Common Organic Reactions

Why This Matters

Organic reactions are the vocabulary of molecular transformation. On your exam, you're being tested on your ability to predict products, explain mechanisms, and choose the right reaction for a given synthesis problem. These reactions aren't random; they follow predictable patterns based on nucleophilicity, electrophilicity, substrate structure, and reaction conditions. Master the underlying logic, and you'll be able to tackle any mechanism question thrown at you.

The reactions in this guide represent the core toolkit of organic synthesis. From building carbon-carbon bonds to interconverting functional groups, each reaction type illustrates fundamental principles like carbocation stability, stereoelectronic effects, and kinetic vs. thermodynamic control. Don't just memorize reagents and products. Know why each reaction proceeds the way it does and what concept it demonstrates.

---

Substitution and Elimination: Competing Pathways

These reactions share a common starting point (an alkyl halide or similar substrate) but diverge based on nucleophile strength, base strength, substrate structure, and solvent choice. Understanding when substitution wins over elimination is one of the most heavily tested skills in organic chemistry.

Nucleophilic Substitution (SN1 and SN2)

SN2 is a concerted, one-step mechanism. The nucleophile attacks the electrophilic carbon from the backside as the leaving group departs, resulting in inversion of configuration (Walden inversion). Because the nucleophile must access the carbon directly, steric hindrance matters a lot. Primary substrates and methyl halides are ideal SN2 candidates.

SN1 proceeds through a carbocation intermediate. The leaving group departs first in a slow, rate-determining ionization step, and then the nucleophile attacks the planar carbocation. Because the nucleophile can attack from either face, you get racemization at the stereocenter. Tertiary substrates favor SN1 because they form stable 3° carbocations. Polar protic solvents (like water or alcohols) stabilize both the carbocation and the departing leaving group, further promoting this pathway.

Elimination (E1 and E2)

E2 is a concerted process that requires anti-periplanar geometry between the $\beta$-hydrogen and the leaving group. A strong base abstracts the proton while the leaving group departs simultaneously, forming an alkene in one step. Strong, bulky bases (like $KOtBu$) strongly favor E2.

E1 shares the carbocation intermediate with SN1. After ionization, a weak base removes a proton from a carbon adjacent to the carbocation to form the alkene. Weak bases and polar protic solvents favor this stepwise pathway.

Zaitsev's rule governs regioselectivity: the more substituted (more stable) alkene typically predominates. The exception is when a bulky base like tert-butoxide is used, which has trouble reaching the more hindered proton and instead gives the less substituted Hofmann product.

---

Addition Reactions: Building Complexity from Unsaturation

Addition reactions transform $\pi$ bonds into $\sigma$ bonds, converting alkenes and alkynes into more saturated products. The key is understanding electrophilic attack, carbocation intermediates, and stereochemical outcomes.

Addition to Alkenes

Electrophilic addition follows Markovnikov's rule. The electrophile (often $H^+$) adds to the less substituted carbon of the double bond, placing the positive charge (or eventual nucleophile attachment) on the more substituted carbon. This happens because the more substituted carbocation is more stable.

Stereochemistry depends on the mechanism:

• Halogenation (e.g., $Br_2$) proceeds through a cyclic halonium ion intermediate. The nucleophile must attack from the opposite face, giving anti addition.
• Hydroboration-oxidation ($BH_3$ then $H_2O_2/NaOH$) delivers both H and OH from the same face of the alkene, giving syn addition. It also gives anti-Markovnikov regiochemistry because boron adds to the less hindered carbon.
• Hydrohalogenation (e.g., $HBr$) follows Markovnikov's rule through a carbocation intermediate. Adding peroxides ($ROOR$) switches the mechanism to a radical pathway, giving anti-Markovnikov addition instead.

Diels-Alder Reaction

The Diels-Alder reaction is a [4+2] cycloaddition that forms six-membered rings in a single concerted step. A conjugated diene (4 $\pi$ electrons) reacts with a dienophile (2 $\pi$ electrons) through a pericyclic mechanism with no intermediates.

The reaction is stereospecific: cis substituents on the dienophile remain cis in the product, and trans stays trans. Secondary orbital interactions favor the endo transition state, which typically gives the major product.

Electronic matching matters. The reaction is fastest when an electron-rich diene pairs with an electron-poor dienophile (normal electron demand). Electron-withdrawing groups on the dienophile (like $-COOR$ or $-CN$) and electron-donating groups on the diene speed things up dramatically.

One more requirement: the diene must be in the s-cis conformation to react. If the diene is locked in s-trans (as in some rigid ring systems), the Diels-Alder cannot proceed.

---

Aromatic Reactions: Preserving the Ring

Aromatic compounds undergo substitution rather than addition to maintain their stabilizing aromaticity. Electrophilic aromatic substitution (EAS) is the key mechanism, and directing effects determine where new substituents land.

Electrophilic Aromatic Substitution

The mechanism proceeds in two stages:

1. The electrophile attacks the $\pi$ electron cloud of the ring, forming a resonance-stabilized arenium ion (also called a sigma complex). This step temporarily disrupts aromaticity and is the slow, rate-determining step.
2. A base removes a proton from the carbon bearing the electrophile, restoring aromaticity. The ring regains its aromatic stabilization energy, which is why substitution is favored over addition.

Substituent directing effects are critical for predicting products:

• Electron-donating groups ($-OH$, $-NH_2$, $-OR$, alkyl groups) are ortho/para directors and ring activators. They stabilize the arenium ion through resonance or induction when the electrophile lands at the ortho or para positions.
• Electron-withdrawing groups ($-NO_2$, $-CF_3$, $-COOR$) are meta directors and ring deactivators. They destabilize the arenium ion at ortho/para positions (where positive charge is placed directly on the carbon bearing the substituent), making meta attack relatively more favorable.
• Halogens are the exception to memorize: they're ortho/para directors but ring deactivators. Their lone pairs donate by resonance (directing ortho/para), but their electronegativity withdraws electron density inductively (deactivating).

Common EAS reactions and the electrophiles they require:

• Halogenation: $Br_2/FeBr_3$ or $Cl_2/AlCl_3$ (Lewis acid generates $Br^+$ or $Cl^+$)
• Nitration: $HNO_3/H_2SO_4$ (generates $NO_2^+$, the nitronium ion)
• Friedel-Crafts alkylation: $RCl/AlCl_3$ (generates a carbocation)
• Friedel-Crafts acylation: $RCOCl/AlCl_3$ (generates an acylium ion, $RCO^+$)

Note that Friedel-Crafts reactions don't work on strongly deactivated rings (e.g., nitrobenzene) because the ring isn't nucleophilic enough.

---

Carbonyl Chemistry: The Heart of Organic Synthesis

Carbonyl compounds are electrophilic at carbon and can undergo nucleophilic addition, substitution at the carbonyl, or reactions at the $\alpha$-carbon. These reactions form the basis of most carbon-carbon bond-forming strategies.

Aldol Condensation

The aldol reaction forms $\beta$-hydroxy carbonyl compounds through these steps:

1. A base deprotonates the $\alpha$-carbon of one carbonyl compound, generating a nucleophilic enolate.
2. The enolate attacks the electrophilic carbonyl carbon of a second molecule, forming a new C–C bond.
3. Protonation of the resulting alkoxide gives the $\beta$-hydroxy carbonyl (the "aldol" product).

Dehydration can follow under heating or acid/base conditions: water is eliminated to give an $\alpha,\beta$-unsaturated carbonyl, a conjugated system stabilized by resonance. When dehydration occurs, the overall process is called an aldol condensation.

Crossed aldol reactions (using two different carbonyl compounds) can give mixtures of products. To get selectivity, you can use a non-enolizable partner (like benzaldehyde, which has no $\alpha$-hydrogens) as the electrophilic carbonyl, or use LDA (lithium diisopropylamide) to form one specific enolate quantitatively at low temperature.

Grignard Reaction

Grignard reagents ($RMgX$) are powerful carbon nucleophiles formed by reacting an alkyl or aryl halide with magnesium metal in anhydrous ether. They attack electrophilic carbonyl carbons to form new C–C bonds.

The product class depends on the carbonyl substrate:

• Formaldehyde ($HCHO$) → primary alcohol
• Aldehydes ($RCHO$) → secondary alcohol
• Ketones ($RCOR'$) → tertiary alcohol
• Esters react with two equivalents of the Grignard reagent → tertiary alcohol
• $CO_2$ → carboxylic acid (after acidic workup)

Anhydrous conditions are essential. Grignard reagents are strong bases and react rapidly with any protic source (water, alcohols, carboxylic acids, amines), destroying the reagent before it can attack the carbonyl. Even moisture in the air can ruin the reaction.

---

Oxidation and Reduction: Interconverting Functional Groups

These reactions change the oxidation state of carbon without forming new C–C bonds. Mastering the oxidation ladder ($\text{alkane} \rightarrow \text{alcohol} \rightarrow \text{aldehyde/ketone} \rightarrow \text{carboxylic acid}$) helps you predict products and plan retrosyntheses.

Oxidation of Alcohols

• Primary alcohols can be oxidized to aldehydes or carboxylic acids. PCC (pyridinium chlorochromate) in $CH_2Cl_2$ stops at the aldehyde because it operates under anhydrous, non-aqueous conditions. Aqueous oxidants like Jones reagent ($CrO_3/H_2SO_4$) or $KMnO_4$ push all the way to the carboxylic acid because the aldehyde intermediate is further oxidized in the presence of water.
• Secondary alcohols oxidize to ketones with any of these reagents. No over-oxidation occurs because there's no $C-H$ bond remaining on the carbonyl carbon to break.
• Tertiary alcohols resist oxidation under standard conditions. They lack a hydrogen on the carbinol carbon, so there's no bond for the oxidant to cleave.

Reduction of Carbonyl Compounds

• $LiAlH_4$ is a powerful, non-selective reducing agent. It reduces aldehydes, ketones, esters, carboxylic acids, and even amides to their corresponding alcohols (or amines, in the case of amides). It must be used in anhydrous ether solvents and requires a separate aqueous workup step.
• $NaBH_4$ is milder and more selective. It reduces aldehydes and ketones to alcohols but leaves esters, carboxylic acids, and amides untouched. It can even be used in protic solvents like methanol or ethanol.
• The mechanism for both involves hydride ($H^-$) delivery to the electrophilic carbonyl carbon, forming a tetrahedral alkoxide intermediate. Protonation during workup gives the alcohol product.

---

Carboxylic Acid Derivatives: Acyl Transfer Reactions

Carboxylic acids and their derivatives undergo nucleophilic acyl substitution, where a nucleophile replaces the leaving group while preserving the carbonyl. Reactivity follows leaving group ability: acyl chloride > anhydride > ester > amide. This order reflects how good each leaving group is: $Cl^-$ is a much better leaving group than $NH_2^-$.

A derivative can be converted into any derivative lower on the reactivity scale (e.g., acyl chloride → ester), but converting up the scale (e.g., amide → ester) requires special activation.

Esterification

Fischer esterification combines a carboxylic acid and an alcohol under acid catalysis. The mechanism proceeds as follows:

1. The acid catalyst protonates the carbonyl oxygen, activating the carbonyl toward nucleophilic attack.
2. The alcohol attacks the electrophilic carbonyl carbon.
3. A proton transfer occurs, and water is lost to give the ester.

The reaction is reversible and equilibrium-controlled. To drive it forward, you can apply Le Chatelier's principle: use excess alcohol, remove water (with a Dean-Stark trap or molecular sieves), or both.

Transesterification exchanges one alcohol group for another on an existing ester, using acid or base catalysis. This reaction is used industrially in biodiesel production and polymer chemistry.

---

Quick Reference Table

---

Self-Check Questions

1. Which two reaction types share a carbocation intermediate, and how does this affect the competition between them when treating a tertiary alkyl halide with a weak nucleophile in a polar protic solvent?

2. Compare the stereochemical outcomes of SN2 and electrophilic bromination of an alkene. What specific mechanistic feature (backside attack vs. halonium ion) explains why one gives inversion and the other gives anti addition?

3. A student wants to convert a primary alcohol to an aldehyde without over-oxidizing to the carboxylic acid. Which reagent should they choose, and why does it stop at the aldehyde while Jones reagent does not?

4. Explain why electron-donating groups on a benzene ring direct incoming electrophiles to the ortho and para positions. Draw or describe the resonance structures of the sigma complex to support your answer.

5. You need to form a new C–C bond to convert benzaldehyde into a secondary alcohol. Compare the Grignard approach with the aldol approach. Which gives you more straightforward control over the product, and why?