Summary of electrophilic aromatic substitution reactions

• 3. Substituents – Activation: Electron-donating groups at a ring increase nucleophilicity and reactivity. Electron-withdrawing groups work the opposite.
• 4. Substituent – Regioselectivity: Activators lead to ortho and para products. Deactivating groups direct meta (excl. halogens).
• 5. Examples: TNT synthesis nicely exemplifies ring activation. Pharmaceuticals use electrophilic aromatic substitution – sometimes with heterocycles!
• 6. Orbitals: Addition is fastest where overlap of donor (HOMO) and acceptor (LUMO) is best. However, orbital models do not explain the full story!
• Common mistakes and reaction examples at the end!

1. mechanism of electrophilic aromatic substitution

So what is electrophilic aromatic substitution?
Substitution as it replaces a C-H bond at an aromatic ring with a new C-E bond.
Electrophilic because our new E group was introduced as an electrophile.

Due to its aromaticity, benzene is relatively unreactive. Unlike alkenes, strong electrophiles give substitution products and not addition products.

Because our new group is an electrophile, the double bond of the aromatic ring has to be the nucleophile (just like in electrophilic additions)! Here’s how to identify nucleophiles vs electrophiles.
Note that the electrophile can be a neutral molecule that’s positively polarized, it does not have to be positively charged.

Note: The order is ‘form C-E, then break C-H’. While the other way around can work, it requires different reaction conditions (very strong base to deprotonate C-H) and is not as broadly applicable.

Let’s see what we can learn from this energy diagram.
1. One of the double bonds attacks the electrophile (here: NO₂⁺). Because this breaks the aromaticity of the starting material, the step requires quite a bit of activation energy (the molecule has to have energy to climb the hill of TS1).

2. The addition product is a carbocation (the double bond was ‘invested’ by one carbon to form the bond with E⁺, the other carbon has one electron less in its proximity and is now a non-aromatic carbocation). The positive charge sits next to the other double bonds , so it is somewhat stabilized and delocalized. This is a real intermediate whereas the transition states are just “snapshots at maximum energy”. This is also called Wheland intermediate or sigma complex.

3. The deprotonation occurs quite easily (the hill to TS2 is lower than the first one) and gives the stable substituted aromatic product. By the way, you don’t need to add base (e.g., KOH) for this step; the proton will get lost to other molecules present in the reaction or solvent. If the final product is lower in energy vs. starting material (more specifically, “enthalpy”), the reaction is exothermic.

But benzene is very simple and boring. In sections 2-4, we cover:
2. What types of electrophiles we can add and how we generate them
3. How other ring substituents can accelerate or slow down this reaction (activation)
4. How other ring substituents influence where the reaction occurs (regioselecitvity)

By the way, this is an old reaction! Pioneering work came from the Brit Armstrong in the 1880s already, and the American George Wheland in the 20th century.

Source: J. Chem. Soc., Trans., 1887, 51, 258

2. Key electrophilic aromatic substitution reactions

1. Bromination or chlorination: Uses molecular bromine or chlorine to form a C-Br or C-Cl bond, needs Lewis acid
2. Friedel Crafts alkylation & acylation: Forms a C-C bond, needs Lewis acid
3. Nitration: Incorporation of a nitro group (-NO₂), needs acid
4. Sulfonation: Incorporation of a sulfonic acid (-SO₃H), needs acid

These reactions have the same fundamental mechanism… but they differ in how they generate their reactive electrophile. They all use some sort of reagent (green/purple boxes) to get to the true electrophilic species that is attacked by the aromatic ring.

Bromination, chlorination and Friedel-Crafts reactions use a Lewis acid (=electrophilic metal compounds that things with electron pairs can coordinate to). This makes the Br, Cl, R or C(O)R centers more positively polarized, so they are more reactive with the double bond.

Nitration and sulfonation use a ‘normal’ acid (e.g., sulfuric acid) to protonate the reactants and activate them into more electrophilic species. Nitration is a particularly useful reaction as the group can converted to amino or hydroxyl groups.

After initial electrophile generation, all reactions follow the same steps and experience the same substituent effects (Sections 3. and 4. below). For full clarity, I might explain the nuances of each reaction in more detail in future posts.

There are two important points I want to point out on the halogenation reactions above: bromination and chlorination.

1) The typical conditions are bromine or chlorine + Lewis acid, but students will see in more advanced classes that there are other sources of electrophilic bromine or chlorine, like NBS or NCS (N-bromo/chloro-succinimide). I’ll probably explain these reagents more in separate posts.

In organic chemistry, there are always multiple ways of achieving a certain reaction or generating a certain reactive species, e.g., an electrophile.

2) Chemistry class syllabus usually ignores the other two cousins in the halogen family: iodine and fluorine. But that doesn’t mean that they cannot participate in these reactions! The point is more that these reactions are less common and straightforward, so they are usually not discussed.
If you can somehow generate activated/ polarized electrophiles (I⁺ or F⁺), they will also react with electron-rich aromatic rings just like Cl⁺ or Br⁺ shown above. While there are several options for iodination (using I₂ and additional reactants like acids), fluorination is more challenging and requires special reagents (not F₂). Aryl fluorides are thus usually made with nucleophilic aromatic substitution reactions like the Balz-Schiemann reaction.

3. Activating and deactivating groups

Recall: Our aromatic ring is a nucleophile, attracted to positive charge or polarization (which are electrophiles) because it has a decent amount of electron density.

The higher the electron-density in a ring, the more nucleophilic and more reactive it will be. This accelerates aromatic electrophilic substitution (higher reaction rate).

The electron-density of aromatic systems is influenced by the ring substituents. For example, nitrobenzene does not undergo normal Friedel-Crafts acylations.

Activating groups are electron-donating groups that increase nucleophilicity and reactivity of an aromatic ring, usually through mesomeric π effects (resonance).
Deactivating groups are electron-withdrawing groups that decrease nucleophilicity and reactivity either via inductive σ or mesomeric π effects.

Here are the key groups, (directional) strength and primary drivers.
Activators tend to be π donors (they push/ delocalize their electron pair into the ring) while deactivators tend to be π acceptors (they accept delocalized electrons, acting as an electron sink). If this doesn’t make sense, please read up on resonance.

Note the key counterintuitive example: halogens deactivate rings more strongly (due to their negative inductive σ effect, think high electronegativity) than they activate them (due to their mesomeric π effect, they have a free electron pair).

Another way to think about these groups is to revisit our energy diagram. The TS1 is partially positively charged and the intermediate is fully positively charged. Obviously, this positive charge will be very comfortable if there is a lot of electron density in the ring (charges like to be spread across and stabilized across atoms). Inversely, deactivators would make the intermediate unhappy. It’s like robbing someone who’s already very poor – not the best look.

4. Regioselectivity of aromatic electrophilic substitutions (Directing Effects)

All activating groups and halogens direct/favor substitution at ortho & para positions.
All deactivating groups excluding halogens direct/favor substitution at meta.

This regioselectivity can be rationalized by looking at the delocalization/ stabilization of the carbocation intermediate. Ortho and para additions favor carbocations where the positive charge sits next to the R group (either directly in case of ortho or after delocalization in the case of para).
If R can stabilize this positive charge as a σ or π electron donor, it will lower the energy of the carbocation and prefer these pathways over the meta addition.

Well if R is an electron-withdrawing group, the positive charge will absolutely hate being next to it (electron-sink next to something that already doesn’t have enough electrons). Thus, deactivating groups avoid ortho and para substitution and show meta selectivity.

Halogens are again sneaky. Regarding ring activation, their negative inductive effect (electron-withdrawal) overrides their positive mesomeric effect (electron pair donation). Regarding regioselectivity, the mesomeric effect is more important (deal with it). Outside of this special case, all groups follow the same rules.

5. Examples: Tnt & pHARMACEUTICALS

Our first example is 2,4,6-trinitrotoluene or TNT. One of many ways of synthesizing TNT is exactly what you think: take toluene and nitrate the heck out of it.
The issue? Substituent effects!
You see, while toluene is decently nucleophilic (it’s slightly activated through the methyl group), it becomes less and less reactive the more nitro groups are attached.

The first addition gives a mix of ortho and para substituted products. final nitration only occurs at high temperatures and use of fuming sulfuric acid, a particularly reactive form of sulfuric acid containing additional sulfur trioxide. There are easier and more clever ways to make TNT, but that shouldn’t be our focus.

You also see that just because TNT is deactivated towards electrophilic aromatic substitution, it still likes to explode violently. Reactivity is always relative. This is because detonation does not depend on the nucleophilicity of the aromatic ring 🙂

All reactions can happen either between two molecules (intermolecularly) or also within a single molecule (intramolecularly), if it has all the needed functional groups.

Most pharmaceuticals contain aromatic rings so we can find these reactions in their syntheses. One example is the drug lifitegrast. Its synthesis uses an intramolecular Friedel-Crafts alkylation to create the bicyclic core.

Final lesson: Heterocycles can also be nucleophiles! (aromatic ring with heteroatom)

The synthesis of the antibiotic metronidazole is very simple. The first step is nitration of the ring with carbon as the nucleophile. In the second step, the nitrogen acts as the nucleophile and undergoes a SN2 reaction with the alkyl chloride.

The five-membered rings pyrrole (heteroatom: N) and furan (heteroatom: O) are very electron-rich so we also often see them engage in electrophilic substitution reactions.

This is because the electron pair can stabilize the positive charge during the reaction mechanism. It’s like having an activating substituent effect within the ring!

6. Orbitals in aromatic substitutions

You probably shouldn’t read this section if you’re just learning about aromatic substitutions.
Drawing resonance structures is useful for us mortal humans. However, they are just tools and don’t correspond to reality. After all, we’re taught that “real structure” of a molecule is a mix of all “good” resonance structures. Advanced readers might ask themselves if orbitals can be useful predictors for aromatic reactions?

We won’t go through orbital theory here, but in short: When atoms form bonds in a molecule, their atomic orbitals combine to molecular orbitals. These can be filled with electrons or empty (or half-empty, if it’s a radical). The highest-energy filled orbital (HOMO, occupied) influences nucleophilic behavior and the lowest-energy empty orbital (LUMO, unoccupied) influences electrophilic behavior.

Looking at orbitals can be partially insightful. Here’s a 3D visualization of the early days of an electrophilic aromatic nitration. The HOMO of chlorobenzene (nucleophile) is getting close to the LUMO of the nitronium cation (electrophile). How will they add?

Electrophilic attack will occur where p orbitals contribute most to the π HOMO. The higher the overlap of donor (HOMO) and acceptor (LUMO), the faster the reaction.

You can see that on the ring, para and (to a slightly lesser degree) ortho positions have high contributions, while there is “almost no orbital” on meta. Any electrophilic attack at meta would thus be disfavored (low orbital overlap).
Our nitronium electrophile has a slightly higher LUMO localization at the central nitrogen, meaning the nitrogen is more electrophilic than the oxygens!

So, it looks like molecular orbitals can nicely predict the regioselectivity that we observe for chlorobenzene. So why don’t people talk about orbitals in the same fashion as they do e.g., for the Diels-Alder reaction?

1. Aromatic substitutions are one of the first reactions students, so going into orbitals would be an overkill that makes everyone hate chemistry even more.
2. More importantly, they don’t always give the full picture. Consider the HOMO of nitrobenzene below. This aromatic ring is deactivated and should attack meta.

We do see that the para position is not contributing to the HOMO at all, but the orbital structure does not tell us why there is no substitution at ortho! In this case, our resonance structure analysis is actually more helpful because it tells us that the ortho-position of nitro groups is particularly electron-poor.

There are other ways to analyse this, e.g., by computing charge density. Below you can find an atomic charge analysis for benzene, aniline and nitrobenzene. Ignore the method or units – simply put, a more negative number equals more electron-density at a given atom. More electron-density means more nucleophilic and more reactive towards electrophiles.

Question to you: What are important takeaways from this charge analysis?

Source: Phys. Chem. Chem. Phys., 2016, 18, 11624

Here are some thoughts:

1. Benzene: Obviously, hydrogens are more electropositive than carbons (they have a positive charge number). The molecule is symmetrical.
2. Aniline: Electron-density is higher at ortho and para relative to meta, explaining the directing effect. Relative to benzene, ortho and para have higher electron density, i.e., the aniline ring is more activated and reactive .
   Note that there is a lot of electron density on the amine as well! (Aniline can also react as a N-nucleophile! See common mistakes)
3. Nitrobenzene: Electron-density is highest at meta relative to ortho and para, explaining the directing effect. Now, the carbons all have lower electron density, in line with deactivation / lowering of reactivity due to the nitro group.
   Sidenote: The nitro group’s electron-withdrawing effect further polarizes the C-H hydrogens as they are more electron-poor in nitrobenzene.

So, orbital theory is sometimes more, and sometimes less useful. Generally, combining multiple models and perspectives gives us a better appreciation. For now, you can happily ignore orbitals for these reactions (but not for others!).

Common Mistakes in Electrophilic Aromatic Substitutions

Students can feel overwhelmed trying to remember effects or specific aromatic substitutions. This can lead to common mistakes or errors, including:

Mixing up ortho, para and meta: This is the first hurdle for new students. If you’re struggling with this, try remembering it this way: Meta is in the middle between the other two. The letter o comes before p in the alphabet, so ortho is closer to R.

Thinking too superficially: Although electrophilic substitution is the most common reaction of aromatic compounds you’ll see, don’t jump to conclusions too quickly. In this example, an acyl chloride (electrophile) would lead to O-acylation instead of electrophilic aromatic substitution. The benzene ring is deactivated and thus not nucleophilic enough.

Along the same lines: In section 6. Orbitals, we saw that charge analysis suggests high electron density at the nitrogen of aniline. Again, under many conditions, anilines can react as N nucleophiles instead of C nucleophiles (e.g., alkylation at nitrogen instead of at carbon).

Electrophilic or nucleophilic?: Get your terms right. Nucleophilic aromatic substitution reaction does not substitute C-H but rather C-X, where X is a good leaving group. This is the opposite of what saw for the electrophilic substitution: our aromatic ring is the electrophile here. This reaction is explained here.

Misunderstanding substituent effects: Abbreviations can be confusing, and we might wrongly believe a specific atom or an abbreviated group to be activating or deactivating. Before you go with it, double-check why a substituent would be an electron-donating group or an electron-withdrawing group. E.g., can you really find an electron-pair that is driving a positive mesomeric effect?

Remember to consider if a newly introduced functional group is more or less activating. Reactions often use an excess of reagents (more moles of reagent than starting material). Adding one activating group? The ring might add more (e.g., polyalkylation in Friedel-Crafts alkylations). Want to add more than one deactivating group? This might be challenging (remember our TNT example)!

Electrophilic Aromatic Substitution Examples

Here are additional questions to test your knowledge of the reaction mechanism and directing effects of substituents.

The first exercise is pretty straight-forward, with the fluoro-substituted ring being less activated (thus, bromination occurs on the other one, para to the aryl-aryl bond).
The same idea applies to the question on the right, where we expect the inductive acceptor effect of the trifluoromethyl group to deactivate the ring towards sulfonation.
The Friedel-Crafts acylation is pretty obvious (para to the electron-donating ether group).
Last, we have a Friedel-Crafts like C-C bond formation. Instead of a alkyl halide and Lewis acid, we generate our carbon electrophile by protonation of the double bond with sulfuric acid.

Hope this summary helped you get a good overview of this class of aromatic reactions.
Feel free to check out my page or my videos for more learning and fun content!

Functional groups are the foundation of organic chemistry as they define the structure, reactivity, and properties of organic compounds. Here, we explain what functional groups are (by looking at – wait for it – fruit salad), and introduce the most common functional groups.
Did you know that functional groups were at the root of dispute and friendship of two chemistry legends? Let’s get into it!

What are Functional Groups in Organic Chemistry?

Functional groups in organic chemistry are specific groups of atoms that have characteristic properties (e.g., polarity). Functional groups determine the reactivity of molecules.

Instead of blindly memorizing a long list of functional groups, let us try to understand three key ideas first.

1. Many functional groups are related to each other. For instance, by putting a C=O double bond next to an amine, we get an amide. Others are variants of each other. For example, a sulfur atom instead of an oxygen turns an ether group (R-O-R) into a thioether (R-S-R). When learning these groups, try to find the similarities and differences between them.
There are different sub-families of functional groups. For instance, everything with a C=O double bond can be called a carbonyl. Aldehydes, ketones, amides, esters… are all relatives of the carbonyl family! Similarly, primary amines, secondary amines and tertiary amines are all amines!

2. Properties of functional groups are largely independent of the molecule’s broader environment. The hydroxyl group in ethanol behaves the same way as in octanol (even though the latter is much bigger!).

3. Connected to the above, functional groups have an inherent polarity and thus, nucleophilicity or electrophilicity (link). For example, aldehydes are electrophilic on carbon but nucleophilic on oxygen. This baseline polarity of each functional group actually already explains most of the organic chemistry reactions that you will encounter. Interconversion of functional groups can change this natural polarity. For instance, enol forms of carbonyls are not electrophilic at the central carbon anymore, and are nucleophilic at the alpha-carbon!

What are Functional Groups – SIMPLY EXPLAINED?

Functional groups are just like different fruits in a fruit salad. Let’s see how the points above match to this analogy.

1. Some fruits are related, like lemons and oranges as they are both citrus fruits. We mentioned carbonyls and ethers above. Another example are primary amines and tertiary amines – very similar but not identical!

2. Whether you catch a strawberry in one fruit salad or another one (these are different molecules in our analogy), they basically taste the same.

3. Lemons are inherently acidic. Well, carboxylic acids are also always acidic. (Sometimes more, sometimes less – due to things like inductive and mesomeric effects.) Just like fruits have characteristic taste, functional groups have characteristic properties.
This also nicely illustrates the keto-enol interconversion or even the advanced idea of “Umpolung“. Here, chemists invert the natural reactivity of the original functional group. The key example is conversion of aldehydes to dithianes which can be nucleophilic at the carbon (instead of electrophilic)!
Using our fruit analogy, by cooking and caramelizing lemons (Umpolung), we can make them more sweet instead of bitter.

History of Functional Groups in Organic Chemistry

Here’s some random background (if you know my content, you will realize I like this type of stuff):
As the backbone of organic chemistry, functional groups as a concept have their origin in the early 19th century. At that point, elemental analysis had allowed chemists to determine the molecular formula of most inorganic compounds. These lack carbon-hydrogen bonds and are thus not organic (shocker!). The widespread theory of vitalism suggested that only living organisms can produce organic substances.

Many students know that the German chemist Friedrich Wöhler overthrew this theory by synthesizing urea from inorganic ammonium cyanate in 1828. Less known is the controversy between Wöhler and Justus Liebig:
Both of them were doing experiments on inorganic salts that they believed had the molecular formula “AgCNO“. However, Liebig’s salt was a powerful explosive while Wöhler’s was not.

“The obvious conclusion was that one of the analyses must be wrong, and one of the chemists must be a poor analyst! Liebig, pushed by his aggressive character, rapidly accused Wöhler of erroneous results. But Liebig analyzed a sample of the silver cyanate supplied by Wöhler and verified that they were correct. At this point, Liebig openly admitted that he had made a mistake in his initial accusation. And curiously this was the starting point of a friendship and even a scientific collaboration between the two scientists.”

S. Esteban in J. Chem. Educ. 2008, 85, 9, 1201

The legendary Swedish chemist Berzelius (Wöhler’s professor) explained this controversy by proposing the concept of isomers. The realization that constitution of molecules can be different despite having the same atoms paved the way for discovery of all the functional groups we know today.

Common functional groups

Here are the most common functional groups. The bold ones are particularly important as they are invoked to explain some of the basic reactions in organic chemistry, such as nucleophilic substitutions (alkyl halides) or electrophilic additions.

Instead of belabouring basic information you can find everywhere already, I want to draw your attention to two themes:

1. Functional group relationships:
   What makes functional groups (in a certain row or across rows) similar?
   For instance, the first row are C-H hydrocarbon functional groups.
   Which functional groups are based on combinations of simpler functional groups?
   For example, an enone is an alkene that is connected to a ketone.
   Which functional groups are oxidized/ reduced versions of each other, and which have the same oxidation state?
   For instance, carboxylic acids are more oxidized versions of aldehydes and ketones, and have the same oxidation state as nitriles. This means nitriles can be converted to acids without reductants or oxidants!
   
2. Functional group polarity:
   What do the red and blue colored atoms correspond to? How does the polarity and reactivity differ across related functional groups?
   For example, why is the central carbonyl carbon blue in aldehydes and ketones, but not blue anymore in carboxylic acids?
   Why is the hydrogen of the O-H bond of the carboxylic acid blue but not blue for the C-H in the aldehyde?
   Should the carbons of alkenes and arenes be marked red or rather blue? What does this depend on?
   
3. Advanced: Functional group geometry: Can you rationalize all bond angles (e.g., alkynes vs. alkenes) and geometries of functional groups? Which parts of them are flat/ in one plane, and which ones are not?
   For example, why are in esters both the C=O and C-O-R bonds in the same plane? Why do esters prefer the Z-conformer where both C=O and C-O-R bond are facing the same side?

In other posts, we will deep dive into individual functional groups and families to explain properties and most common reactions in more detail. Functional groups clearly also form the basis of protecting groups and their reactivity.

Some final advice: Instead of learning a bunch of facts about 30 functional groups by heart in a brain dead manner, try to work first identify the commonalities and differences from a high level. The names might seem random at first but many of them will make sense once you take a look at what atoms or combinations of functional groups are present!

Ever struggle with how to identify if a group is a nucleophile vs. electrophile?
If you are in a rush and don’t care about learning chemistry (bruh), the first sections got you. I recommend you try to truly understand the concept as it’s arguably the most important skill in organic chemistry.

Nucleophile vs electrophile: Summary

1. Nucleophiles (nucleus-loving) are neutral or negatively charged species that donate high energy electrons to form new bonds with electrophiles (electron-loving), which are neutral or positively charged species that can easily accept electrons

2. Nucleophiles are Lewis bases (e.g. NH₃); electrophiles are acids (e.g. H⁺, BF₃)

3. The chemical bonding occurs between the highest occupied (HOMO) of the nucleophile and the lowest unoccupied molecular orbital (LUMO) of the electrophile

4. Single atoms, sigma-bonds and pi-bonds can be nucleophilic or electrophilic – and the same molecule can contain both (one part nucleophilic, one part electrophilic)

Nucleophiles and electrophiles are complementary, they react with each other. You will never see a reaction where two groups react with each other as nucleophiles!

Level 0: Chemical bonds are like … financial transactions?

Chemistry is like finance! Simply swap electrons (chemical currency) for money.

If you’re a student, you’re likely broke (you are in need of, and easily accept money => you are electrophilic).
You go to your parents to borrow some money for a dinner (they can donate money => they are nucleophilic).
By getting money and the food, you get happier (you are energetically stable). Your parents are also stoked they can spend some time with their favorite child (they are also energetically stabilized).

This explains how we draw curly arrows, representing electron movement: There are no electrons at the electrophile (it is broke). Instead, the electron donation arrow starts at the nucleophile and points to the acceptor, the electrophile.

Level 1: Nucleophile vs electrophile

You have two options on how to remember which is which:
1. Not recommended: You force-memorize some analogy like above with no brain cell activation, setting you up for nice failures in organic chemistry exams

2. Recommended: You just use your brain and simply remember that “phile” means liking or loving (if you struggle to remember, you know a highly criminal term…)

	Nucleophile	Electrophile	P*d*phile
What it has	Has more than enough electrons	Has some sort of positive polarization	Problems, chocolate & puppies
What it wants	Wants to share its electrons (likes positive charges)	Wants to accept other electrons (likes electrons)	Kids
Charge	Neutral or negative	Neutral or positive	Prison sentence
Orbitals	High-energy occupied	Low-energy unoccupied	Orbits around kids and playground
Acid or base	Lewis base	Lewis acid	Puts them in his base(ment)

The electrons that a nucleophile donates form the new bond with the electrophile. A simple example is the protonation of water. Which is the nucleophile vs electrophile?

Reviewing the more complex mechanism for the hydration of formaldehyde, you will realize that:
1. Specific atoms or also bonds can have nucleophilic or electrophilic behavior
For example, in the first step, the carbonyl pi-bond is the electrophile. In the second step, the proton H+ is the electrophile.

2. For reactions with multiple mechanistic steps, there can be many different nucleophiles and electrophiles
For example, after the first addition to the carbonyl, the previously nucleophilic water molecule turns into a cationic intermediate which is now electrophilic (which is why it reacts with another nucleophilic water in a deprotonation)

Level 2: Types of nucleophiles

How do we identify electron donors and electron acceptors? There are three categories for both. It’s easier for nucleophiles, so let’s start there.

To donate an electron pair, you need to have an electron pair somewhere (duh).
In our analogy, you need to find the bank vaults that are filled with cash (electrons)!

1A) Lone electron pairs, e.g., water H₂O or ammonia NH₃ (neutral nucleophile)
Reaction example: Protonation of neutral bases
1B) Negative charges (also electron pairs), e.g., hydroxide OH^– or cyanide CN^– anions
Reaction example: Basic hydrolysis of an ester
2) Bonding pi-orbitals, most notably C=C double bonds, e.g., alkene or aromatic ring
Reaction example: Bromination of alkenes, electrophilic aromatic substitution
3) Bonding sigma-orbitals with highly electropositive atoms, e.g., methyllithium Li-CH₃
Reaction example: Carbonyl reduction with LiAlH₄, organometallics

This should make sense. These are the only “ways” you will ever find electrons in a molecule. Either as an unbound electron, in a pi-bond, or in a sigma-bond. This corresponds to the idea of highest occupied molecular orbitals (see below).

Level 2: Types of electrophiles

What about electrophiles? Two categories are similar, and one is different.

To accept an electron pair, you need to have an empty orbital somewhere (duh). Here, we need to find the empty wallets that are eager to get filled with money!

Like nucleophiles, we have pi- and sigma-bonds as acceptors (as they have empty orbitals that can be filled with electrons). However, instead of electron pairs for nucleophiles, we need to look for empty orbitals on single atoms. Think of the empty orbitals like filled purses

1A) Positive charges representing an empty p orbitals, e.g., proton H⁺
Reaction example: Protonation of any base
1B) Neutral molecule with empty p orbital, e.g., Lewis acids like BF₃ or AlCl₃
Reaction example: Friedel-Crafts acylation
2) Pi-bond next to electronegative/ stabilized system, e.g., carbonyl
Reaction example: Aldehyde hydration, conjugate addition
3) Sigma-bond to electronegative atom, e.g., methyl iodide CH₃-I
Reaction example: SN2 reaction, bromination of alkenes

For both of these categories, I always represented the nucleophile as “Nu-” and electrophile as “E+”. But any combination of these categories works – e.g., an nucleophilic pi-bond can attack an electrophilic pi-bond!

If you know a fair share of reactions, try to think about additional examples for each!

Level 3: Orbitals

Let’s get to the bottom of this (without me writing another text book on orbitals).

Remember that reactions take place if molecules…

1. Overcome their electronic repulsion via charge attraction and/or orbital overlap
(all reactions have activation energies)
2. Have orbitals of appropriate energy to interact
(if orbital energies are too different, there is no energy gain from bonding)
3. Orient in a geometry that allows their orbitals to overlap in a bonding interaction
(if a key can’t get into a lock, the door can’t be unlocked)

Point #2 is critical: energy levels of the nucleophile and electrophile orbitals.
The strongest stabilization comes from interacting orbitals with similar energies.

All molecules have many low-energy, unfilled orbitals and high-energy, empty orbitals (illustrative grey orbitals). We can ignore all because the energy differences between them are too large. The most relevant interaction will be the one between the lowest-energy unoccupied (LUMO) and highest-energy occupied molecular orbital (HOMO).

The higher-energy a HOMO is, the easier it can donate electrons into LUMOs.
The lower-energy a LUMO is, the easier it can accept electrons.

This picture explains the types of electrophiles…
1A + B) Empty orbitals can be LUMOs (neutral or positively charged atom)
2) Pi-bonds always have an empty antibonding pi-star MO which can be a LUMO
3) Similarly, sigma-bonds have an antibonding sigma-star MO which can be LUMO

… and types of nucleophiles:
1A +B) Lone pairs can be HOMOs (neutral or negatively neutral charged atom)
2) Pi-bonds always have a filled bonding pi MO which can be a HOMO
3) Similarly, sigma-bonds have a filled bonding sigma MO which can be a LUMO

Recap: Nucleophile vs electrophile

By now you should be able to identify a nucleophile vs electrophile, and know the different types that exist. As an exercise, review reactions you already know or that I discuss on my channel, or functional groups (e.g., protecting groups) to apply your learnings.

There are more nuances and explanations which are not digestible in a single post. So, future posts will explain things like:
– What are the most common nucleophiles and electrophiles?
– How does conjugation to electron-donating or -withdrawing groups influence nucleophilicity or electrophilicity?