Acylation is a chemical reaction in which an acyl group is attached to a molecule. An acyl group is essentially a fragment of a carboxylic acid (the carbon-oxygen core, written as RCO) that bonds to another compound, creating products like esters and amides. This reaction is fundamental in organic chemistry, pharmaceutical manufacturing, and biology, where it governs everything from gene expression to hormone signaling.
The Acyl Group and How It Transfers
An acyl group forms when you remove the hydroxyl (OH) portion from a carboxylic acid, leaving behind a carbon double-bonded to oxygen and single-bonded to some other carbon chain. That leftover fragment is reactive and ready to attach to a target molecule. The target could be an oxygen atom (producing an ester), a nitrogen atom (producing an amide), or a carbon on an aromatic ring.
Not all acyl-donating molecules are equally reactive. Acyl halides, where the acyl group is paired with a halogen like chlorine, are the most reactive. Anhydrides come next. Esters and free acids are considerably less reactive, and amides are the least reactive of all. This hierarchy matters in practice because chemists choose their starting reagent based on how aggressive they need the reaction to be.
Friedel-Crafts Acylation
The most widely taught example of acylation in organic chemistry is the Friedel-Crafts acylation, which attaches an acyl group to an aromatic ring like benzene. The reaction uses an acid chloride (or an acid anhydride) along with a Lewis acid catalyst, most commonly aluminum chloride (AlCl₃).
The process works in three stages. First, the catalyst pulls the chlorine away from the acid chloride, generating a positively charged acylium ion. This ion is the attacking species. Second, electrons from the aromatic ring reach out and bond to the acylium ion, temporarily disrupting the ring’s stable electron arrangement. Third, a proton leaves the ring, restoring aromaticity and yielding the final product: a ketone attached directly to the ring. The aluminum chloride regenerates during this last step, so it acts as a true catalyst.
Why Acylation Beats Alkylation
Friedel-Crafts acylation has a cleaner cousin called alkylation, which attaches a simple carbon chain instead of an acyl group. Alkylation has two significant drawbacks that acylation avoids. First, the intermediate carbocation in alkylation is not stabilized by resonance, so it readily rearranges into a different structure, often giving you the wrong product. The acylium ion in acylation is resonance-stabilized and does not rearrange.
Second, alkylation tends to keep going. Alkyl groups are electron-donating, which makes the product more reactive than the starting material, so multiple alkyl groups pile onto the same ring. Acyl groups are electron-withdrawing, which deactivates the ring after one addition. A ring can only be acylated once, giving you precise, predictable control over the product.
Acylation in Everyday Chemistry: Aspirin
One of the most familiar products of acylation is aspirin. Salicylic acid reacts with an excess of acetic anhydride in the presence of sulfuric acid as a catalyst. The acetic anhydride donates an acetyl group (a two-carbon acyl group) to the hydroxyl group on salicylic acid, converting it into acetylsalicylic acid. The mixture is heated in a water bath for about 15 minutes to drive the reaction forward. This is a textbook O-acylation, meaning the acyl group attaches to an oxygen atom, forming an ester bond.
O-Acylation vs. N-Acylation
When a molecule has both an oxygen (hydroxyl) and a nitrogen (amino) group available, the acyl group can end up on either one. O-acylation produces an ester, while N-acylation produces an amide. The selectivity depends on reaction conditions. In solvent-free systems with free fatty acids, the reaction tends to favor O-acylation because the amino group’s charge state changes in ways that make it less available. Under other conditions, particularly when water is removed during the reaction, the selectivity shifts toward amide formation. Enzymes like lipases can catalyze both pathways, and researchers manipulate solvent choice and reagent addition to steer the outcome.
Acylation in Your Body: Gene Expression
Acylation plays a major role in how your cells turn genes on and off. DNA wraps around proteins called histones, and how tightly it wraps determines whether a gene can be read. When an acetyl group (a small acyl group) is added to specific amino acids on histones, the grip loosens, and nearby genes become accessible for transcription into proteins. Genome-wide studies show that histone acetylation levels correlate strongly with transcription activity. Most of the enzyme complexes responsible for this modification are not very picky about which specific amino acid they target. They modify multiple sites within the same histone, and the overall level of acetylation, rather than any single site, generally drives the effect on gene expression.
Protein Acylation and Cell Membranes
Cells also use acylation to anchor proteins to membranes. Two major types of fatty acid acylation handle this job: myristoylation and palmitoylation.
Myristoylation attaches myristic acid, a 14-carbon fatty acid chain, to the very first amino acid (glycine) at the start of a protein. This attachment is permanent, forming a stable amide bond. It gives the protein enough hydrophobic character to loosely associate with a membrane, but the connection is weak. A myristoylated protein bound to a membrane has a half-life on the order of minutes.
Palmitoylation adds palmitic acid, a 16-carbon chain, to cysteine amino acids through a reversible thioester bond. Because it can be added and removed, palmitoylation acts as a dynamic switch, controlling where a protein sits in the cell, how stable it is, and whether it functions. Many proteins need myristoylation first as a prerequisite: the initial weak membrane attachment positions the protein close enough for palmitoylation enzymes to complete the anchoring. A protein with both modifications stays membrane-bound for hours instead of minutes.
The Src protein, involved in cell growth signaling, requires both myristoylation and palmitoylation to position itself correctly at the cell membrane. Akt, another signaling protein, depends on myristoylation for membrane anchoring and maintaining its activity.
Ghrelin: Acylation Controls Hunger Signaling
One striking example of acylation’s biological importance involves ghrelin, the “hunger hormone.” Ghrelin must have an eight-carbon fatty acid chain (an octanoyl group) attached to one of its amino acids before it can bind to its receptor and trigger appetite and growth hormone release. Without this acylation, ghrelin floats around in the bloodstream but cannot activate signaling. The receptor has a nonpolar pocket specifically shaped to accommodate the fatty acid chain, while separate polar contacts grip the amino acid portion of ghrelin. An enzyme called ghrelin O-acyltransferase performs this modification, making it a potential target for therapies related to appetite and metabolism.
Acylation in Cancer Research
Because acylation controls so many cellular processes, disrupting it can contribute to disease. In cancer cells, abnormal palmitoylation of PD-L1, a protein that helps tumors hide from the immune system, has become a target of interest. Blocking PD-L1 palmitoylation or restoring the acylation of immune-sensing proteins like cGAS could enhance immunotherapy effectiveness. Separately, researchers have found that one enzyme promotes palmitoylation of histone H4, increasing gene transcription in ways that drive castration-resistant prostate cancer progression. These discoveries point toward a broader principle: the same acylation chemistry that manufactures aspirin in a flask also governs critical switches in human health.