Chapter 24 Organic Compounds

Conformational Isomers

The C–C single bonds in ethane, propane, and other alkanes are formed by the overlap of an sp³ hybrid orbital on one carbon atom with an sp³ hybrid orbital on another carbon atom, forming a σ bond (Figure 24.3 "Carbon–Carbon Bonding in Alkanes"). Each sp³ hybrid orbital is cylindrically symmetrical (all cross-sections are circles), resulting in a carbon–carbon single bond that is also cylindrically symmetrical about the C–C axis. Because rotation about the carbon–carbon single bond can occur without changing the overlap of the sp³ hybrid orbitals, there is no significant electronic energy barrier to rotation. Consequently, many different arrangements of the atoms are possible, each corresponding to different degrees of rotation. Differences in three-dimensional structure resulting from rotation about a σ bond are called differences in conformation, and each different arrangement is called a conformational isomer (or conformer)Isomers whose three-dimensional structures differ because of rotation about a σ bond..

Figure 24.3 Carbon–Carbon Bonding in Alkanes

Overlapping sp³ hybrid orbitals on adjacent carbon atoms form a cylindrically symmetrical σ bond. Because rotation about the bond does not affect the overlap of the bonding orbitals, there is no electronic energy barrier to rotation.

The simplest alkane to have a conformational isomer is ethane. Differences between the conformations of ethane are depicted especially clearly in drawings called Newman projections, such as those shown in part (a) in Figure 24.4 "Eclipsed and Staggered Conformations of Ethane". In a Newman projection, the ethane molecule is viewed along the C–C axis, with the carbon that is in front shown as a vertex and the carbon that is in back shown as a circle. The three hydrogen atoms nearest the viewer are shown bonded to the front carbon, and the three hydrogen atoms farthest from the viewer are shown bonded to the circle. In one extreme, called the eclipsed conformation, the C–H bonds on adjacent carbon atoms lie in the same plane. In the other extreme, called the staggered conformation, the hydrogen atoms are positioned as far from one another as possible. Rotation about the C–C bond produces an infinite number of conformations between these two extremes, but the staggered conformation is the most stable because it minimizes electrostatic repulsion between the hydrogen atoms on adjacent carbons.

Figure 24.4 Eclipsed and Staggered Conformations of Ethane

(a) In a Newman projection, the molecule is viewed along a C–C axis. The carbon in front is represented as a vertex, whereas the carbon that is bonded to it is represented as a circle. In ethane, the C–H bonds to each carbon are positioned at 120° from each other. In the fully eclipsed conformation, the C–H bonds on adjacent carbon atoms are parallel and lie in the same plane. In the staggered conformation, the hydrogen atoms are positioned as far apart as possible. (b) The eclipsed conformation is 12.6 kJ/mol higher in energy than the staggered conformation because of electrostatic repulsion between the hydrogen atoms. An infinite number of conformations of intermediate energy exist between the two extremes.

In a Newman projection, the angles between adjacent C–H bonds on the same carbon are drawn at 120°, although H–C–H angles in alkanes are actually tetrahedral angles of 109.5°, which for chains of more than three carbon atoms results in a kinked structure. (For more information on bond angles and molecular modeling, see Chapter 2 "Molecules, Ions, and Chemical Formulas", Section 2.1 "Chemical Compounds".) Despite this three-dimensional inaccuracy, Newman projections are useful for predicting the relative stability of conformational isomers. As shown in part (b) in Figure 24.4 "Eclipsed and Staggered Conformations of Ethane", the higher energy of the eclipsed conformation represents an energy barrier of 12.6 kJ/mol that must be overcome for rotation about the C–C bond to occur. This barrier is so low, however, that rotation about the C–C bond in ethane is very fast at room temperature and occurs several million times per second for each molecule.

Longer-chain alkanes can also be represented by Newman projections. In more complex alkanes and alkane derivatives, rotation can occur about each C–C bond in a molecule. Newman projections are therefore useful for revealing steric barriers to rotation at a particular C–C bond due to the presence of bulky substituents. Figure 24.5 "Potential Energy Plot and Newman Projections of Eclipsed and Staggered Conformations of " shows a plot of potential energy versus the angle of rotation about the central C–C bond (between carbon atoms 2 and 3) of n-butane (C₄H₁₀). The structure that minimizes electrostatic repulsion is the one in which the methyl groups, corresponding to carbon atoms 1 and 4, are as far apart as possible; that is, the staggered conformation. Notice that because the substituents on C2 and C3 in n-butane are not all the same, energetically nonequivalent eclipsed and staggered conformations are possible; most molecules interconvert rapidly between these conformations by a series of simple rotations.

Figure 24.5 Potential Energy Plot and Newman Projections of Eclipsed and Staggered Conformations of n-Butane

In these projections, the molecule is viewed along the C2–C3 axis. The least stable structure is the eclipsed conformation in which the two methyl groups (C1 and C4) are adjacent to each other. The most stable structure is the staggered conformation in which the methyl groups are as far apart as possible. Because the substituents on each central carbon atom are not all the same, a 120° rotation about the C2–C3 bond generates energetically nonequivalent eclipsed and staggered conformations.

Example 1

Draw Newman projections showing the staggered and eclipsed conformations of 1,1,1-trichloroethane (CCl₃CH₃).

Given: organic molecule

Asked for: staggered and eclipsed conformations

Strategy:

A Identify the C–C bond of interest. Then draw the Newman projection by representing one carbon as a vertex and the other as a circle.

B Draw bonds to each carbon at 120° angles from one another, with one arrangement representing the staggered conformation and the other the eclipsed conformation.

C Complete the Newman projections by attaching the appropriate atoms or substituent groups to the central C atoms in each conformation.

Solution:

A There is only one C–C bond: C1 is connected to three Cl atoms and C2 to three H atoms. We draw C1 as a point and C2 as a circle.

B Now we draw bonds on each carbon at 120° angles from one another to represent the staggered conformation and the eclipsed conformation.

C We then attach the H and Cl atoms to the carbon atoms in each conformation as shown.

Exercise

Draw Newman projections to illustrate the staggered and eclipsed conformations of propane (C₃H₈) as viewed along the C1–C2 axis.

Answer:

Structural Isomers

Unlike conformational isomers, which do not differ in connectivity, structural isomersIsomers that have the same molecular formula but differ in which atoms are bonded to one another. differ in connectivity, as illustrated here for 1-propanol and 2-propanol. (For more information on structural isomers, see Chapter 23 "The ", Section 23.4 "Coordination Compounds".) Although these two alcohols have the same molecular formula (C₃H₈O), the position of the –OH group differs, which leads to differences in their physical and chemical properties.

In the conversion of one structural isomer to another, at least one bond must be broken and reformed at a different position in the molecule. Consider, for example, the following five structures represented by the formula C₅H₁₂:

Of these structures, (a) and (d) represent the same compound, as do (b) and (c). No bonds have been broken and reformed; the molecules are simply rotated about a 180° vertical axis. Only three—n-pentane (a) and (d), 2-methylbutane (b) and (c), and 2,2-dimethylpropane (e)—are structural isomers. Because no bonds are broken in going from (a) to (d) or from (b) to (c), these alternative representations are not structural isomers. The three structural isomers—either (a) or (d), either (b) or (c), and (e)—have distinct physical and chemical properties.

Example 2

Draw all the structural isomers of C₆H₁₄.

Given: organic molecule

Asked for: all structural isomers

Strategy:

A Draw the simplest structural isomer, which is often the straight-chain alkane.

B Obtain branched isomers by substituting one hydrogen along the chain with an appropriate group from the chain.

C If possible, substitute more than one hydrogen with appropriate groups to obtain isomers that are more highly branched.

Solution:

A The simplest structural isomer is the straight-chain alkane n-hexane (CH₃CH₂CH₂CH₂CH₂CH₃).

B Removing a methyl group from one end and reattaching it to adjacent carbons while substituting hydrogen in its place give two other structures:

C To obtain yet another structural isomer, move two methyl groups to create a molecule with two branches:

We create one more structural isomer by attaching two methyl groups to the same carbon atom:

Thus there are four structural isomers of C₆H₁₄.

Exercise

Draw all the structural isomers of C₄H₉Cl.

Answer:

Stereoisomers

Molecules with the same connectivity but different arrangements of the atoms in space are called stereoisomersMolecules that have the same connectivity but whose component atoms have different orientations in space.. There are two types of stereoisomers: geometric and optical. Geometric isomers differ in the relative position(s) of substituents in a rigid molecule. (For more information on stereoisomers, see Chapter 23 "The ", Section 23.4 "Coordination Compounds".) Simple rotation about a C–C σ bond in an alkene, for example, cannot occur because of the presence of the π bond. The substituents are therefore rigidly locked into a particular spatial arrangement (part (a) in Figure 2.16 "Some Simple (a) Alkenes, (b) Alkynes, and (c) Cyclic Hydrocarbons"). Thus a carbon–carbon multiple bond, or in some cases a ring, prevents one geometric isomer from being readily converted to the other. The members of an isomeric pair are identified as either cis or trans, and interconversion between the two forms requires breaking and reforming one or more bonds. Because their structural difference causes them to have different physical and chemical properties, cis and trans isomers are actually two distinct chemical compounds.

Optical isomers are molecules whose structures are mirror images but cannot be superimposed on one another in any orientation. Optical isomers have identical physical properties, although their chemical properties may differ in asymmetric environments. Molecules that are nonsuperimposable mirror images of each other are said to be chiral (pronounced “ky-ral,” from the Greek cheir, meaning “hand”). Examples of some familiar chiral objects are your hands, feet, and ears. As shown in part (a) in Figure 24.6 "Chiral and Achiral Objects", your left and right hands are nonsuperimposable mirror images. (Try putting your right shoe on your left foot—it just doesn’t work.) An achiral object is one that can be superimposed on its mirror image, as shown by the superimposed flasks in part (b) in Figure 24.6 "Chiral and Achiral Objects".

Figure 24.6 Chiral and Achiral Objects

(a) Objects that are nonsuperimposable mirror images of each other are chiral, such as the left and the right hand. (b) The unmarked flask is achiral because it can be superimposed on its mirror image.

Most chiral organic molecules have at least one carbon atom that is bonded to four different groups, as occurs in the bromochlorofluoromethane molecule shown in part (a) in Figure 24.7 "Comparison of Chiral and Achiral Molecules". This carbon, often designated by an asterisk in structural drawings, is called a chiral center or asymmetric carbon atom. If the bromine atom is replaced by another chlorine (part (b) in Figure 24.7 "Comparison of Chiral and Achiral Molecules"), the molecule and its mirror image can now be superimposed by simple rotation. Thus the carbon is no longer a chiral center. Asymmetric carbon atoms are found in many naturally occurring molecules, such as lactic acid, which is present in milk and muscles, and nicotine, a component of tobacco. A molecule and its nonsuperimposable mirror image are called enantiomers (from the Greek enantiou, meaning “opposite”).

Figure 24.7 Comparison of Chiral and Achiral Molecules

(a) Bromochlorofluoromethane is a chiral molecule whose stereocenter is designated with an asterisk. Rotation of its mirror image does not generate the original structure. To superimpose the mirror images, bonds must be broken and reformed. (b) In contrast, dichlorofluoromethane and its mirror image can be rotated so they are superimposable.

Optical Activity of Enantiomers

Although enantiomers have identical densities, melting and boiling points, colors, and solubility in most solvents, they differ in their interaction with plane-polarized light, which consists of electromagnetic waves oscillating in a single plane. In contrast, normal (unpolarized) light consists of electromagnetic waves oscillating in all directions perpendicular to the axis of propagation. When normal light is passed through a substance called a polarizer, only light oscillating in one direction is transmitted. A polarizer selectively filters out light that oscillates in any but the desired plane (Figure 24.8 "Detecting the Optical Activity of Chiral Substances").

Figure 24.8 Detecting the Optical Activity of Chiral Substances

When polarized light is passed through a solution that contains an achiral compound, there is no net rotation of the plane of polarization of the light. In contrast, when polarized light is passed through a solution that contains one enantiomer of a chiral compound, as shown here, the light is rotated either clockwise [dextrorotatory, (+) enantiomer] or counterclockwise [levorotatory, (−) enantiomer] by an angle that depends on the molecular structure and concentration of the compound, the path length, and the wavelength of the light.

When plane-polarized light is passed through a solution, electromagnetic radiation interacts with the solute and solvent molecules. If the solution contains an achiral compound, the plane-polarized light enters and leaves the solution unchanged because achiral molecules cause it to rotate in random directions. The solute is therefore said to be optically inactive. If the solution contains a single enantiomer of a chiral compound, however, the plane-polarized light is rotated in only one direction, and the solute is said to be optically active. A clockwise rotation is called dextrorotatory (from the Latin dextro, meaning “to the right”) and is indicated in the name of the compound by (+), whereas a counterclockwise rotation is called levorotatory (from the Latin levo, meaning “to the left”) and is designated (−). As you will soon discover, this designation is important in understanding how chiral molecules interact with one another.

Note the Pattern

Chiral molecules are optically active; achiral molecules are not.

The magnitude of the rotation of plane-polarized light is directly proportional to the number of chiral molecules in a solution; it also depends on their molecular structure, the temperature, and the wavelength of the light. Because of these variables, every chiral compound has a specific rotationThe amount (in degrees) by which the plane of polarized light is rotated when the light is passed through a solution that contains 1.0 g of a solute per 1.0 mL of solvent in a tube 10.0 cm long., which is defined as the amount (in degrees) by which the plane of polarized light is rotated when the light is passed through a solution containing 1.0 g of solute per 1.0 mL of solvent in a tube 10.0 cm long. A chiral solution that contains equal concentrations of a pair of enantiomers is called a racemic mixture. In such a solution, the optical rotations exactly cancel one another, so there is no net rotation, and the solution is optically inactive. The categories of stereoisomers are summarized in Figure 24.9 "Classification of Stereoisomers".

Figure 24.9 Classification of Stereoisomers

In both types of stereoisomer—geometric and optical—isomeric molecules have identical connectivity, but the arrangement of atoms in space differs. Cis and trans isomers exhibit different physical and chemical properties, whereas enantiomers differ only in their interaction with plane-polarized light and reactions in asymmetric environments. Depending on the direction in which they rotate polarized light, enantiomers are identified as (+) or (−). The designations L- and D- represent an alternative labeling system.

Interactions of Enantiomers with Other Chiral Molecules

In living organisms, virtually every molecule that contains a chiral center is found as a single enantiomer, not a racemic mixture. At the molecular level, our bodies are chiral and interact differently with the individual enantiomers of a particular compound. For example, the two enantiomers of carvone produce very different responses in humans: (−)-carvone is the substance responsible for the smell of spearment oil, and (+)-carvone—the major flavor component of caraway seeds—is responsible for the characteristic aroma of rye bread.

A pharmaceutical example of a chiral compound is ibuprofen, a common analgesic and anti-inflammatory agent that is the active ingredient in pain relievers such as Motrin and Advil (Figure 24.16 "Biologically Active Substituted Arenes"). The drug is sold as a racemic mixture that takes approximately 38 minutes to achieve its full effect in relieving pain and swelling in an adult human. Because only the (+) enantiomer is active in humans, however, the same mass of medication would relieve symptoms in only about 12 minutes if it consisted of only the (+) enantiomer. Unfortunately, isolating only the (+) enantiomer would substantially increase the cost of the drug. Conversion of the (−) to (+) enantiomer in the human body accounts for the delay in feeling the full effects of the drug. A racemic mixture of another drug, the sedative thalidomide, was sold in Europe from 1956 to the early 1960s. It was prescribed to treat nausea during pregnancy, but unfortunately only the (+) enantiomer was safe for that purpose. The (−) enantiomer was discovered to be a relatively potent teratogen, a substance that causes birth defects, which caused the children of many women who had taken thalidomide to be born with missing or undeveloped limbs. As a result, thalidomide was quickly banned for this use. It is currently used to treat leprosy, however, and it has also shown promise as a treatment for AIDS (acquired immunodeficiency syndrome).

These examples dramatically illustrate the point that the biological activities of enantiomers may be very different. But how can two molecules that differ only by being nonsuperimposable mirror images cause such different responses? The biological effects of many substances—including molecules such as carvone that have a scent and drugs such as ibuprofen and thalidomide—depend on their interaction with chiral sites on specific receptor proteins. As schematically illustrated in Figure 24.10 "The Interaction of Chiral Molecules with Biological Receptors", only one enantiomer of a chiral substance interacts with a particular receptor, thereby initiating a response. The other enantiomer may not bind at all, or it may bind to another receptor, producing a different response.

Figure 24.10 The Interaction of Chiral Molecules with Biological Receptors

Only one enantiomer of a chiral molecule fits into a chiral receptor site, which typically is a small portion of a large protein. The binding of a molecule to its receptor elicits a characteristic response. The other enantiomer cannot fit into the same site and thus elicits no response. It may, however, produce a different response by binding to another site.

Summary

Isomers are different compounds that have the same molecular formula. For an organic compound, rotation about a σ bond can produce different three-dimensional structures called conformational isomers (or conformers). In a Newman projection, which represents the view along a C–C axis, the eclipsed conformation has the C–H bonds on adjacent carbon atoms parallel to each other and in the same plane, representing one conformational extreme. In the staggered conformation, the opposite extreme, the hydrogen atoms are as far from one another as possible. Electrostatic repulsions are minimized in the staggered conformation. Structural isomers differ in the connectivity of the atoms. Structures that have the same connectivity but whose components differ in their orientations in space are called stereoisomers. Stereoisomers can be geometric isomers, which differ in the placement of substituents in a rigid molecule, or optical isomers, nonsuperimposable mirror images. Molecules that are nonsuperimposable mirror images are chiral molecules. A molecule and its nonsuperimposable mirror image are called enantiomers. These differ in their interaction with plane-polarized light, light that oscillates in only one direction. A compound is optically active if its solution rotates plane-polarized light in only one direction and optically inactive if its rotations cancel to produce no net rotation. A clockwise rotation is called dextrorotatory and is indicated in the compound’s name by (+), whereas a counterclockwise rotation is called levorotatory, designated by (−). The specific rotation is the amount (in degrees) by which the plane of polarized light is rotated when light is passed through a solution containing 1.0 g of solute per 1.0 mL of solvent in a tube 10.0 cm long. A solution that contains equal concentrations of each enantiomer in a pair is a racemic mixture; such solutions are optically inactive.

Key Takeaways

• Isomers can be conformational or structural.
• Stereoisomers have the same connectivity but can be optical or geometric isomers.

Conceptual Problems

1. What hybrid orbitals are used to form C–C bonds in saturated hydrocarbons? Describe the bond.

2. How are conformational isomers related? Sketch two conformational isomers of propane, looking along the C1–C2 axis.

3. Why do alkanes with more than two carbons have a kinked structure? Explain why a kinked structure is so stable.

4. Are n-pentane and 2-methylbutane conformational isomers or structural isomers? How would you separate these compounds from a mixture of the two?

5. How are structural isomers different from stereoisomers? Do stereoisomers have free rotation about all carbon–carbon bonds? Explain your answers.

6. Which of these objects is chiral?

   1. a shoe
   2. a laced football
   3. an automobile
   4. a fork

7. Which of these objects is chiral?

   1. a rollerblade
   2. an unmarked baseball bat
   3. a bicycle
   4. your arms
   5. a spoon

8. Are all stereoisomers also enantiomers? Are all enantiomers stereoisomers? Explain your answers.

Answers

1. sp³; it is a σ bond that is cylindrically symmetrical (all cross sections perpendicular to the internuclear axis are circles).

3. The sp³ hybridized orbitals form bonds at tetrahedral angles (109.5°), which forces the carbon atoms to form a zigzag chain.

7. (a), (c), and (d)

Structure and Reactivity

1. Single bonds between carbon atoms are free to rotate 360°.

   1. Explain what happens to the potential energy of an n-hexane molecule as rotation occurs around the C2–C3 bond.

   2. Draw Newman projections of the n-hexane conformations corresponding to the energy minima and maxima in the diagram, which shows potential energy versus degrees of rotation about the C3–C4 axis.

      

2. Sketch all the structural isomers of each compound.

   1. C₆H₁₃Br
   2. C₃H₆Cl₂

3. Draw all the possible structural isomers of each compound.

   1. C₅H₁₁Br
   2. C₄H₈Cl₂

4. Sketch all the isomers of each compound. Identify the cis- and trans-isomers.

   1. monochlorobutene
   2. bromochloropropene

5. Which molecules are chiral? On the structural formulas of the chiral molecules, identify any chiral centers with an asterisk.

   1. 2,2-dimethylpentane
   2. 1,2-dimethylpentane
   3. 2,4-dimethylpentane
   4. 1-chloro-2-methylpentane

6. Which molecules are chiral? On the structural formulas of the chiral molecules, identify any chiral centers with an asterisk.

   1. 1,1-dichloropropane
   2. 1,2-dichloropropane
   3. 1,3-dichloropropane
   4. 1,1,2-trichloropropane

7. Draw the structures of the enantiomers of each compound.

   1. CH₂CHCHClBr
   2. 4-chloro-2-hexene
   3. methylethylpropylamine

8. Draw the structures of the enantiomers of each compound.

   1. 4-methyl-2-hexene
   2. methylethylhexylamine
   3. CH₃CH₂CH(CH₃)Cl

9. Draw the structures of the enantiomers of each compound.

   1. 
   2. 

10. Draw the structures of the enantiomers of each compound.

    1. 
    2. 
    3. 

Answers

3.  

   1. 

   2. 

5. (b) and (d);

   

Reactive Intermediates

Cleaving a C–H bond can generate either –C⁺ and H⁻, −C· and H· or −C⁻ and H⁺, all of which are unstable and therefore highly reactive. The most common species formed is –C⁺, which is called a carbocationA highly reactive species that can form when a C–H bond is cleaved, carbocations have only six valence electrons and are electrophiles. (part (a) in Figure 24.11 "Transient Intermediates in Organic Reactions"). A carbocation has only six valence electrons and is therefore electron deficient. It is an electrophileAn electron-deficient species that needs electrons to complete its octet. (from “electron” and the Greek suffix phile, meaning “loving”), which is a species that needs electrons to complete its octet. (Recall that electron-deficient compounds, such as those of the group 13 elements, act as Lewis acids in inorganic reactions.) In general, when a highly electronegative atom, such as Cl, is bonded to a carbocation, it draws electrons away from the carbon and destabilizes the positive charge. In contrast, alkyl groups and other species stabilize the positive charge by increasing electron density at the carbocation. Thus a tertiary carbocation (R₃C⁺) is more stable than a primary carbocation (RCH₂⁺).

Adding one electron to a carbocation produces a neutral species called a radicalHighly reactive species that have an unpaired valence electron.. (For more information on radicals, see Chapter 14 "Chemical Kinetics", Section 14.6 "Reaction Rates—A Microscopic View".) An example is the methyl radical (·CH₃), shown in part (b) in Figure 24.11 "Transient Intermediates in Organic Reactions". Because the carbon still has less than an octet of electrons, it is electron deficient and also behaves as an electrophile. Like carbocations, radicals can be stabilized by carbon substituents that can donate some electron density to the electron-deficient carbon center. Like carbocations, a tertiary radical (R₃C·) is more stable than a primary radical (RCH₂·).

Figure 24.11 Transient Intermediates in Organic Reactions

(a) The simplest carbocation is the methyl cation (CH₃⁺), which has six valence electrons and is an electrophile. Its structure is trigonal planar, with an sp² hybridized carbon and a vacant p orbital. (b) The methyl radical (·CH₃) is a radical that, like the carbocation, is trigonal planar and an electrophile. It is also sp² hybridized, but there is a single electron in the unhybridized p orbital. (c) The simplest organic carbanion is CH₃⁻, which has a trigonal pyramidal structure with an sp³ hybridized carbon that has a lone pair of electrons. Because it has a strong tendency to share its lone pair with another atom or molecule, a carbanion is a nucleophile.

Adding an electron to a radical produces a carbanionA highly reactive species that can form when a C–H bond is cleaved, carbanions have eight valence electrons and are nucleophiles., which contains a negatively charged carbon with eight valence electrons (part (c) in Figure 24.11 "Transient Intermediates in Organic Reactions"). The methyl anion (CH₃⁻) has a structure that is similar to NH₃ with its lone pair of electrons, but it has a much stronger tendency to share its lone pair with another atom or molecule. A carbanion is a nucleophileAn electron-rich species that has a pair of electrons available to be shared with another atom. (from “nucleus” and phile), an electron-rich species that has a pair of electrons available to share with another atom. Carbanions are destabilized by groups that donate electrons, so the relationship between their structure and reactivity is exactly the opposite of carbocations and radicals. That is, a tertiary carbanion (R₃C⁻) is less stable than a primary carbanion (RCH₂⁻). Carbanions are most commonly encountered in organometallic compounds such as methyllithium (CH₃Li) or methylmagnesium chloride (CH₃MgCl), where the more electropositive metal ion stabilizes the negative charge on the more electronegative carbon atom.

Electrophiles such as carbocations seek to gain electrons and thus have a strong tendency to react with nucleophiles, which are negatively charged species or substances with lone pairs of electrons. Reacting electrophiles with nucleophiles is a central theme in organic reactions.

Substitution

In a substitution reactionA chemical reaction in which one atom or a group of atoms in a substance is replaced by another atom or a group of atoms from another substance., one atom or a group of atoms in a substance is replaced by another atom or group of atoms from another substance. A typical substitution reaction is reacting the hydroxide ion with methyl chloride:

Methyl chloride has a polar C–Cl bond, with the carbon atom having a partial positive charge. In Equation 24.1, the electronegative Cl atom is replaced by another electronegative species that is a stronger nucleophile, in this case OH⁻. Reactions of this sort are called nucleophilic substitution reactions. For this type of reaction to occur, the nucleophilic reactant must possess a pair of electrons and have a greater affinity for the electropositive carbon atom than the original substituent.

One type of nucleophilic substitution reaction is shown in Equation 24.1. It proceeds by a mechanism in which the lone pair of electrons on the entering nucleophile (OH⁻) attacks the partially positively charged carbon atom of the polar C–Cl bond, causing the C–Cl bond to weaken and break:

Figure 24.12

 

The convention for writing such a mechanism is to draw arrows showing the direction of electron flow—that is, from the electron-rich center (the nucleophile) to the electron-poor center (the electrophile). The intermediate species, enclosed by square brackets, represents a transient arrangement of atoms that is only postulated to exist. If the atom under attack (in this case, the partially positively charged carbon atom) had –CH₃ groups bonded to it rather than H atoms, the bulky methyl groups would interfere with the attack by OH⁻, making the reaction sterically hindered. The reaction would then proceed in two discrete steps in a second type of substitution reaction: the C–Cl bond would break, forming the (CH₃)₃C⁺ carbocation (the electrophile), which would then react with hydroxide (the nucleophile) in a separate step to give the product, (CH₃)₃COH.

Mustard gas.

An example of a nucleophilic substitution reaction involves the chemical warfare agent known as mustard gas [(ClCH₂CH₂)₂S], which caused about 400,000 casualties during World War I. Mustard gas is toxic because it contains a chloride that can be displaced by nucleophilic amino groups in proteins, thereby allowing the molecule to irreversibly bond to a protein. Because the other product of the reaction is HCl, mustard gas causes severe burns to mucous membranes in the respiratory tract. If mustard gas reacts with DNA (deoxyribonucleic acid), cross-linking of the DNA strands through sulfur occurs, which results in coding errors, the inhibition of replication, and disruption of other DNA functions. If mustard gas reacts with RNA (ribonucleic acid), protein synthesis is altered (see Section 24.6 "The Molecules of Life").

Elimination

Some reactions involve the removal, or “elimination,” of adjacent atoms from a molecule. This results in the formation of a multiple bond and the release of a small molecule, so they are called elimination reactionsA chemical reaction in which adjacent atoms are removed, or “eliminated,” from a molecule, resulting in the formation of a multiple bond and a small molecule.. They have the general form

Figure 24.13

 

and are similar to cleavage reactions in inorganic compounds. (For more information on cleavage reactions, see Chapter 3 "Chemical Reactions", Section 3.5 "Classifying Chemical Reactions".) A typical example is the conversion of ethyl chloride to ethylene:

Much of the approximately 26 million tons of ethylene produced per year in the United States is used to synthesize plastics, such as polyethylene. In Equation 24.2, the A–B molecule eliminated is HCl, whose components are eliminated as H⁺ from the carbon atom on the left and Cl⁻ from the carbon on the right. When an acid is produced, as occurs here, the reaction is generally carried out in the presence of a base (such as NaOH) to neutralize the acid.

Addition

A reaction in which the components of a species A–B are added to adjacent atoms across a carbon–carbon multiple bond is called an addition reactionA chemical reaction in which the components of a species A–B are added to adjacent atoms across a carbon-carbon multiple bond.. An example is the reverse of the reaction shown in Equation 24.2, reacting HCl with ethylene to give ethyl chloride:

Although a multiple bond is stronger than a single bond, the π bonds of the multiple bond are weaker than the σ bond. The high electron density located between multiply bonded carbon atoms, however, causes alkenes and alkynes to behave like nucleophiles, where nucleophilic attack occurs from the more weakly bound π electrons. Hence alkenes and alkynes are regarded as functional groups. Nucleophilic attack occurs on the H^δ+ atom of the polar HCl bond, initially producing a species with a carbon that has only three bonds, a carbocation. In a second nucleophilic attack, Cl⁻, the electrophile in Equation 24.3, attacks the carbocation:

Alcohols, an important class of organic compounds, are often produced by addition reactions. Initial attack by the π bond of an alkene on a H^δ+ of H₃O⁺ produces a carbocation. The carbocation then undergoes nucleophilic attack by a lone pair of electrons from H₂O followed by elimination of H⁺ to form the alcohol.

Radical Reactions

Many important organic reactions involve radicals, such as the combustion of fuels. Probably the best known is reacting a saturated hydrocarbon, such as ethane, with a halogen, such as Br₂. The overall reaction is as follows:

Radical chain reactions occur in three stages: initiation, propagation, and termination. (For more information on radicals, see Chapter 14 "Chemical Kinetics", Section 14.6 "Reaction Rates—A Microscopic View".) At high temperature or in the presence of light, the relatively weak Br–Br bond is broken in an initiation step that produces an appreciable number of Br atoms (Br·). During propagation, a bromine atom attacks ethane, producing a radical, which then reacts with another bromine molecule to produce ethyl bromide:

The sum of the two propagation steps corresponds to the balanced chemical equation for the overall reaction. There are three possible termination steps: the combination of (1) two bromine atoms, (2) two ethyl radicals, or (3) an ethyl and a bromine radical:

Because radicals are powerful nucleophiles and hence highly reactive, such reactions are not very selective. For example, the chlorination of n-butane gives a roughly 70:30 mixture of 2-chlorobutane, formed from the more stable radical by reacting a secondary carbon and 1-chlorobutane.

Oxidation–Reduction Reactions

Oxidation–reduction reactions, which are common in organic chemistry, can often be identified by changes in the number of oxygen atoms at a particular position in the hydrocarbon skeleton or in the number of bonds between carbon and oxygen at that position. An increase in either corresponds to an oxidation, whereas a decrease corresponds to a reduction. Conversely, an increase in the number of hydrogen atoms in a hydrocarbon is often an indication of a reduction. We can illustrate these points by considering how the oxidation state of the carbon atom changes in the series of compounds, which is shown in part (a) in Figure 24.14 "The Oxidation State of Carbon in Oxygen- and Nitrogen-Containing Functional Groups". (For a review of oxidation states and formal changes, see Chapter 3 "Chemical Reactions", Section 3.5 "Classifying Chemical Reactions", and Chapter 8 "Ionic versus Covalent Bonding", Section 8.5 "Lewis Structures and Covalent Bonding"). The number of oxygen atoms or the number of bonds to oxygen changes throughout the series. Hence the conversion of methane to formic acid is an oxidation, whereas the conversion of carbon dioxide to methanol is a reduction. Also, the number of hydrogen atoms increases in going from the most oxidized to least oxidized compound. As expected, as the oxidation state of carbon increases, the carbon becomes a more potent electrophile. Thus the carbon of CO₂ is a stronger electrophile (i.e., more susceptible to nucleophilic attack) than the carbon of an alkane such as methane.

Figure 24.14 The Oxidation State of Carbon in Oxygen- and Nitrogen-Containing Functional Groups

(a) In a hydrocarbon, oxidation is indicated by an increase in the number of oxygen atoms or carbon–oxygen bonds or a decrease in the number of hydrogen atoms. (b) In nitrogen-containing compounds, the number of carbon–nitrogen bonds changes with the oxidation state of carbon.

Similarly, in compounds with a carbon–nitrogen bond, the number of bonds between the C and N atoms increases as the oxidation state of the carbon increases (part (b) in Figure 24.14 "The Oxidation State of Carbon in Oxygen- and Nitrogen-Containing Functional Groups"). In a nitrile, which contains the –C≡N group, the carbon has the same oxidation state (+2) as in a carboxylic acid, characterized by the –CO₂H group. We therefore expect the carbon of a nitrile to be a rather strong electrophile.

Alkanes, Alkenes, and Alkynes

The boiling points of alkanes increase smoothly with increasing molecular mass. They are similar to those of the corresponding alkenes and alkynes because of similarities in molecular mass between analogous structures (Table 24.1 "Boiling Points (in °C) of Alkanes, Alkenes, and Alkynes of Comparable Molecular Mass"). In contrast, the melting points of alkanes, alkenes, and alkynes with similar molecular masses show a much wider variation because the melting point strongly depends on how the molecules stack in the solid state. It is therefore sensitive to relatively small differences in structure, such as the location of a double bond and whether the molecule is cis or trans.

Because alkanes contain only C–C and C–H bonds, which are strong and not very polar (the electronegativities of C and H are similar; Figure 7.15 "Pauling Electronegativity Values of the "), they are not easily attacked by nucleophiles or electrophiles. Consequently, their reactivity is limited, and often their reactions occur only under extreme conditions. For example, catalytic cracking can be used to convert straight-chain alkanes to highly branched alkanes, which are better fuels for internal combustion engines. Catalytic cracking is one example of a pyrolysis reactionA high-temperature decomposition reaction that can be used to form fibers of synthetic polymers. (from the Greek pyros, meaning “fire,” and lysis, meaning “loosening”), in which alkanes are heated to a sufficiently high temperature to induce cleavage of the weakest bonds: the C–C single bonds. The result is a mixture of radicals derived from essentially random cleavage of the various C–C bonds in the chain. Pyrolysis of n-pentane, for example, is nonspecific and can produce these four radicals:

Recombination of these radicals (a termination step) can produce ethane, propane, butane, n-pentane, n-hexane, n-heptane, and n-octane. Radicals that are formed in the middle of a chain by cleaving a C–H bond tend to produce branched hydrocarbons. In catalytic cracking, lighter alkanes are removed from the mixture by distillation.

Radicals are also produced during the combustion of alkanes, with CO₂ and H₂O as the final products. As discussed in Section 24.3 "Reactivity of Organic Molecules", radicals are stabilized by the presence of multiple carbon substituents that can donate electron density to the electron-deficient carbon. The chemical explanation of octane ratings, as described in Chapter 2 "Molecules, Ions, and Chemical Formulas", Section 2.6 "Industrially Important Chemicals", rests partly on the stability of radicals produced from the different hydrocarbon fuels. Recall that n-heptane, which does not burn smoothly, has an octane rating of 0, and 2,2,4-trimethylpentane (“isooctane”), which burns quite smoothly, has a rating of 100 (Figure 2.25 "The Octane Ratings of Some Hydrocarbons and Common Additives"). Isooctane has a branched structure and is capable of forming tertiary radicals that are comparatively stable.

In contrast, the radicals formed during the combustion of n-heptane, whether primary or secondary, are less stable and hence more reactive, which partly explains why burning n-heptane causes premature ignition and engine knocking.

In Section 24.2 "Isomers of Organic Compounds", we explained that rotation about the carbon–carbon multiple bonds of alkenes and alkynes cannot occur without breaking a π bond, which therefore constitutes a large energy barrier to rotation (Figure 24.15 "Carbon–Carbon Bonding in Alkenes and Interconversion of "). Consequently, the cis and trans isomers of alkenes generally behave as distinct compounds with different chemical and physical properties. A four-carbon alkene has four possible isomeric forms: three structural isomers, which differ in their connectivity, plus a pair of geometric isomers from one structural isomer (2-butene). These two geometric isomers are cis-2-butene and trans-2-butene. The four isomers have significantly different physical properties.

Figure 24.15 Carbon–Carbon Bonding in Alkenes and Interconversion of Cis and Trans Isomers

In butane, there is only a small energy barrier to rotation about the C2–C3 σ bond. In the formation of cis- or trans-2-butene from butane, the p orbitals on C2 and C3 overlap to form a π bond. To convert cis-2-butene to trans-2-butene or vice versa through rotation about the double bond, the π bond must be broken. Because this interconversion is energetically unfavorable, cis and trans isomers are distinct compounds that generally have different physical and chemical properties.

Alkynes in which the triple bond is located at one end of a carbon chain are called terminal alkynes and contain a hydrogen atom attached directly to a triply bonded carbon: R–C≡C–H. Terminal alkynes are unusual in that the hydrogen atom can be removed relatively easily as H⁺, forming an acetylide ion (R–C≡C⁻). Acetylide ions are potent nucleophiles that are especially useful reactants for making longer carbon chains by a nucleophilic substitution reaction. As in earlier examples of such reactions, the nucleophile attacks the partially positively charged atom in a polar bond, which in the following reaction is the carbon of the Br–C bond:

Alkenes and alkynes are most often prepared by elimination reactions (Figure 24.13). A typical example is the preparation of 2-methyl-1-propene, whose derivative, 3-chloro-2-methyl-1-propene, is used as a fumigant and insecticide. The parent compound can be prepared from either 2-hydroxy-2-methylpropane or 2-bromo-2-methylpropane:

The reaction on the left proceeds by eliminating the elements of water (H⁺ plus OH⁻), so it is a dehydration reactionA reaction that proceeds by eliminating the elements of water ${\text{(H}}^{+}{\text{ and OH}}^{-}\text{)}\text{.}$. If an alkane contains two properly located functional groups, such as –OH or –X, both of them may be removed as H₂O or HX with the formation of a carbon–carbon triple bond:

Arenes

Most arenes that contain a single six-membered ring are volatile liquids, such as benzene and the xylenes, although some arenes with substituents on the ring are solids at room temperature. In the gas phase, the dipole moment of benzene is zero, but the presence of electronegative or electropositive substituents can result in a net dipole moment that increases intermolecular attractive forces and raises the melting and boiling points. For example, 1,4-dichlorobenzene, a compound used as an alternative to naphthalene in the production of mothballs, has a melting point of 52.7°C, which is considerably greater than the melting point of benzene (5.5°C). (For more information on 1,4-dichlorobenzene, see Chapter 11 "Liquids", Section 11.5 "Changes of State".)

Certain aromatic hydrocarbons, such as benzene and benz[a]pyrene, are potent liver toxins and carcinogens. In 1775, a British physician, Percival Pott, described the high incidence of cancer of the scrotum among small boys used as chimney sweeps and attributed it to their exposure to soot. His conclusions were correct: benz[a]pyrene, a component of chimney soot, charcoal-grilled meats, and cigarette smoke, was the first chemical carcinogen to be identified.

Although arenes are usually drawn with three C=C bonds, benzene is about 150 kJ/mol more stable than would be expected if it contained three double bonds. This increased stability is due to the delocalization of the π electron density over all the atoms of the ring. (For more information on delocalization, see Chapter 9 "Molecular Geometry and Covalent Bonding Models", Section 9.3 "Delocalized Bonding and Molecular Orbitals".) Compared with alkenes, arenes are poor nucleophiles. Consequently, they do not undergo addition reactions like alkenes; instead, they undergo a variety of electrophilic aromatic substitution reactionsA reaction in which a −H of an arene is replaced (substituted) by an electrophilic group in a two-step process. that involve the replacement of –H on the arene by a group –E, such as –NO₂, –SO₃H, a halogen, or an alkyl group, in a two-step process. The first step involves addition of the electrophile (E) to the π system of benzene, forming a carbocation. In the second step, a proton is lost from the adjacent carbon on the ring:

The carbocation formed in the first step is stabilized by resonance.

Many substituted arenes have potent biological activity. Some examples include common drugs and antibiotics such as aspirin and ibuprofen, illicit drugs such as amphetamines and peyote, the amino acid phenylalanine, and hormones such as adrenaline (Figure 24.16 "Biologically Active Substituted Arenes").

Figure 24.16 Biologically Active Substituted Arenes

Aspirin (antifever activity), ibuprofen (antifever and anti-inflammatory activity), and amphetamine (stimulant) have pharmacological effects. Phenylalanine is an amino acid. Adrenaline is a hormone that elicits the “fight or flight” response to stress. Chiral centers are indicated with an asterisk.

Alcohols and Ethers

Both alcohols and ethers can be thought of as derivatives of water in which at least one hydrogen atom has been replaced by an organic group, as shown here. Because of the electronegative oxygen atom, the individual O–H bond dipoles in alcohols cannot cancel one another, resulting in a substantial dipole moment that allows alcohols to form hydrogen bonds. Alcohols therefore have significantly higher boiling points than alkanes or alkenes of comparable molecular mass, whereas ethers, without a polar O–H bond, have intermediate boiling points due to the presence of a small dipole moment (Table 24.2 "Boiling Points of Alkanes, Ethers, and Alcohols of Comparable Molecular Mass"). The larger the alkyl group in the molecule, however, the more “alkane-like” the alcohol is in its properties. Because of their polar nature, alcohols and ethers tend to be good solvents for a wide range of organic compounds.

Alcohols are usually prepared by adding water across a carbon–carbon double bond or by a nucleophilic substitution reaction of an alkyl halide using hydroxide, a potent nucleophile (Figure 24.12). As you will see in Section 24.6 "The Molecules of Life", alcohols can also be prepared by reducing compounds that contain the carbonyl functional group (C=O; part (a) in Figure 24.14 "The Oxidation State of Carbon in Oxygen- and Nitrogen-Containing Functional Groups"). Alcohols are classified as primary, secondary, or tertiary, depending on whether the –OH group is bonded to a primary, secondary, or tertiary carbon. For example, the compound 5-methyl-3-hexanol is a secondary alcohol.

Ethers, especially those with two different alkyl groups (ROR′), can be prepared by a substitution reaction in which a nucleophilic alkoxide ion (RO⁻) attacks the partially positively charged carbon atom of the polar C–X bond of an alkyl halide (R′X):

Although both alcohols and phenols have an –OH functional group, phenols are 10⁶–10⁸ more acidic than alcohols. This is largely because simple alcohols have the –OH unit attached to an sp³ hybridized carbon, whereas phenols have an sp² hybridized carbon atom bonded to the oxygen atom. The negative charge of the phenoxide ion can therefore interact with the π electrons in the ring, thereby delocalizing and stabilizing the negative charge through resonance. (For more information on resonance, see Chapter 8 "Ionic versus Covalent Bonding", Section 8.5 "Lewis Structures and Covalent Bonding".) In contrast, the negative charge on an alkoxide ion cannot be stabilized by these types of interactions.

Alcohols undergo two major types of reactions: those involving cleavage of the O–H bond and those involving cleavage of the C–O bond. Cleavage of an O–H bond is a reaction characteristic of an acid, but alcohols are even weaker acids than water. The acidic strength of phenols, however, is about a million times greater than that of ethanol, making the pK_a of phenol comparable to that of the NH₄⁺ ion (9.89 versus 9.25, respectively):

Cleavage of the C–O bond in alcohols occurs under acidic conditions. The –OH is first protonated, and nucleophilic substitution follows:

In the absence of a nucleophile, however, elimination can occur, producing an alkene (Figure 24.13).

Ethers lack the –OH unit that is central to the reactivity of alcohols, so they are comparatively unreactive. Their low reactivity makes them highly suitable as solvents for carrying out organic reactions.

Aldehydes and Ketones

Aromatic aldehydes, which have intense and characteristic flavors and aromas, are the major components of such well-known flavorings as vanilla and cinnamon (Figure 24.17 "Some Familiar Aldehydes and Their Uses"). Many ketones, such as camphor and jasmine, also have intense aromas. Ketones are found in many of the hormones responsible for sex differentiation in humans, such as progesterone and testosterone. (For more information on aldehydes and ketones, see Chapter 4 "Reactions in Aqueous Solution", Section 4.1 "Aqueous Solutions".)

Figure 24.17 Some Familiar Aldehydes and Their Uses

In compounds containing a carbonyl group, nucleophilic attack can occur at the carbon atom of the carbonyl, whereas electrophilic attack occurs at oxygen.

Aldehydes and ketones contain the carbonyl functional group, which has an appreciable dipole moment because of the polar C=O bond. The presence of the carbonyl group results in strong intermolecular interactions that cause aldehydes and ketones to have higher boiling points than alkanes or alkenes of comparable molecular mass (Table 24.3 "Boiling Points of Alkanes, Aldehydes, and Ketones of Comparable Molecular Mass"). As the mass of the molecule increases, the carbonyl group becomes less important to the overall properties of the compound, and the boiling points approach those of the corresponding alkanes.

Aldehydes and ketones are typically prepared by oxidizing alcohols (part (a) in Figure 24.14 "The Oxidation State of Carbon in Oxygen- and Nitrogen-Containing Functional Groups"). In their reactions, the partially positively charged carbon atom of the carbonyl group is an electrophile that is subject to nucleophilic attack. Conversely, the lone pairs of electrons on the oxygen atom of the carbonyl group allow electrophilic attack to occur. Aldehydes and ketones can therefore undergo both nucleophilic attack (at the carbon atom) and electrophilic attack (at the oxygen atom).

Aldehydes and ketones react with many organometallic compounds that contain stabilized carbanions. One of the most important classes of such compounds are the Grignard reagentsAn organometallic compound that has stabilized carbanions, whose general formula is RMgX, where X is Cl, Br, or I., organomagnesium compounds with the formula RMgX (X is Cl, Br, or I) that are so strongly polarized that they can be viewed as containing R⁻ and MgX⁺. These reagents are named for the French chemist Victor Grignard (1871–1935), who won a Nobel Prize in Chemistry in 1912 for their development. In a Grignard reaction, the carbonyl functional group is converted to an alcohol, and the carbon chain of the carbonyl compound is lengthened by the addition of the R group from the Grignard reagent. One example is reacting cyclohexylmagnesium chloride, a Grignard reagent, with formaldehyde:

The nucleophilic carbanion of the cyclohexyl ring attacks the electrophilic carbon atom of the carbonyl group. Acidifying the solution results in protonation of the intermediate to give the alcohol. Aldehydes can also be prepared by reducing a carboxylic acid group (–CO₂H) (part (a) in Figure 24.14 "The Oxidation State of Carbon in Oxygen- and Nitrogen-Containing Functional Groups"), and ketones can be prepared by reacting a carboxylic acid derivative with a Grignard reagent. The former reaction requires a powerful reducing agent, such as a metal hydride.

Carboxylic Acids

The pungent odors of many carboxylic acids are responsible for the smells we associate with sources as diverse as Swiss cheese, rancid butter, manure, goats, and sour milk. The boiling points of carboxylic acids tend to be somewhat higher than would be expected from their molecular masses because of strong hydrogen-bonding interactions between molecules. In fact, most simple carboxylic acids form dimers in the liquid and even in the vapor phase. (For more information on the vapor phase, see Chapter 11 "Liquids", Section 11.2 "Intermolecular Forces".) The four lightest carboxylic acids are completely miscible with water, but as the alkyl chain lengthens, they become more “alkane-like,” so their solubility in water decreases.

Compounds that contain the carboxyl functional group are acidic because carboxylic acids can easily lose a proton: the negative charge in the carboxylate ion (RCO₂⁻) is stabilized by delocalization of the π electrons:

As a result, carboxylic acids are about 10¹⁰ times more acidic than the corresponding simple alcohols whose anions (RO⁻) are not stabilized through resonance.

Carboxylic acids are typically prepared by oxidizing the corresponding alcohols and aldehydes (part (a) in Figure 24.14 "The Oxidation State of Carbon in Oxygen- and Nitrogen-Containing Functional Groups"). They can also be prepared by reacting a Grignard reagent with CO₂, followed by acidification:

The initial step in the reaction is nucleophilic attack by the R⁻ group of the Grignard reagent on the electrophilic carbon of CO₂:

Delocalization of π bonding over three atoms (O–C–O) makes carboxylic acids and their derivatives less susceptible to nucleophilic attack than aldehydes and ketones with their single π bond. The reactions of carboxylic acids are dominated by two factors: their polar –CO₂H group and their acidity. Reaction with strong bases, for example, produce carboxylate salts, such as sodium stearate:

where R is CH₃(CH₂)₁₆. As you learned in Chapter 13 "Solutions", Section 13.6 "Aggregate Particles in Aqueous Solution", long-chain carboxylate salts are used as soaps.

Carboxylic Acid Derivatives

Replacing the –OH of a carboxylic acid with groups that have different tendencies to participate in resonance with the C=O functional group produces derivatives with rather different properties. Resonance structures have significant effects on the reactivity of carboxylic acid derivatives, but their influence varies substantially, being least important for halides and most important for the nitrogen of amides. In this section, we take a brief look at the chemistry of two of the most familiar and important carboxylic acid derivatives: esters and amides.

Esters

Esters have the general formula RCO₂R′, where R and R′ can be virtually any alkyl or aryl group. Esters are often prepared by reacting an alcohol (R′OH) with a carboxylic acid (RCO₂H) in the presence of a catalytic amount of strong acid. (For more information on esters and catalysts, see Chapter 3 "Chemical Reactions", Section 3.5 "Classifying Chemical Reactions".) The purpose of the acid (an electrophile) is to protonate the doubly bonded oxygen atom of the carboxylic acid (a nucleophile) to give a species that is more electrophilic than the parent carboxylic acid.

The nucleophilic oxygen atom of the alcohol attacks the electrophilic carbon atom of the protonated carboxylic acid to form a new C–O bond. The overall reaction can be written as follows:

Figure 24.18

 

Because water is eliminated, this is a dehydration reaction. If an aqueous solution of an ester and strong acid or base is heated, the reverse reaction will occur, producing the parent alcohol R′OH and either the carboxylic acid RCO₂H (under strongly acidic conditions) or the carboxylate anion RCO₂⁻ (under basic conditions).

As stated earlier, esters are familiar to most of us as fragrances, such as banana and pineapple. Other esters with intense aromas function as sex attractants, or pheromones, such as the pheromone from the oriental fruit fly. Research on using synthetic insect pheromones as a safer alternative to insecticides for controlling insect populations, such as cockroaches, is a rapidly growing field in organic chemistry.

Amides

In the general structure of an amide,

the two substituents on the amide nitrogen can be hydrogen atoms, alkyl groups, aryl groups, or any combination of those species. Although amides appear to be derived from an acid and an amine, in practice they usually cannot be prepared by this synthetic route. In principle, nucleophilic attack by the lone electron pair of the amine on the carbon of the carboxylic acid could occur, but because carboxylic acids are weak acids and amines are weak bases, an acid–base reaction generally occurs instead:

Equation 24.11

RCO₂H + R′NH₂ → RCO₂⁻ + R′NH₃⁺

Amides are therefore usually prepared by the nucleophilic reaction of amines with more electrophilic carboxylic acid derivatives, such as esters.

The lone pair of electrons on the nitrogen atom of an amide can participate in π bonding with the carbonyl group, thus reducing the reactivity of the amide (Figure 24.19 "The Electronic Structure of an Amide") and inhibiting free rotation about the C–N bond. Amides are therefore the least reactive of the carboxylic acid derivatives. The stability of the amide bond is crucially important in biology because amide bonds form the backbones of peptides and proteins. (For more information on peptides and proteins, see Chapter 12 "Solids", Section 12.8 "Polymeric Solids".) The amide bond is also found in many other biologically active and commercially important molecules, including penicillin; urea, which is used as fertilizer; saccharin, a sugar substitute; and valium, a potent tranquilizer. (For more information on the structure of penicillin, see Chapter 3 "Chemical Reactions", Section 3.2 "Determining Empirical and Molecular Formulas".)

Note the Pattern

Amides are the least reactive of the carboxylic acid derivatives because amides participate in π bonding with the carbonyl group.

Figure 24.19 The Electronic Structure of an Amide

(a) An unhybridized 2p_z orbital on nitrogen, containing a lone electron pair of electrons, can interact with the π orbital of the carbonyl group to give a three-center, four-electron bond. This interaction reduces the reactivity of the amide, making amides the least reactive of the carboxylic acid derivatives. (b) A comparison of the electrostatic potential maps of acetaldehyde and formamide shows that the negative charge (indicated in blue) is more localized on the oxygen atom of acetaldehyde than it is in formamide. Formamide is therefore less reactive.

Amines

Amines are derivatives of ammonia in which one or more hydrogen atoms have been replaced by alkyl or aryl groups. They are therefore analogous to alcohols and ethers. Like alcohols, amines are classified as primary, secondary, or tertiary, but in this case the designation refers to the number of alkyl groups bonded to the nitrogen atom, not to the number of adjacent carbon atoms. In primary amines, the nitrogen is bonded to two hydrogen atoms and one alkyl group; in secondary amines, the nitrogen is bonded to one hydrogen and two alkyl groups; and in tertiary amines, the nitrogen is bonded to three alkyl groups. With one lone pair of electrons and C–N bonds that are less polar than C–O bonds, ammonia and simple amines have much lower boiling points than water or alcohols with similar molecular masses. Primary amines tend to have boiling points intermediate between those of the corresponding alcohol and alkane. Moreover, secondary and tertiary amines have lower boiling points than primary amines of comparable molecular mass.

Tertiary amines form cations analogous to the ammonium ion (NH₄⁺), in which all four H atoms are replaced by alkyl groups. Such substances, called quaternary ammonium saltsA salt that consist of an anion and a cation in which all four H atoms of the ammonium ion ${\text{(NH}}_{\text{4}}{}^{\text{+}}\text{)}$ are replaced by alkyl groups., can be chiral if all four substituents are different. (Amines with three different substituents are also chiral because the lone pair of electrons represents a fourth substituent.)

Alkylamines can be prepared by nucleophilic substitution reactions of alkyl halides with ammonia or other amines:

The primary amine formed in the first reaction (Equation 24.12) can react with more alkyl halide to generate a secondary amine (Equation 24.13), which in turn can react to form a tertiary amine (Equation 24.14). Consequently, the actual reaction mixture contains primary, secondary, and tertiary amines and even quaternary ammonium salts.

The reactions of amines are dominated by two properties: their ability to act as weak bases and their tendency to act as nucleophiles, both of which are due to the presence of the lone pair of electrons on the nitrogen atom. Amines typically behave as bases by accepting a proton from an acid to form an ammonium salt, as in the reaction of triethylamine (the ethyl group is represented as Et) with aqueous HCl (the lone pair of electrons on nitrogen is shown):

which gives triethylammonium chloride. Amines can react with virtually any electrophile, including the carbonyl carbon of an aldehyde, a ketone, or an ester. Aryl amines such as aniline (C₆H₅NH₂) are much weaker bases than alkylamines because the lone pair of electrons on nitrogen interacts with the π bonds of the aromatic ring, delocalizing the lone pair through resonance (Figure 24.20 "Structures and Basicity of Aniline and Cyclohexylamine").

Figure 24.20 Structures and Basicity of Aniline and Cyclohexylamine

Delocalization of the lone electron pair on N over the benzene ring reduces the basicity of aryl amines, such as aniline, compared with that of alkylamines, such as cyclohexylamine. These electrostatic potential maps show that the electron density on the N of cyclohexylamine is more localized than it is in aniline, which makes cyclohexylamine a stronger base.

Example 8

Predict the products formed in each reaction and show the initial site of attack and, for part (b), the final products.

1. C₆H₅CH₂CO₂H + KOH →

2.  

   

Given: reactants

Asked for: products and mechanism of reaction

Strategy:

Use the strategy outlined in Example 7.

Solution:

1. The proton on the carboxylic acid functional group is acidic. Thus reacting a carboxylic acid with a strong base is an acid–base reaction, whose products are a salt—in this case, C₆H₅CH₂CO₂⁻K⁺—and water.
2. The nitrogen of cyclohexylamine contains a lone pair of electrons, making it an excellent nucleophile, whereas the carbonyl carbon of ethyl acetate is a good electrophile. We therefore expect a reaction in which nucleophilic attack on the carbonyl carbon of the ester produces an amide and ethanol. The initial site of attack and the reaction products are as follows:

Exercise

Predict the products of each reaction. State the initial site of attack.

1. acetic acid with 1-propanol
2. aniline (C₆H₅NH₂) with propyl acetate [CH₃C(=O)OCH₂CH₂CH₃]

Answer:

1. Initial attack occurs with protonation of the oxygen of the carbonyl. The products are:

   

2. Initial attack occurs at the carbon of the carbonyl group. The products are:

   

Reactions like we have discussed in this section and Section 24.4 "Common Classes of Organic Reactions" are used to synthesize a wide range of organic compounds. When chemists plan the synthesis of an organic molecule, however, they must take into consideration various factors, such as the availability and cost of reactants, the need to minimize the formation of undesired products, and the proper sequencing of reactions to maximize the yield of the target molecule and minimize the formation of undesired products. Because the synthesis of many organic molecules requires multiple steps, in designing a synthetic scheme for such molecules, chemists must often work backward from the desired product in a process called retrosynthesis. Using this process, they can identify the reaction steps needed to synthesize the desired product from the available reactants.

Proteins

In Chapter 12 "Solids", Section 12.8 "Polymeric Solids", we described proteinsA biological polymer with more than 50 amino acid residues linked together by amide bonds. as biologically active polymers formed from amino acids linked together by amide bonds. In addition to an amine group and a carboxylic acid group, each amino acid contains a characteristic R group (Figure 5.16 "The Structures of 10 Amino Acids"). In the simplest amino acid, glycine, the R group is hydrogen (–H), but in other naturally occurring amino acids, the R group may be an alkyl group or a substituted alkyl group, a carboxylic group, or an aryl group. The nature of the R group determines the particular chemical properties of each amino acid. In Figure 5.16 "The Structures of 10 Amino Acids", all the amino acids found in proteins except glycine are chiral compounds, which suggests that their interactions with other chiral compounds are selective. Some proteins, called enzymes, catalyze biological reactions, whereas many others have structural, contractile, or signaling functions. Because we have described proteins previously, we will not discuss them further.

The general structure of an amino acid. An amino acid is chiral except when R is an H atom.

Carbohydrates

Carbohydrates are the most abundant of the organic compounds found in nature. They constitute a substantial portion of the food we consume and provide us with the energy needed to support life. Table sugar, milk, honey, and fruits all contain low-molecular-mass carbohydrates that are easily assimilated by the human body. In contrast, the walls of plant cells and wood contain high-molecular-mass carbohydrates that we cannot digest.

Once thought to be hydrates of carbon with the general formula C_n(H₂O)_m, carbohydratesA polyhydroxy aldehyde or a polyhydroxy ketone with the general formula ${\text{C}}_n{({\text{H}}_2\text{O})}_m\text{.}$ are actually polyhydroxy aldehydes or polyhydroxy ketones (i.e., aldehydes or ketones with several –OH groups attached to the parent hydrocarbon). The simplest carbohydrates consist of unbranched chains of three to eight carbon atoms: one carbon atom is part of a carbonyl group, and some or all of the others are bonded to hydroxyl groups. The structure of a carbohydrate can be drawn either as a hydrocarbon chain, using a Fischer projection, or as a ring, using a Haworth projection (Figure 24.21 "Fischer Projection and Haworth Projection of Glucose"). The Haworth projection is named after the British chemist Sir Walter Norman Haworth, who was awarded a Nobel Prize in Chemistry in 1937 for his discovery that sugars exist mainly in their cyclic forms, as well as for his collaboration on the synthesis of vitamin C. The cyclic form is the product of nucleophilic attack by the oxygen of a hydroxyl group on the electrophilic carbon of the carbonyl group within the same molecule, producing a stable ring structure composed of five or six carbons that minimizes bond strain (Figure 24.21 "Fischer Projection and Haworth Projection of Glucose"). The substituents on the right side of the carbon chain in a Fischer projection are in the “down” position in the corresponding Haworth projection. Attack by the hydroxyl group on either side of the carbonyl group leads to the formation of two cyclic forms, called anomers: an α form, with the –OH in the “down” position, and a β form, with the –OH in the “up” position.

Figure 24.21 Fischer Projection and Haworth Projection of Glucose

In solution, simple sugars exist predominantly in the ring form, the product of nucleophilic attack by the oxygen of a hydroxyl group on the electrophilic carbon of the carbonyl group. The α and β forms, called anomers, differ in the configuration at C1.

Carbohydrates are classified according to the number of single saccharide, or sugar, units they contain (from the Latin saccharum, meaning “sugar”). The simplest are monosaccharides; a disaccharide consists of two linked monosaccharide units; a trisaccharide has three linked monosaccharide units; and so forth. Glucose is a monosaccharide, and sucrose (common table sugar) is a disaccharide. The hydrolysis of sucrose produces glucose and another monosaccharide, fructose, in a reaction catalyzed by an enzyme or by acid:

Polysaccharides hydrolyze to produce more than 10 monosaccharide units.

The common monosaccharides contain several chiral carbons and exist in several isomeric forms. One isomer of glucose, for example, is galactose, which differs from glucose in the position of the –OH bond at carbon-4:

Because carbons-2, -3, -4, and -5 of glucose are chiral, changing the position of the –OH on carbon-4 does not produce an enantiomer of glucose but a different compound, galactose, with distinct physical and chemical properties. Galactose is a hydrolysis product of lactose, a disaccharide found in milk. People who suffer from galactosemia lack the enzyme needed to convert galactose to glucose, which is then metabolized to CO₂ and H₂O, releasing energy. Galactose accumulates in their blood and tissues, leading to mental retardation, cataracts, and cirrhosis of the liver.

Because carbohydrates have a carbonyl functional group and several hydroxyl groups, they can undergo a variety of biochemically important reactions. The carbonyl group, for example, can be oxidized to form a carboxylic acid or reduced to form an alcohol. The hydroxyl groups can undergo substitution reactions, resulting in derivatives of the original compound. One such derivative is Sucralose, an artificial sweetener that is six times sweeter than sucrose; it is made by replacing two of the hydroxyl groups on sucrose with chlorine. Carbohydrates can also eliminate hydroxyl groups, producing alkenes.

Two familiar polysaccharides are starch and cellulose, which both hydrolyze to produce thousands of glucose units. They differ only in the connection between glucose units and the amount of branching in the molecule (Figure 24.22 "The Polysaccharides Starch and Cellulose"). Starches can be coiled or branched and are hydrolyzed by the enzymes in our saliva and pancreatic juices. Animal starch, called glycogen, is stored in the liver and muscles. It consists of branched glucose units linked by bonds that produce a coiled structure. The glucose units in cellulose, in contrast, are linked to give long, unbranched chains. The chains in cellulose stack in parallel rows held together by hydrogen bonds between hydroxyl groups. This arrangement produces a rigid structure that is insoluble in water.

Figure 24.22 The Polysaccharides Starch and Cellulose

Starches (a) and cellulose (b) differ in the connection between glucose units and the amount of branching in the molecule. Starches can be coiled or branched, whereas cellulose, the primary structural material of plants, has long, unbranched chains held together by hydrogen bonds.

Cellulose is the primary structural material of plants and one of the most abundant organic substances on Earth. Because our enzymes are not able to hydrolyze the bonds between the glucose units in cellulose, we are unable to digest it. A recently marketed product containing a high percentage of cellulose was sold as a dietetic substance for rapid weight loss, but those who consumed it experienced severe intestinal discomfort because the cellulose could not be digested. The product was quickly removed from the market.

Example 9

The Fischer projection of xylose, found in many varieties of apples, is shown. Draw the ring form (Haworth projection) of xylose.

Given: Fischer projection of a sugar

Asked for: cyclic structure

Strategy:

A Identify the nucleophile and the electrophile. Indicate the point of attack, remembering that cyclic structures are most stable when they contain at least five atoms in the ring to prevent bond strain from bond angles that are too small.

B Draw the cyclic form of the structure.

Solution:

A The carbonyl carbon (C1) is a good electrophile, and each oxygen is a good nucleophile. Nucleophilic attack occurs from the –OH group on C4, producing a stable five-membered ring.

B Because of rotation about the bond between C1 and C2, ring formation gives both a and b anomers, with the following structures (H atoms have been omitted for clarity):

Exercise

Draw the cyclic form(s) of galactose, whose Fischer projection is shown in the previous discussion.

Answer:

Lipids

LipidsA family of compounds that includes fats, waxes, some vitamins, and steroids and characterized by their insolubility in water. (from the Greek lipos, meaning “fat” or “lard”) are characterized by their insolubility in water. They form a family of compounds that includes fats, waxes, some vitamins, and steroids. Fatty acids, the simplest lipids, have a long hydrocarbon chain that ends with a carboxylic acid functional group. In saturated fatty acids, the hydrocarbon chains contain only C–C bonds, so they can stack in a regular array (part (a) in Figure 24.23 "Fatty Acids, the Simplest Class of Lipids"). In contrast, unsaturated fatty acids have a single double bond in the hydrocarbon chain (monounsaturated) or more than one double bond (polyunsaturated). These double bonds give fatty acid chains a kinked structure, which prevents the molecules from packing tightly (part (b) in Figure 24.23 "Fatty Acids, the Simplest Class of Lipids"). As a result of reduced van der Waals interactions, the melting point of an unsaturated fatty acid is lower than that of a saturated fatty acid of comparable molecule mass, thus producing an oil rather than a solid. (For more information on van der Waals interactions, see Chapter 11 "Liquids", Section 11.2 "Intermolecular Forces".) Fish oils and vegetable oils, for example, have a higher concentration of unsaturated fatty acids than does butter.

Figure 24.23 Fatty Acids, the Simplest Class of Lipids

Fatty acids are composed of a long chain that terminates in a carboxylic acid functional group. (a) Molecules of saturated fatty acids, which contain no carbon–carbon double bonds, can stack in a regular array. (b) Molecules of unsaturated fatty acids, which contain one or more cis carbon–carbon double bonds, have kinked structures that cannot pack closely together.

The double bonds of unsaturated fatty acids can by hydrogenated in an addition reaction that produces a saturated fatty acid:

They can also be oxidized to produce an aldehyde or carboxylic acid. (For more information on hydrogenation, see Chapter 14 "Chemical Kinetics", Section 14.8 "Catalysis".)

Unsaturated fatty acids are the starting compounds for the biosynthesis of prostaglandins. These hormone-like substances are involved in regulating blood pressure, tissue inflammation, and contracting and relaxing smooth muscles. Drugs such as aspirin and ibuprofen inhibit the production of prostaglandins, thereby reducing inflammation.

Waxes are esters produced by the nucleophilic attack of an alcohol on the carbonyl carbon of a long-chain carboxylic acid (Figure 24.18). For example, the wax used in shoe polish and wax paper, which is derived from beeswax, is formed from a straight-chain alcohol with 15 carbon atoms and a fatty acid with 31 carbon atoms. Triacylglycerols are a particularly important type of ester in living systems; they are used by the body to store fats and oils. These compounds are formed from one molecule of glycerol (1,2,3-trihydroxypropane) and three fatty acid molecules. During warmer months of the year, animals that hibernate consume large quantities of plants, seeds, and nuts that have a high fat and oil content. They convert the fatty acids to triacylglycerols and store them. Hydrolysis of stored triacylglycerols during hibernation (the reverse of Figure 24.18) releases alcohols and carboxylic acids that the animal uses to generate energy for maintaining cellular activity, respiration, and heart rate. Derivatives of triacylglycerols with a phosphate group are major components of all cell membranes.

Steroids are lipids whose structure is composed of three cyclohexane rings and one cyclopentane ring fused together. The presence of various substituents, including double bonds, on the basic steroid ring structure produces a large family of steroid compounds with different biological activities. For example, cholesterol, a steroid found in cellular membranes, contains a double bond in one ring and four substituents: a hydroxyl group, two methyl groups, and a hydrocarbon chain.

Cholesterol is the starting point for the biosynthesis of steroid hormones, including testosterone, the primary male sex hormone, and progesterone, which helps maintain pregnancy. These cholesterol derivatives lack the long hydrocarbon side chain, and most contain one or more ketone groups.

Cholesterol is synthesized in the human body in a multistep pathway that begins with a derivative of acetic acid. We also consume cholesterol in our diets: eggs, meats, fish, and diary products all contain cholesterol, but vegetables and other plant-derived foods do not contain cholesterol. Excess cholesterol in the human body can cause gallstones, which are composed of nearly 100% cholesterol, or lipid deposits called plaque in arteries. A buildup of plaque can block a coronary artery and result in a heart attack (Figure 24.24 "Plaque in an Artery").

Figure 24.24 Plaque in an Artery

Plaque, a lipid deposit, forms from excess cholesterol in the body. This artery is nearly blocked by a thick deposit of plaque, which greatly increases the risk of a heart attack due to reduced blood flow to the heart.

Nucleic Acids

Nucleic acidsA linear polymer of nucleotides that is the basic structural component of DNA and RNA. are the basic structural components of DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), the biochemical substances found in the nuclei of all cells that transmit the information needed to direct cellular growth and reproduction. Their structures are derived from cyclic nitrogen-containing compounds called pyrimidines and purines, which can engage in hydrogen bonding through the lone electron pair on nitrogen (in pyrimidine and purine) or through the hydrogen of the amine (in purine):

The same cyclic structures are found in substances such as caffeine, a purine that is a stimulant, and the antifungal agent flucytosine, a pyrimidine. (For more information on the structure of caffeine, see Chapter 3 "Chemical Reactions", Section 3.2 "Determining Empirical and Molecular Formulas".)

When a pyrimidine or a purine is linked to a sugar by a bond called a glycosidic bond, a nucleoside is formed. Adding a phosphoric acid group to the sugar then produces a nucleotide (part (a) in Figure 24.25 "The Formation of Nucleic Acids"). The linkage of nucleotides forms a polymeric chain that consists of alternating sugar and phosphate groups, which is the backbone of DNA and RNA (part (b) in Figure 24.25 "The Formation of Nucleic Acids").

While the function of DNA is to preserve genetic information, RNA translates the genetic information in DNA and carries that information to cellular sites where proteins are synthesized. Many antibiotics function by interfering with the synthesis of proteins in one or more kinds of bacteria. Chloramphenicol, for example, is used against infections of the eye or outer ear canal; it inhibits the formation of peptide bonds between amino acids in a protein chain. Puromycin, which is used against herpes simplex type I, interrupts extension of a peptide chain, causing the release of an incomplete protein and the subsequent death of the virus.

Figure 24.25 The Formation of Nucleic Acids

(a) When pyrimidine or purine and a sugar react to form a glycosidic bond, a nucleoside is produced. Adding a phosphoric acid group to the sugar of a nucleoside produces a nucleotide. (b) Nucleotides link together to form long polymeric chains. A DNA molecule consists of two such chains held together by hydrogen bonding between the purine and pyrimidine components on different chains.

Mutations in the DNA of an organism may lead to the synthesis of defective proteins. Phenylketonuria (PKU), for example, is a condition caused by a defective enzyme. Left untreated, it produces severe brain damage and mental retardation. Albinism is caused by a defective enzyme that is unable to produce melanin, the pigment responsible for the color of skin and hair. Cystic fibrosis, the most common inherited disease in the United States, blocks pancreatic function and causes thick mucus secretions that make breathing difficult. An area of intense research in combating cancer involves the synthesis of drugs that stop uncontrolled cell growth by interfering with DNA replication.