Master MCAT isomers with clear explanations of structural, stereoisomers, enantiomers, diastereomers, R/S configuration, and practice questions.

(Note: This guide is part of our MCAT Organic Chemistry series.)

Part 1: Introduction to isomers

Isomers are compounds with the same chemical formula but different arrangements of atoms. Often, different isomers will behave differently. This is especially important in considering how chemicals react with one another. For instance, it is important to keep isomers in mind when creating drugs so that the chemical interacts with the body as desired--without any lethal side effects.

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Part 2: Structural isomers

Recall that covalent bonds form when one or more electron pairs are shared between atoms. Covalent bonds arrange atoms in space and influence the overall geometry of molecules. (For more information on this topic, be sure to refer to our guide on bonds and interactions.)

Hence, covalent bonds are crucial in any discussion of isomers, because isomers arise from different spatial connectivities of atoms in three-dimensional space.

Chemical structures should always be considered in their three-dimensional configurations. In other words: the bonding of individual atoms within a molecule must be taken into account. Structural isomers arise from forming covalent bonds in different arrangements despite having the same number and types of atoms. As a result, structural isomers have different structures in three-dimensional space due to the unique arrangements of atoms by covalent bonds.

Let’s compare two molecules with the formula C₄H₁₀: butane and isobutane. Both butane and isobutane have four carbons and ten hydrogens, but the arrangement of individual atoms within the molecule varies.

The spatial arrangement of atoms in three-dimensional space is important when discussing isomers. It can be difficult to depict these arrangements on a two-dimensional sheet of paper. By convention, bonds that are drawn on a wedge are said to be “coming out of” the page. Bonds that are drawn on a dash are said to be “going into” the page. Bonds that are drawn with a solid line are in the same plane as the page.

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Part 3: Chirality

Take a look at your left and right hands. With both palms facing up, place your left hand onto your right one by putting your left hand on top of your right hand. You will see that your hands are non-superimposable. The pinky of your left hand aligns with the thumb of your right hand rather than matching congruently.

Your hands are like chiral molecules. Chiral molecules are non-superimposable mirror images of one another. Chirality depends heavily on symmetry. Consider how a plane of symmetry can split a molecule into symmetrical halves. For instance, boron trifluoride (BF₃) has a plane of symmetry that can divide the molecule into two exact halves that mirror each other.

**Figure 3** Boron trifluoride contains an internal plane of symmetry that creates two identical halves.

Chiral molecules lack this plane of symmetry. For instance, lactic acid has no plane of symmetry where a plane can bisect the molecule to form mirror images. The following mirror images of lactic acid are non-superimposable upon each other. As a result, the molecule is chiral.

**Figure 4** Example of a chiral molecule, lactic acid. The top of the figure shows the molecule reflected across itself. The bottom of the figure shows the mirror images superimposed on top of one another.

a) Chiral centers

A chiral center is an atom that has four different substituents connected to it. Generally, a molecule with at least one chiral center is chiral. A molecule that is not chiral is said to be achiral.

In organic chemistry, chiral centers are often sp³-hybridized carbon atoms. Recall that sp³ hybridization simply means that the atom is bonded to four different groups using one s orbital and three p orbitals. When optimizing the structure of one s orbital and three p orbitals, a tetrahedral shape forms.

The MCAT may ask you to identify the number of chiral structures within a molecule. When given a structure, it might be helpful to identify which atoms are sp³-hybridized when locating possible chiral centers.

Note that an sp³-hybridized carbon may not be a chiral center, particularly if the atom does not have four different substituents connected to it. Consider methanol (COH₄). Although the central carbon is sp³-hybridized, the carbon is not connected to four different substituents. Thus, the molecule can create a self-superimposable mirror image of itself.

Chiral molecules are often optically active, meaning that they are able to interact with and polarize light. However, a compound that has multiple chiral centers may not be optically active!

In some cases, a molecule may have multiple chiral centers but still be achiral. Meso compounds, for instance, contain multiple chiral centers. Meso compounds also contain an internal plane of symmetry. As a result, a meso compound containing multiple chiral centers can still be achiral overall. To determine whether a compound is meso, first check that it has at least two chiral centers. Then, bisect the structure into halves via a plane of symmetry. If the compound reflects the same connectivity of substituents on both sides, then it is meso.

**Figure 6** An example of a meso compound with two chiral centers (marked with *) and an internal plane of symmetry. This structure is not chiral, despite the fact that it has two chiral centers.

b) R, S configuration

Like hands can be either left- or right-handed, the absolute configuration of a chiral center can be either R or S. To determine whether a chiral center has an R or an S configuration, first determine the priorities of the four groups connected to the chiral center.

What does “priority” refer to? The Cahn-Ingold-Prelog priority rules are conventions that determine the “priority” of substituent functional groups. Each substituent connected to a chiral center can be assigned a hierarchical priority. The basics are as follows:

The groups with higher atomic numbers receive a higher priority.

If the groups are isotopes, however, the ones with higher atomic mass receive higher priority.
If the groups are the same, then the priority can be assigned by the atomic number of mass at the first point of difference.
Any double bonds should be treated as two single bonds to an identical substituent. Any triple bonds should be treated as three single bonds to an identical substituent.

Let’s determine the absolute configuration of the compound 3-chloro-1-butene (C₄H₇Cl). 3-chloro-1-butene has one sp³ hybridized carbon atom that is connected to -H, -Cl, -CH₃, H₂C=CH-, which are all four different groups. Thus, this is the chiral center.

Then, the priorities of the attached substituents can be determined. Recall that atoms with higher atomic weight receive higher priority. In this case, the chlorine atom receives the highest priority (1), while the hydrogen atom receives the lowest priority (4).

The other two substituents are both connected to the chiral center at a carbon atom. Thus, the attached bonds must be traced further to determine the first point of difference. The -CH₃ group is attached to three other hydrogen atoms, while the -CH=CH₂ group can be thought of as being attached to one other hydrogen atom and two other carbon atoms. Thus, the -CH₃ group receives a lower priority.

**Figure 7** Priorities of each group bonded to the chiral carbon of 3-chloro-1-butene determined by atomic mass

Determining the priority of each of the groups is the first part of determining R or S. Then, be sure to orient the molecule so that the group with the lowest priority is pointed backward, which is represented as a dashed line. With the lowest priority substituent pointing backward, draw an arrow around the chiral center from the highest priority group, to the second-highest priority group, then to the third-highest priority group as shown. If the arrow travels in the counterclockwise direction, the molecule is in the S configuration. If the arrow travels in the clockwise direction, it is the R configuration.

**Figure 8** Example of an R configuration compound based on the order of priority going in a clockwise direction

Note that these directions are reversed if the lowest-priority substituent is pointing out of the page. If the arrow travels in the clockwise direction, the chiral center is in S configuration. If the arrow travels in the counterclockwise direction, the chiral center is in R configuration.

c) E, Z configuration

While the R, S system describes the configuration of sp³-hybridized carbon atoms, the E, Z system describes the configurations of sp²-hybridized carbon atoms. In other words: the E, Z system is used to describe the orientation of substituents around two double-bonded carbons.

This system is somewhat similar to the cis-trans system. Recall that a cis configuration has two of the same groups on the same side, while the trans configuration has two of the same groups on the other side of one another. While this system is commonly used, it is difficult to use in the context of compounds with multiple different constituents.

To determine the configuration of substituents, first, determine the priority of each group. If the two groups of higher priority lie on the same side of the double bond, the compound is in Z configuration. If the two groups of higher priority lie on opposite sides of the double bond, then label that E.

For instance, let’s determine the configuration of the following structural isomers of 1,2-dichloroethene.

**Figure 9** Example of E,Z configurations determined by the order of priority groups

Note that each carbon involved in the double bond is bonded to one hydrogen and one chlorine atom. Out of hydrogen and chlorine, the chlorine atoms hold a higher priority. In the E configuration, the two chlorine atoms lie on opposite sides of the double bond. In the Z configuration, the two chlorine atoms lie on the same side of the double bond.

d) Diastereomers and enantiomers

Unlike structural isomers, stereoisomers do not differ in atomic connectivity. Rather, they have a different spatial arrangement of bonds around an atom.

For instance, both E 1,2-dichloroethane and Z 1,2-dichloroethane are stereoisomers. Subcategories of stereoisomers include diastereomers and enantiomers. Both of these types of isomers contain and are different at least one chiral center.

Diastereomers are stereoisomers that are non-superimposable, non-mirror images of one another. They are different at one or more chiral centers. Enantiomers are stereoisomers that are non-superimposable mirror images of one another. Thus, for a pair of enantiomers, every chiral center is the opposite configuration.

A good formula to remember to find the number of possible stereoisomers is 2ⁿ, where n represents the number of n chiral centers of a molecule. For example, 2-bromo-3-chlorobutane contains 2 chiral centers. Therefore, 4 stereoisomeric configurations arise because each of the chiral centers can demonstrate stereoisomerism.

**Figure 10** The structure of 2-bromo-3-chlorobutane. Note that two chiral centers are present.

Recall that stereoisomers are also optically active molecules. This means that when light passes through an enantiomer, the enantiomer will rotate the field of light by a certain angle. The direction of optical rotation is either towards the right or towards the left. A compound that rotates light to the right is said to be dextrorotatory, while a compound that rotates light to the left is said to be levorotatory.

Optical rotation is unrelated to R or S conformation. Rather, it is determined experimentally. A sample of a compound would undergo experiments to determine its optical rotation. Specific rotation quantifies the optical activity of 1 g/mL of such a sample by describing the angle of rotation upon a path length of 1 dm.

e) Conformational isomers

Conformational isomers, also referred to as rotamers, are isomers that possess the same connectivity and orientation of substituents. These are isomers that differ in the rotations of individual bonds.

Rotamers are depicted using Newman projections. These are diagrams that depict the angles of substituents around a single bond. These can be considered as diagrams of bonds that are sighted “head-on” down the length of the bond itself.

Each Newman project begins with a single circle. The center of the circle depicts bonds close to the atom from the chosen perspective, while the space “behind” the circle depicts bonds away from the atom. For instance, consider a Newman projection of the central C-C bond in butane.

**Figure 11** A Newman projection of butane.

The center of the circle represents the C-C bond that is being “sighted” down. Attached to the first carbon are -CH₃, -H, and -H. These are drawn with bonds that originate from the center of the circle. Attached to the second carbon are -H, -H, and -CH₃. These are drawn with bonds that originate from behind the circle.

The single bond can also be rotated to depict different rotamers.

**Figure 12** Three conformational isomers of butane.

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Part 4: In biological systems

a) Amino acids

Chirality is important in determining the possible functions of molecules within the body. For instance, nearly all of the naturally occurring amino acids are of the S configuration at the central carbon.

A few exceptions occur. For instance, glycine is achiral, as the central alpha carbon is bound to two hydrogen atoms. Cysteine, which possesses a thiol group in its side chain, has an R configuration. This is because the sulfur of the side chain has a higher priority than oxygens of the carboxylic acid, thus leading to an R configuration.

Try determining the priorities of the functional groups on the amino acids below, and see for yourself.

**Figure 13** The amino acid structures of glycine, R-cysteine, and S-valine. Alpha carbons are marked with *

For more information on this topic, be sure to refer to our guide on proteins.

b) Carbohydrates

Monosaccharides often have multiple chiral centers. A common monosaccharide in biology is glucose, a sugar with six carbons. Glucose is classified as an aldohexose. Aldohexoses have four carbon chiral centers. Hence, there are 2⁴ = 16 different configurations possible, broadly categorized as two enantiomeric groups with eight diastereomers in each one. Since each aldohexose, or any other monosaccharide, has an enantiomer, it is important to specify the form of enantiomer via the D, L system.

The stereochemistry of glucose, or aldohexose, depends on the location of hydroxyl groups during cyclization. This is easily visualized using a Fischer projection. Fischer projections consist of horizontal lines indicating relevant substituents across a vertical backbone. Bonds that are drawn vertically are assumed to go into the page, while bonds that are drawn horizontally are assumed to come out of the page. The intersections of these bonds occur at chiral centers.

**Figure 14** Fischer projections of common carbohydrates

D-glucose, D-mannose, and D-galactose are three biologically relevant monosaccharides. D-mannose and D-galactose are epimers of glucose, which means that they are diastereomers that differ in configuration at one chiral carbon. D-mannose and D-glucose only differ at carbon 2. On the other hand, D-glucose and D-galactose only differ at carbon 4. The carbon at which epimers are formed is called the anomeric carbon.

Alpha and beta carbohydrates differ in how the straight-line molecules cyclize. In an alpha isomer, the -OH group linked to the anomeric carbon points opposite, or underneath, the in-ring oxygen. In contrast, beta isomers can be identified when the -OH group is linked to the anomeric carbon points in the same direction as, or above, the in-ring oxygen.

For instance, D-glucose can take on the form of alpha-D-glucose or beta-D-glucose, depending on the position of the -OH group in relation to the -CH₂OH group. An -OH group attached to the anomeric carbon (C1) on the same side of the -CH₂OH at C5 would yield beta-D-glucose, while bonding that results in those two groups on opposite sides would yield alpha-D-glucose.

**Figure 15** Cyclized forms of D-glucose which yield alpha-D-glucose and beta-D-glucose.

For more information on this topic, be sure to refer to our guide on carbohydrates.

c) Boat and chair conformations

Other ways to represent three-dimensional structures include chair and boat conformations. These are terms that generally refer to the conformation of cyclohexanes.

The chair conformation minimizes torsional strain and takes on a planar form to produce the most stable structure possible. The boat conformation of the same cyclohexane is slightly less stable due to the steric strain and narrow bond angles that are assumed.

**Figure 16** A chair and boat conformation of cyclohexane.

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Part 5: High-yield terms

Isomers: compounds with the same chemical formula but different arrangements of atoms

Structural isomer: compounds with the same number and types but different arrangements of atoms by covalent bonds, thus resulting in different conformations in three-dimensional space

Covalent bond: when one or more electron pairs are shared between atoms

R, S system: description of handedness used to specify chirality by setting priority on certain atomic groups

E, Z system: description of specific stereochemistry to understanding connectivity in double-bonded compounds

D, L system: description of monosaccharides to specify configuration based on the location of the -OH group of the bottom chiral center

Stereoisomers: types of isomers that do not differ in atomic connectivity but in spatial arrangements of bonds around an atom

Enantiomer: stereoisomers that are non-superimposable mirror images of one another

Diastereomer: stereoisomers that are non-superimposable, non-mirror images of one another

Chiral: describes molecules that are non-superimposable mirror images

Chiral center: atoms with four different atoms connected to it

Achiral: molecules that are superimposable and or non-mirror images of one another

Monosaccharide: a single unit of a carbohydrate sugar

Epimers: diastereomers that differ only by one chiral carbon

Anomeric carbon: asymmetric carbon at which epimers occur

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Part 6: Passage-based questions and answers

Drugs such as ibuprofen are common anti-inflammatory drugs. Isomers of ibuprofen, specifically the S isomers, bind to proteins and alter natural homeostasis in body systems such as the gastrointestinal tract. Hence, the structures of these compounds are essential to understanding their role in the human body.

In a recent study, scientists purified and analyzed phospholipids with ibuprofen and naproxen moieties. In this process, phospholipid diastereomers formed and the varying structural results yielded varying toxicity in cell lines. To further study these complex mechanisms and investigate the chirality of the resulting products, NMR spectroscopy was used in conjunction with a solvating agent that forms a diastereomer with the chiral guest. The structures of the ibuprofen and the naproxen products are shown in Figure 1.

**Figure 1** The chemical structures of ibuprofen and naproxen.

The reagent producing the diastereomer is particularly sensitive because it relates to enantiomeric excess—a comparison of how much the R configuration is present versus the S—of a molecule via analyzing the component resonances.

_{Creator and Attribution party: Kłobucki, M., Urbaniak, A., Grudniewska, A. et al. Syntheses and cytotoxicity of phosphatidylcholines containing ibuprofen or naproxen moieties. Sci Rep 9, 220 (2019). The article’s full text is available here: https://www.nature.com/articles/s41598-018-36571-1 . The article is not copyrighted by Shemmassian Academic Consulting. Disclaimer: Shemmassian Academic Consulting does not own the passage presented here. Creative common license: http://creativecommons.org/licenses/by/4.0/. Changes were made to the original article to create an MCAT-style passage.}

Question 1: Which of the following correctly describes the absolute stereochemistry of ibuprofen and naproxen, respectively?

A) R, R

B) R, S

C) S, R

D) S, S

Question 2: Refer to the atomic sites labeled in Figure 1. Which of the following sites are the chiral center(s) in ibuprofen?

A) 1 only

B) 3 only

C) 1 and 2

D) 3 and 4

Question 3: A common solvent used in NMR spectroscopy is chloroform-d. Chloroform-d replaces a hydrogen in chloroform (CHCl₃) with deuterium, an isotope of hydrogen. Which of the following statements best describes the chirality of chloroform versus chloroform-d?

A) Chloroform is chiral while chloroform-d is achiral

B) Chloroform is achiral while chloroform-d is chiral

C) Both chloroform and chloroform-d are chiral

D) Both chloroform and chloroform-d are achiral

Answer key for passage-based questions

1. Answer choice A is correct. Refer to the structures presented in Figure 1. Note that the chiral center is found at the rightmost end of the molecule. The -COOH group takes highest priority based on the atomic number, then the rest of the ring structure, then the -CH₃ group, and finally, the H group. The three functional groups with the highest priority trace a circle in the clockwise direction. The functional group of lowest priority, the hydrogen molecule, faces the back. Thus, the stereochemistry of both molecules is R.
2. Answer choice B is correct. There is a chiral center in ibuprofen because there is an sp³-hybridized carbon connected to four different groups. The chiral center must have four different groups attached to it, which is the case for the carbon at position 3. It is bonded to one methyl group, a carboxylic acid, a hydrogen atom, and the cyclic portion of the ibuprofen molecule (choice B is correct). The carbon at position 1 is bonded to two identical methyl groups (choices A and C are incorrect). The carbon at position 4 is sp² hybridized (choice D is incorrect).
3. Answer choice D is correct. Recall that a chiral center must be an sp³-hybridized carbon bonded to four different substituents. While the chloroform-d sees the hydrogen of chloroform replaced with deuterium, it is still connected to three other identical chlorine atoms (answer choices A and B are incorrect). Hence, both chloroform and chloroform-d remain achiral (answer choice C is incorrect).

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Part 7: Standalone questions and answers

Question 1: How many chiral centers exist in the following compound?

A) 0

B) 2

C) 3

D) 4

Question 2: Which of the following compounds can be referred to using E or Z configuration?

Question 3: What is the configuration of the two structures below?

A) E, Z

B) E, E

C) Z, E

D) Z, Z

Question 4: The following structures can be best described as:

A) Rotamers

B) Enantiomers

C) Structural isomers

D) They are not isomers

Answer key for standalone questions

1. Answer choice C is correct. The chiral centers are located at the following locations:

2. Answer choice C is correct. Recall that E and Z configurations are used to refer to alkene compounds. These compounds have double-bonded carbon atoms that are both attached to different functional groups (choice C is correct).

3. Answer choice A is correct. In the E configuration, the groups of highest priority lie on opposite sides of the double bond. In the first structure, the two high-priority methyl groups lie on different sides. Thus, it is in E configuration (answer choices B and D are incorrect). In the Z configuration, the groups of highest priority lie on the same side of the double bond. In the second structure, the two high-priority alkyl groups lie on the same side. Thus, it is in Z configuration (answer choice A is correct).

4. Answer choice A is correct. Because the two structures share the same molecular formula, they are indeed isomers (answer choice D is incorrect). They are rotational isomers, which are also known as rotamers or conformational isomers (choice A is correct). Since each atom is connected to another in the same manner, they are not structural isomers (answer choice C is incorrect). Since they are not mirror images of one another, they are not enantiomers (answer choice B is incorrect).

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Isomers for the MCAT: Everything You Need to Know

Master MCAT isomers with clear explanations of structural, stereoisomers, enantiomers, diastereomers, R/S configuration, and practice questions.

Table of Contents

Part 1: Introduction to isomers

Part 2: Structural isomers