Nucleophilic means "nucleus loving." A nucleophilic species has electrons willing to donate to an electrophile, creating a new bond. Bases are a subclass of nucleophiles that donate their electrons to protons. The nucleophilicity of various species is compared by the reaction rates of reactions where these species act as nucleophiles. Nucleophilic addition reactions are important reactions that allow us to convert a carbonyl into a range of other functional groups. In nucleophilic addition, a nucleophile reacts with an electrophile to form a single molecular product.
A substitution reaction is any reaction in which an atom, ion, or functional group in a molecule is substituted by another atom, ion, or group. Organic compounds with good leaving groups, such as alkyl halides, serve as excellent starting materials for substitution reactions. Depending on the type of atom or group that acts as a substituent, substitution reactions generally fall into three classes: Nucleophilic substitution, Electrophilic substitution reactions, and Radical substitution reactions.
Image from Labste'rs Nucleophilic Substitution Reaction: Alkyl halides substrates Virtual Lab,
Why do students struggle to learn nucleophilic addition and substitution reactions?
1. Lack of basic knowledge
Before going for any topic, the basics of the topic must be cleared. To teach the organic compound, you must first clear the concepts of basic organic chemistry. They don't know about the functional groups, attacking and leaving groups in any compound. Before going further, you must clarify what saturated and unsaturated organic compounds are. They also face difficulties when they have to identify any organic compound by the IUPAC name.
2. A large number of reactions and reaction mechanisms
In organic chemistry, there is more than one possible reaction and reaction mechanism. Students face difficulties selecting the major pathway for the compounds, so you must be clear when there is more than one functional group, what the major product will be, and which mechanism it will follow. If there is more than one attacking and leaving group, students get confused about which group will attack and which is the good leaving group. These terms must be cleared first to study any organic compound and its reactions.
3. It’s conceptually challenging
Theoretical studies of organic compounds and reactions are tricky because most compounds have 3D structures. Organic reactions involve complex reactions mechanisms that are difficult to understand theoretically. You can use 3D models of organic molecules so that students easily understand the structures of molecules. For reactions, mechanisms must use video graphics; if possible, draw the complete mechanism along with arrows identifying the reaction sites and reacting groups.
5 ways to make nucleophilic addition and substitution reactions interesting for students
1. Review the basics of organic reactions
Before going to organic reactions following terms must be cleared:
Regioselectivity: Regioselective can describe any process that favors bond formation at a particular atom over other possible atoms. The ‘Regio-’ prefix comes from the Latin for ‘Region’ or an area of something. A reaction has high regioselectivity when one major product dominates due to the reaction being highly favored at one atomic position over another.
Stereochemistry: Stereochemistry relates to the three-dimensional arrangement of atoms and molecules and the effect of this spatial arrangement on chemical reactions.
An attacking group is a part of a molecule that attacks a substrate or intermediate to produce the product. In organic reactions, it may be an electrophile or a nucleophile. Electrophiles are the attacking groups that make chemical bonds with nucleophiles by accepting the electron pair. In contrast, nucleophiles make chemical bonds by donating the electron pair to the substrate or the intermediate.
A leaving group is a part of a molecule that can break away (leave the molecule) during a reaction. The key factor contributing to a species' suitedness as leaving group is its basicity: The weaker the base, the better the leaving group. Halogens are often used as the leaving group, e.g., in alkyl halides. The general order of "ability to leave" for them is I > Br > Cl > F.
Steric effects are non-bonding molecular interactions that influence the shape and reactivity of ions and molecules. Steric effects resulting from repulsive forces between functional groups arise from overlapping electron clouds. Steric hindrance is slowing a chemical reaction rate due to steric bulk interactions. Steric hindrance usually refers to the interaction of intermolecular groups. Understanding steric hindrance can allow the design of chemical reactions to force regioselectivity or stereoselectivity in a reaction or to minimize undesirable side reactions.
A catalyst is a component in a chemical reaction that increases the reaction rate by changing the reaction mechanism. A catalyst is not used in the reaction and thus is often effective in sub-stoichiometric amounts.
A lone pair is a pair of valence electrons that do not take part in bonding.
A substrate is a chemical specie that is consumed during a chemical reaction to give a product.
2. Explain factors that contribute to nucleophilicity
Four key factors contribute to a species' nucleophilicity:
A nucleophile reacts by donating electrons. This means, that the higher the electron density on a species, the more nucleophilic it is, all other things being equal. Generally, a negatively charged species will be more nucleophilic than its neutral counterpart.
A nucleophile donates electrons to an electrophile, but to do so, it needs to be in close proximity to the electrophile. This can be hard if the nucleophile is a large and bulky molecule. In general, a smaller nucleophile is a stronger nucleophile!
Highly electronegative atoms have a high electron density but a high electron affinity, meaning that they attract electrons strongly. A nucleophile reacts by donating electrons, which a highly electronegative atom is less willing to do. Therefore, a less electronegative atom is more nucleophilic, all other things being equal.
Solvents can be either protic or aprotic. A protic solvent can participate in hydrogen bonding with the nucleophile, which causes the nucleophile to be cushioned by the solvent. This makes the nucleophile less reactive than if it was dissolved in an aprotic solvent.
3. Explain nucleophilic addition reaction
Nucleophilic addition reactions are important reactions that allow us to convert a carbonyl into a range of other functional groups. In nucleophilic addition, a nucleophile reacts with an electrophile to form a single molecular product.
Figure 1: General reaction scheme for nucleophilic addition reaction (Image source: Labster theory).
The Grignard reaction
The Grignard reaction is an organometallic chemical reaction in which an organomagnesium halide (also known as a Grignard reagent) adds to the carbonyl group of an aldehyde or ketone to form an alcohol. The Grignard reaction is one of the most important synthetic methods for forming carbon-carbon bonds.
Being extremely good nucleophiles, Grignard reagents are highly reactive compounds. This means that we would prepare these in situ in the lab just before we carry out our Grignard reaction. It also means we need to keep any trace of moisture out of our reaction. All glassware and solvents must be anhydrous (dry), and the reaction must be kept in a closed system where water and air cannot get in.
Once the Grignard reagent has been prepared, we can add a solution of our carbonyl compound (aldehyde or ketone) to the reagent to perform the Grignard addition reaction.
The final work-up step involves pouring the reaction mixture into a mixture of sulfuric acid and ice to break down the Grignard transition complex and produce our alcohol product.
4. Explain nucleophilic substitution reactions
Nucleophilic substitution is a classic chemical reaction in which an electron-rich nucleophile selectively attacks an electrophilic center to substitute a leaving group.The electron pair (:) from the nucleophile attacks the substrate and uses the lone pair to form a new R-Nu bond, while the leaving group (LG) leaves with an electron pair. The nucleophile might be negatively charged or neutral, whereas the substrate is usually neutral or positively charged.
Nucleophilic substitution can occur via one of two competing reaction mechanisms. The two main mechanisms are the SN1 reaction and the SN2 reaction. The S denotes 'substitution,' N for 'nucleophilic', and the number represents the kinetic order of the reaction - or the number of reagents involved in the rate-limiting step. There are several factors that could affect whether a substitution reaction occurs via the SN1 or SN2 reaction mechanism, not limited to the high nucleophilicity of the nucleophile, willingness of the leaving group, solvent type, and steric bulk of the alkyl substrate.
The SN1 Reaction
An SN1 reaction is a nucleophilic substitution reaction in which the rate-determining step involves one component. The reaction name derives from S standing for 'substitition', N for 'nucleophilic', and 1 denoting the kinetic order of the reaction - or simply the number of reaction components involved in the rate-determining step.
SN1 reactions are two-step, unimolecular reactions and proceed via an intermediate carbocation. The first carbocation-forming step is the slower of the two and therefore determines the rate of the reaction. The second step involves the rapid attack of the nucleophile to the newly-formed carbocation. The reaction has two transition states, one before and one after the intermediate. Lowering the energy of these transition states will lower the activation energy of the reaction.
Figure 4: General SN1 reaction mechanism. L is the leaving group. Nu is the nucleophile. The carbocation intermediate is an electrophile (Image source: Labster theory).
The SN2 Reaction
An SN2 reaction is a nucleophilic substitution reaction in which the rate-determining step involves two components. The reaction name derives from S standing for 'substitition', N for 'nucleophilic', and the 2 denoting the kinetic order of the reaction - or simply the number of reaction components involved in the rate-determining step.
An SN2 reaction arises from combining a good nucleophile and a substrate with an electrophilic reaction center attached to a good leaving group. A good example of this is the carbon-halogen (C-X) bond you'd find in an alkyl halide.
Figure 5: General SN2 reaction mechanism. L is the leaving group. Nu is the nucleophile. The partially positive carbon is an electrophile (Image source: Labster theory).
Alkyl halides (also known as haloalkanes) are hydrocarbon compounds in which one or more of the hydrogen atoms have been replaced by a halogen atom (iodine, bromine, chlorine, or fluorine). Incorporating halogen atoms into a hydrocarbon changes the compounds' physical properties, affecting size, electronegativity, bond length, and strength.
Alkyl halides are ideal substrates for reactions that require a good leaving group. The high reactivity of alkyl halides can be explained in terms of the nature of the C-X bond. The differences in electronegativity between the carbon and halogen atoms create a highly polarized bond resulting in a slightly electropositive carbon and slightly electronegative halogen. This electron-deficient carbon becomes a hotspot for nucleophilic attack, making alkyl halides excellent substrates for nucleophilic substitution and elimination reactions.
In general - due to the steric bulk of three alkyl groups surrounding the halogen in tertiary alkyl halides - tertiary alkyl halides are far less reactive than the other classes and may only participate in elimination reactions. The general reactivity trend across alkyl halide classes is Primary > Secondary > Tertiary. However - this alkyl halide reactivity trend is reversed if the rate of a specific reaction (e.g., SN1 reaction) is determined by the formation of the most stable carbocation. In these situations, tertiary alkyl halides are highly favored as they would form the most stable reactive intermediate.
Other factors - like which C-X bond you need to break - also contribute to the alkyl halides' reactivity and the likelihood of a reaction occurring or not. In selecting the best halide starting material for a reaction - we also need to consider the strength of the C-X bond we are trying to break. C-F bonds are so strong that fluoroalkanes rarely react, so they don't make great starting materials. C-X bond strength falls as we go down the periodic table, meaning the weakly-bonded iodide is the most willing to leave the group, closely followed by bromide.
5. Use virtual lab simulations
With technological advances, it is much easier to explain complex and challenging processes with the help of simulations. Now, you can simulate experiments without the need for any valuable equipment.
In this regard, you can take help from Labster’s virtual lab simulations. These simulations engage students through interactive learning scenarios. Students dive into a 3D world, where they visually learn and apply their concepts to solving real-life problems.
In Labster’s interactive Nucleophilic Addition: Explore the Grignard Reaction Virtual Lab, you will learn the principles of the nucleophilic addition reaction and put your knowledge into practice by performing a Grignard reaction to synthesize a potential cancer drug candidate. You’ll have the chance to make a ground-breaking drug discovery!
In Labster’s interactive Nucleophilic Substitution Reaction: Alkyl halides substrates Virtual Lab, you will explore the factors that affect substitution reactions and learn how to promote different substitution mechanisms. Put your substitution expertise to the test by using retrosynthesis and reaction design principles to create an assortment of aroma molecules in developing exciting new beverage flavors for a craft brewery!