Constitutional Isomers vs Stereoisomers

Isomers are compounds with the same molecular formula but different structures: constitutional (structural) isomers differ in the order in which their atoms are connected, while stereoisomers have the same connectivity but differ in the arrangement of their atoms in space. In brief: butan-1-ol and diethyl ether are constitutional isomers (C₄H₁₀O), whereas cis-but-2-ene and trans-but-2-ene are stereoisomers, with identical connections and different geometry.

Isomerism is the reason that organic chemistry has so many compounds and why a molecular formula alone never identifies a substance. Even when the connectivity is the same, a different spatial arrangement can change a compound’s melting point, odor or biological activity. This article explains the classification of isomers, compares the two main classes in a table, counts the isomers of some formulas, and gives a procedure for deciding the relationship between two structures, with worked examples.

How are isomers classified?

All isomers have the same molecular formula. They are divided as follows:

• Constitutional isomers (structural isomers): different connectivity. Subtypes: chain (skeletal) isomers, position isomers and functional-group isomers.
• Stereoisomers: the same connectivity, different spatial arrangement. Subtypes: enantiomers (non-superimposable mirror images) and diastereomers (stereoisomers that are not mirror images, including cis–trans (geometric) isomers). Conformers, which interconvert by rotation around single bonds, are also regarded as stereoisomers in a broad sense.

What are constitutional isomers?

The atoms are bonded in a different sequence, so the compounds have different names and often completely different properties. For C₄H₁₀O there are seven constitutional isomers:

• four alcohols: butan-1-ol, butan-2-ol, 2-methylpropan-1-ol and 2-methylpropan-2-ol;
• three ethers: diethyl ether, methyl propyl ether and isopropyl methyl ether.

The alcohols and ethers differ in their functional group (functional-group isomers), the alcohols among themselves in the carbon skeleton or the position of the –OH group. They have different boiling points (diethyl ether 34.6 °C, butan-1-ol 117.7 °C) and chemical behavior.

What are stereoisomers?

Stereoisomers have the same atoms bonded in the same order. They differ only in the three-dimensional orientation. There are two common causes:

• Restricted rotation around a double bond or a ring gives cis–trans isomers (geometric isomers). The groups cannot change from one side to the other without breaking the π bond.
• Stereocenters: a carbon bonded to four different groups can exist in two arrangements that are mirror images of each other. Compounds with more stereocenters have more stereoisomers (up to 2ⁿ).

Comparison of the types of isomers

How many isomers does a formula have?

How do you decide the relationship?

1. Calculate the molecular formulas. If they differ, the compounds are not isomers.
2. Compare the connectivity (name each structure by IUPAC rules). If the connectivity is different, they are constitutional isomers.
3. If the connectivity is the same, look for differences in space. If the two are identical when one is rotated, they are the same compound.
4. If they are not identical, check whether they are mirror images. Mirror images that cannot be superimposed are enantiomers.
5. If they are stereoisomers but not mirror images, they are diastereomers.

Worked examples

Example 1: classify the pairs

• Pentane and 2-methylbutane: both C₅H₁₂, different connectivity: constitutional (chain) isomers.
• cis-Pent-2-ene and trans-pent-2-ene: the same connectivity, different geometry about the double bond: diastereomers (geometric isomers).
• Propan-1-ol (C₃H₈O) and propanone (C₃H₆O): different formulas, so they are not isomers.
• (R)-butan-2-ol and (S)-butan-2-ol: the same connectivity, non-superimposable mirror images: enantiomers.

Example 2: all isomers of C₃H₆O with a C=O group

Only two compounds fit: propanal (CH₃CH₂CHO) and propanone (CH₃COCH₃), which are functional-group (constitutional) isomers. Neither has a stereocenter.

Example 3: dichloroethene

C₂H₂Cl₂ gives 1,1-dichloroethene (both Cl on one carbon) and 1,2-dichloroethene. The latter can have the two chlorine atoms on the same side (cis, boiling point 60.3 °C, dipole moment 1.9 D) or on opposite sides (trans, boiling point 47.5 °C, dipole moment 0 D). The cis and trans forms are stereoisomers, and the 1,1- compound is a constitutional isomer of both.

Example 4: the number of stereoisomers

A molecule with 3 stereocenters has at most 2³ = 8 stereoisomers (four pairs of enantiomers). Glucose in its open-chain form has 4 stereocenters, so 16 stereoisomers (the 8 aldohexoses and their mirror images: D- and L-forms), and the cholesterol molecule has 8, giving 256 possible stereoisomers, of which nature makes only one.

Why do the differences matter?

• Physical properties: constitutional isomers and diastereomers differ in melting point, boiling point and solubility. Maleic acid (cis) melts at 135 °C, and fumaric acid (trans) at about 287 °C.
• Biological activity: enzymes and receptors are chiral, and distinguish between enantiomers. (R)-carvone smells of spearmint, and (S)-carvone of caraway.
• Drugs: the two enantiomers of a drug may have different effects, and regulators now require that each is studied separately.
• Chemical reactivity: stereoisomers often react at different rates and give different products, which is exploited in stereoselective synthesis.

How was stereoisomerism discovered?

Jean-Baptiste Biot found in 1815 that some organic compounds rotate the plane of polarized light. In 1848 Louis Pasteur separated, with tweezers and a microscope, two kinds of crystals of sodium ammonium tartrate that were mirror images and rotated light in opposite directions. In 1874 Jacobus van ‘t Hoff and Joseph Le Bel independently proposed the tetrahedral carbon atom, which explained why a carbon with four different groups can exist in two forms. Johannes Wislicenus showed in 1887 that the existence of two lactic acids and of maleic and fumaric acids can be explained by the arrangement of atoms in space.

Which mistakes are common?

• Calling stereoisomers “structural isomers”: stereoisomers have the same structure (connectivity).
• Treating a rotation about a single bond as a different isomer: conformers interconvert quickly and cannot normally be separated.
• Forgetting to check the formula: isomers must have the same molecular formula.
• Confusing enantiomers and diastereomers: enantiomers are mirror images, diastereomers are not.
• Assuming that all cis–trans pairs are enantiomers: they are diastereomers.