pushing?
Arrow pushing is a technique used to show the conceptual pushing of electrons. It can be used to show both homolytic and heterolytic cleavage, although the focus here is on heterolytic processes. Electrons flow from areas of high electron density to low electron density, much like current in a wire. These areas of high and low electron density are introduced through the presence of groups bearing heteroatoms (called functional groups). The ultimate driving force for this polarity is the electronegativity of the heteroatoms. Nucleophiles are reagents that have an affinity for positively charged species or electrophiles. 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, which is a component of a chemical reaction that detaches from the starting material.
An acid is a molecule that liberates hydrogen ions. Acid dissociation is an equilibrium process that results in the formation of two ionic (charged) species, a proton and an anion. The position of the equilibrium is measured by a term called the acid dissociation constant, or pKa. The degree to which a species is acidic is dependent on the stability of the anion (A- ) that forms during dissociation. There are several important factors dictating the stability of the anion. Among these are polar solvents (which can stabilize anions through charge-charge interactions), inductive effects (which will stabilize or destabilize the negative charge of the anion), and resonance (which stabilizes the anion through delocalization of the negative charge).
Bases and Nucleophiles
Bases are molecules that have an affinity for protons. In order for an acid base reaction to occur, the conjugate acid of a given base must have a pKa value higher than the pKa value associated with the proton of interest. Besides anionic species, atoms and functional groups that possess lone pairs (such as amines and alcohols) will also have measurable basicity. Although some of these species may not be practical as bases (e.g. the oxygen of carbonyls) the basicity of these lone pairs can be important in helping to activate neighboring atoms toward nucleophilic attack.
Most bases are generally able to function as nucleophiles, which are species that have an affinity for positive charge. The degree of nucleophilicity of a given molecule is dependent on several factors, including its basicity, as well as its polarizability, steric factors, and solvent effects. Finally, leaving groups are the molecular fragments that detach from the parent molecule during the course of the reaction. The trends which apply for nucleophilicity roughly apply to leaving groups in the reverse direction. In particular acidity trends are important for assessing leaving group ability. Generally speaking, the weaker the conjugate base, the better the leaving group.
SN2 Substitution Reactions
In the SN2 reaction a nucleophile displaces a leaving group, generating a new molecule. SN2 reactions proceed with inversion of configuration at carbon. In assessing whether a given SN2 reaction will occur, note that SN2 reactions will proceed when incoming nucleophiles are more nucleophilic than their leaving groups. When identifying sites where SN2 reactions can occur, the following criteria should be met: 1) SN2 reactions occur at tetrahedral carbon atoms 2) SN2 reactions occur at molecular sites bearing the greatest degree of positive charge 3) SN2 reactions occur at sites that are sterically accessible to the incoming nucleophile (that is to say, the rate decreases in the order methyl > primary carbon > secondary carbon > tertiary carbon). Finally, if a partial positive charge on a carbon can be delocalized through resonance, a special type of substitution reaction called the SN2′ reaction can occur.
SN1 Substitution Reactions
The SN1 reaction is also a nucleophilic displacement of a leaving group, but instead of the nucleophile and electrophile coming together at the same time (as in the SN2) the reaction proceeds first through dissociation of the leaving group followed by nucleophilic attack. Dissociation of the leaving group leads to formation of a carbocation. A common type of SN1 reaction is solvolysis, where a molecule with a good leaving group is dissolved in a polar solvent. Employing a polar solvent helps to stabilize the positively charged carbocation and its anion. Carbocations derived from alkyl groups are sp2 hybridized with a trigonal planar geometry. Carbocations can be stabilized by donation of lone pairs by adjacent heteroatoms, by resonance, or by hyperconjugation, where adjacent C-H bonds can donate electron density to sites of neighboring electron deficiency. Since there will be more adjacent C-H bonds in a tertiary carbocation, the order of carbocation stability is generally tertiary > secondary > primary.
Carbocations are reactive species, and other products may form in addition to the simple substitution reaction that is anticipated. In particular, 1,2-shifts of hydride and alkyl groups may sometimes be observed. In order to occur it should be noted that each of these reactions requires proper alignment between the empty p orbital and the hydride or alkyl group that is migrating.
Another reaction of carbocations is loss of a proton from the carbon adjacent to the carbocation. This results in the formation of a double bond and is referred to as an elimination reaction, unimolecular (E1). Elimination reactions can also occur when a strong base is added to a molecule with a good leaving group, resulting in a new double bond. Because this mechanism requires the reaction of two species, this is referred to as Elimination, bimolecular (E2). Both these elimination reactions require proper overlap of the C-H bond being removed with either the empty p orbital (E1) or the leaving group (E2).
Just as elimination reactions led to the formation of unsaturated compounds (e.g. double bonds), addition reactions remove sites of unsaturation. For example, carbon carbon double bonds (olefins) are generally electron rich, which allows them to react as nucleophiles under certain conditions. For example, olefins will react with halogens, protic acids, and other electrophiles to produce substituted alkanes. These reactions typically proceed through positively charged intermediates, which then undergo attack by a nucleophile. Unlike reactions of halogens, addition of acids results in formation of asymmetrical products. Markovnikoff’s rule states that when an acid is added across a double bond, the conjugate base adds to the more substituted carbon atom.
Replacing one of the olefinic carbon atoms with oxygen results in formation of a polar carbonyl. Nucleophiles are drawn to the carbonyl carbon atoms in mych the same way that nucleophiles participate in SN2 reactions. Nucleophiles such as Grignard reagents, organolithium reagents and potassium cyanide are useful for adding to carbonyls to give alcohols, a reaction known as 1,2 addition. In analogy to the SN2′ reaction, if there is a double bond adjacent to the carbonyl, certain nucleophiles can similarly add at this position, a reaction known as “conjugate addition” or 1,4 addition. Finally, if the carbonyl is an ester, acid halide, or other carboxylic acid derivative containing a good leaving group, the initial product of nucleophilic addition can collapse to give a carbonyl and a leaving group, a reaction known as addition-elimination.
Using the principles described previously and with an understanding of the mechanistic components of these reactions, readers should be able to apply these concepts to predict reaction products in the many functional group manipulations, oxidation/reduction reactions, name reactions, and other reactions using specific reagents that are included in a typical introductory organic chemistry course. Through application of arrow pushing, a broader and deeper understanding of organic chemistry can be derived.
Is “Arrow Pushing in Organic Chemistry” worth reading?
Arrow Pushing in Organic Chemistry assumes some familiarity with bond-line notation, stereochemistry, and functional groups. So if you’re looking for a book that starts from scratch and holds your hand through every step, Arrow Pushing in Organic Chemistry is probably not the best book for you. But if you want to get a deeper picture of the principles by which the key reactions in organic chemistry operate, Arrow Pushing in Organic Chemistry is an excellent guide, particularly for Org 1 topics. In particular, the book would be very rewarding for those who learn best by doing problems (problems are the best way to learn organic chemistry). One key strength of this book is that almost half of it is devoted to problems, and it contains very thorough answers to each one. A student who takes the time to both read and do the problems in this book will be very well prepared not only for understanding organic chemistry, but also the key chemical principles one encounters in biochemistry and elsewhere. I would especially recommend Arrow Pushing in Organic Chemistry to chemistry majors and also people who took organic chemistry but didn’t feel that they truly understood what was going on and now want to solidify their knowledge.