A Primer On Organic Reactions
What Makes A Good Nucleophile?
Last updated: September 24th, 2022 |
Factors That Determine Whether A Species Is A Good Nucleophile
If you read the last post, you’ll recall that a nucleophile is a species that donates a pair of electrons to form a new covalent bond. Nucleophilicity is measured by comparing reaction rates; the faster the reaction, the better (or, “stronger”) the nucleophile.
Table of Contents
- Reminder: Nucleophilicity Is Measured By Reaction Rate
- The Role Of Charge: Nucleophilicity Increases As An Atom’s Electron Density Increases
- Electronegativity: Across The Periodic Table, Nucleophilicity Increases With Decreasing Electronegativity
- The Choice Of Solvent (Polar Protic vs. Polar Aprotic) Can Drastically Affect Nucleophilicity Trends
- Nucleophilicity Decreases With Increasing Steric Hindrance (“Bulkiness”)
- (Advanced) References and Further Reading
When discussing nucleophilicity we’re specifically talking about donating a pair of electrons to an atom other than hydrogen (usually carbon). When a species is donating a pair of electrons to a hydrogen (more specifically, a proton, H+) we call it a base.
This post attempts to address one of the most vexing question to students of organic chemistry. What are the factors that make a good nucleophile?
For our purposes, there are at least four key factors contributing to nucleophilicity.
- Steric hindrance
The first two should hopefully be familiar from the discussion of what makes something a strong base. After all, basicity and nucleophilicity essentially describe the same phenomenon, except basicity concerns donation of lone pairs to hydrogen, and nucleophilicity concerns donations of lone pairs to all other atoms. It’s the third and fourth points where extra factors come into play.
Since a nucleophile is a species that is donating a pair of electrons, it’s reasonable to expect that its ability to donate electrons will increase as it becomes more electron rich, and decrease as it becomes more electron poor, right? So as electron density increases, so does nucleophilicity.
3. Electronegativity: Across The Periodic Table, Nucleophilicity Increases With Decreasing Electronegativity
Assuming an atom has a pair of electrons to donate, the ability of a species to donate that pair should be inversely proportional to how “tightly held” it is. The key factor for determining how “tightly held” an electron pair is bound is the familiar concept of electronegativity. Bottom line: as electronegativity increases, nucleophilicity decreases. Note: It’s important to restrict application of this trend to atoms in the same row of the periodic table; for instance, C N O F, or Si P S Cl. Going down the periodic table, another factor comes into play (next)
4. The Choice Of Solvent (Polar Protic vs. Polar Aprotic) Can Drastically Affect Nucleophilicity Trends
Nucleophilicity is not a property inherent to a given species; it can be affected by the medium it’s in (otherwise known as “the solvent”). [For an introduction to the different classes of solvents, see this post]
A polar protic solvent can participate in hydrogen bonding with a nucleophile, creating a “shell” of solvent molecules around it like mobs of screaming teenage fans swarming the Beatles in 1962.
In so doing, the nucleophile is considerably less reactive; everywhere it goes, its lone pairs of electrons are interacting with the electron-poor hydrogen atoms of the solvent.
The ability of nucleophiles to participate in hydrogen bonding decreases as we go down the periodic table. Hence fluoride is the strongest hydrogen bond acceptor, and iodide is the weakest. This means that in protic solvent, the lone pairs of iodide ion will be considerably more “free” than those of fluoride, resulting in higher rates (and greater nucleophilicity).
A polar aprotic solvent does not hydrogen bond to nucleophiles to a significant extent, meaning that the nucleophiles have greater freedom in solution. Under these conditions, nucleophilicity correlates well with basicity – and fluoride ion, being the most unstable of the halide ions, reacts fastest with electrophiles.
[Often asked: why don’t we care about “non polar solvents” here? Remember “like dissolves like”? If we want a reaction to take place, we need to use solvents that will actually dissolve our nucleophile. Many nucleophiles are charged species (“ions”) – they don’t dissolve in non-polar solvents.]
Since, when discussing nucleophilicity, we’re often discussing reactions at carbon, we have to take into account that orbitals at carbon that participate in reactions are generally less accessible than protons are. An effect called “steric hindrance” comes into play.
So comparing several deprotonated alcohols, in the sequence methanol – ethanol – isopropanol – t-butanol, deprotonated methanol (“methoxide”) is the strongest nucleophile, and deprotonated t-butanol (“t-butoxide”) is the poorest (or “weakest”) nucleophile.
Note 1. Are there other factors? Yes. This list of four covers the basics, but several other factors are worth noting. 1) the identity of the electrophile 2) atoms with lone pairs adjacent to the nucleophile 3) in the case of ions, the identity of the counter-ion [i.e. positively charged species] can be significant.
- Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides
Gardner Swain and Carleton B. Scott
Journal of the American Chemical Society 1953, 75 (1), 141-147
This paper features one of the earliest nucleophilicity scales (Table II).
- Correlation of Relative Rates and Equilibria with a Double Basicity Scale
John O. Edwards
Journal of the American Chemical Society 1954, 76 (6), 1540-1547
This paper also attempts to develop a nucleophilicity scale, correlating nucleophilicity with other chemical properties (basicity and reduction potential).
- Reactivity of Nucleophilic Reagents toward Esters
William P. Jencks and Joan Carriuolo
Journal of the American Chemical Society 1960, 82 (7), 1778-1786
One of the first papers describing the “alpha effect”, the increased nucleophilicity of an atom due to the presence of an adjacent (alpha) atom with lone pair electrons.
- The rate of displacement of toluene-p-sulphonate relative to bromide ion. A new mechanistic criterion
H. M. R. Hoffmann
J. Chem. Soc. 1965, 6753-6761
- The Factors Determining Nucleophilic Reactivities
John O. Edwards and Ralph G. Pearson
Journal of the American Chemical Society 1962, 84 (1), 16-24
This paper features a rudimentary nucleophilicity scale, the order being HS– > I– > CN– > Br– > Cl– > HO– > F– in polar protic solvents for attack on R-O-O-R. This paper also discusses the difference between nucleophilicity and basicity, a common source of confusion for students.
- Chemical reactivity and the concept of charge- and frontier-controlled reactions
Journal of the American Chemical Society 1968, 90 (2), 223-234
Tables IX and X also support the same nucleophilicity order on the basis of MO calculations. This paper is the origin of the familiar “Klopman equation”, which treats bonding interactions as consisting of a charge component and an orbital overlap component.
- Do general nucleophilicity scales exist?
Herbert Mayr and Armin R. Ofial
Phys. Org. Chem. 2008, 21 (7-8), 584-595
Prof. Herbert Mayr (LMU) has done tremendous work in quantifying and developing scales for nucleophilicity and electrophilicity. As Prof. Mayr explains in this paper, the challenge is developing suitable reference electrophiles when trying to compare similar nucleophiles, and vice-versa. Several challenging experimental techniques had to be employed for this work, including stopped-flow techniques and laser flash photolytic generation of reactive intermediates.