Diphenhydramine

C 17
H 21
N 1
O 1

Ball-and-stick Stick Space-filling

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40 atoms, 41 bonds.

IUPAC name: 2-benzhydryloxy-N,N-dimethylethanamine
Molar mass: 255.361(40) g/mol
Atoms: 40
SMILES: CN(C)CCOC(C1=CC=CC=C1)C2=CC=CC=C2
InChIKey: ZZVUWRFHKOJYTH-UHFFFAOYSA-N
PubChem CID: 3100

Made of

C H N O

Structural formula of diphenhydramine. Each unlabelled corner is a carbon atom, and the 15 hydrogens on carbon are not drawn. It shows which atoms are joined to which, not the shape. The model above shows the shape.

US federal drug rules list diphenhydramine both among antihistamine active ingredients and among night-time sleep-aid active ingredients. The US Food and Drug Administration (FDA) calls it a common over-the-counter allergy medicine, one sold without a prescription. It eases the runny nose and sneezing of hay fever, upper respiratory allergies and colds for a while, the agency adds. It is sold under names such as Benadryl and Nytol.

Chemically it is both an ether and a tertiary amine, as ChEBI, the Chemical Entities of Biological Interest database, classes it. Its oxygen links two carbons, the mark of an ether, and its nitrogen is bonded to three carbon atoms. Its 17 carbon, 21 hydrogen, one nitrogen and one oxygen atom give C₁₇H₂₁NO and a molar mass of 255.36 g/mol. PubChem’s IUPAC name is 2-benzhydryloxy-N,N-dimethylethanamine. Benzhydryl is another name for diphenylmethyl, a carbon carrying two benzene rings.

Structure and bonding

One carbon atom carries two benzene rings, a hydrogen and an oxygen, and from that oxygen a two-carbon chain runs to a nitrogen holding two methyl groups. Labels pick out a single O and a single N among the 40 atoms. In Ball-and-stick, each of the nitrogen’s three C–N–C angles measures 110.5° in PubChem’s computed model. The nitrogen stands out of the plane of its three carbons, like the trigonal pyramid Chem1 describes for ammonia. Space-filling merges the two rings into a bulky end, with the chain and its nitrogen trailing behind.

PubChem draws three double bonds in each ring, alternating with single ones. The ring electrons in fact spread into continuous bands of density above and below each ring’s plane, as in benzene. All twelve ring bonds in the model measure 1.383 to 1.395 Å, whichever way they are drawn. What PubChem models is also the neutral free base, which the Hazardous Substances Data Bank (HSDB) describes as an oil. The medicine is a salt: the hydrochloride, as the US National Cancer Institute (NCI) lists it, or the citrate named in the US night-time sleep-aid rule.

Where it turns up

Diphenhydramine is marketed under the Benadryl brand, as store brands and as generics, FDA notes, and in mixtures with pain relievers, fever reducers and decongestants. It also appears among FDA’s listed active ingredients for cough medicines and for medicines against nausea, as HSDB records. In the World Health Organization’s Anatomical Therapeutic Chemical (ATC) classification it has two places, as an antihistamine for the whole body and as a skin antihistamine for itching.

It also goes into common cold preparations and serves against Parkinson’s disease, according to MeSH, the US National Library of Medicine’s subject vocabulary. That disease itself is described on the dopamine page. It is a veterinary medicine as well. Diphenhydramine is made, HSDB records, from diphenylbromomethane and β-dimethylaminoethanol. The purified base is then turned into the hydrochloride with hydrogen chloride; what an acid does to an amine is set out on the trimethylamine page.

Why it matters

Diphenhydramine is a histamine-1 (H1) receptor antagonist in FDA’s drug classes. It competes with the body’s own histamine for that receptor, the NCI Thesaurus states, easing histamine’s effects on smooth muscle in the airways, small blood vessels and gut. It also blocks muscarinic receptors, a second receptor family, fairly potently, according to HSDB. That second action is in part behind the drying of airway secretions.

Much of it is apparently broken down on its first pass through the liver, HSDB reports, and it appears to be converted mainly into diphenylmethoxyacetic acid. It also loses one or both methyl groups from its nitrogen, giving N-demethyl and N,N-didemethyl products, and the drug and its breakdown products leave the body mainly in urine. No instance of clinically apparent acute liver injury has been tied to diphenhydramine, according to LiverTox, NIDDK and NLM’s liver-injury database.

Its first approval came in 1946, on ChEMBL’s record. Since 1985, US Consumer Product Safety Commission rules have required special packaging for some of its preparations for human use. Methyl salicylate shares that listing.

Properties

Properties of diphenhydramine Molar mass summed from IUPAC/CIAAW 2024 standard atomic weights; formula, atom and bond counts and PubChem's molecular weight from PubChem CID 3100.
Property	Value	Unit	Source
Molecular formula (Hill order)	C₁₇H₂₁NO
Molar mass	255.361(40) g/mol	g/mol	IUPAC/CIAAW 2024
Carbon atoms	17
Hydrogen atoms	21
Nitrogen atoms	1
Oxygen atoms	1
Bonds	41
Single bonds	35
Double bonds	6
PubChem molecular weight	255.35 g/mol	g/mol	PubChem

Safety

On 24 September 2020 FDA warned that diphenhydramine taken in doses above those recommended can cause serious heart trouble, seizures, coma or death. Used as recommended, FDA found, it remains safe and effective. Classed as a pure substance under the Globally Harmonized System (GHS), it is harmful if swallowed, with skin and serious eye irritation added in 66.7% of company reports. The rest of its classification is set out in the PubChem Laboratory Chemical Safety Summary for diphenhydramine.

Questions

Why does diphenhydramine make you sleepy?

Part of the answer is a second action. The drug spreads through the whole body, the central nervous system included, HSDB reports, and besides H1 receptors it blocks muscarinic receptors fairly strongly. That antimuscarinic action is in part responsible for its sedative effect, according to HSDB, and sedative is among the roles ChEBI gives it.

What does a diphenhydramine molecule look like?

Two benzene rings hang from one carbon, which links through an ether oxygen, an oxygen set between two carbons, to a chain ending in a nitrogen with two methyl groups. In PubChem's computed pose the two ring planes sit about 67° apart. All 21 hydrogens are bonded to carbon and none to the oxygen or nitrogen.

What is diphenhydramine hydrochloride?

It is the hydrochloride salt of diphenhydramine, sold in the US under the brand name Benadryl, according to the US National Cancer Institute's drug dictionary. It is a white, odourless crystalline powder with a bitter taste, HSDB records, melting at 166 to 170 °C, dissolving readily in water and slowly darkening in light.

Made of the same elements

C₁₄H₂₂N₂O Lidocaine 39 atoms, 39 bonds.
C₁₃H₂₁NO₃ Albuterol 38 atoms, 38 bonds.
C₂₀H₂₄N₂O₂ Quinine 48 atoms, 51 bonds.
C₁₂H₁₇NO DEET 31 atoms, 31 bonds.
C₁₄H₁₈N₂O₅ Aspartame 39 atoms, 39 bonds.
C₁₃H₁₆N₂O₂ Melatonin 33 atoms, 34 bonds.
C₁₀H₁₂N₂O Serotonin 25 atoms, 26 bonds.
C₁₁H₁₂N₂O₂ Tryptophan 27 atoms, 28 bonds.

All 25 compounds made of carbon, hydrogen, nitrogen and oxygen

C₉H₁₃NO₃ Epinephrine 26 atoms, 26 bonds.
C₉H₁₁NO₂ Phenylalanine 23 atoms, 23 bonds.
C₈H₁₁NO₂ Dopamine 22 atoms, 22 bonds.
C₆H₁₃NO₂ Isoleucine 22 atoms, 21 bonds.
C₆H₁₃NO₂ Leucine 22 atoms, 21 bonds.
C₉H₁₁NO₃ Tyrosine 24 atoms, 24 bonds.
C₈H₉NO₂ Acetaminophen 20 atoms, 20 bonds.
C₈H₁₀N₄O₂ Caffeine 24 atoms, 25 bonds.
C₅H₉NO₄ Glutamic acid 19 atoms, 18 bonds.
C₃H₇NO₂ Alanine 13 atoms, 12 bonds.
C₅H₆N₂O₂ Thymine 15 atoms, 15 bonds.
C₄H₅N₃O Cytosine 13 atoms, 13 bonds.
C₂H₅NO₂ Glycine 10 atoms, 9 bonds.
C₅H₅N₅O Guanine 16 atoms, 17 bonds.
C₄H₄N₂O₂ Uracil 12 atoms, 12 bonds.
CO(NH₂)₂ Urea 8 atoms, 7 bonds.
C₅H₄N₄O₃ Uric acid 16 atoms, 17 bonds.