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M O D U L E

5 ORGANIC CHEMISTRY: FUNCTIONAL GROUPS

O2.1 Functional Groups O2.2 Oxidation­Reduction Reactions O2.3 Alkyl Halides O2.4 Alcohols and Ethers O2.5 Aldehydes and Ketones O2.6 Reactions at the Carbonyl Group O2.7 Carboxylic Acids and Carboxylate Ions O2.8 Esters O2.9 Amines, Alkaloids, and Amides O2.10 Grignard Reagents Chemistry in the World Around Us: The Chemistry of Garlic

O2.1 FUNCTIONAL GROUPS

Bromine reacts with 2-butene to form 2,3-dibromobutane. Br A CH3CHCHCH3 A Br

CH3 CHP CHCH3

Br2

It also reacts with 3-methyl-2-pentene to form 2,3-dibromopentane. CH3 A CH3 CHPCCH2CH3 Br CH3 A A CH3CHCCH2CH3 A Br

Br2

Instead of trying to memorize both equations, we can build a general rule that bromine reacts with compounds that contain a CPC double bond to give the product expected from addition across the double bond. This approach to understanding the chemistry of organic compounds presumes that certain atoms or groups of atoms known as functional groups give these compounds their characteristic properties.

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FUNCTIONAL GROUP CHEMISTRY

Functional groups focus attention on the important aspects of the structure of a molecule. We don't have to worry about the differences between the structures of 1-butene and 2-methyl-2-hexene, for example, when the compounds react with hydrogen bromide. We can focus on the fact that both compounds are alkenes that add HBr across the CPC double bond in the direction predicted by Markovnikov's rule, introduced in Section O1.8. CH2 P CHCH2CH3 CH3 A CH3C PCHCH2CH2CH3 HBr CH3CHCH2CH3 A Br CH3 A CH3C CH2CH2CH2CH3 A Br

HBr

Some common functional groups are given in Table O2.1.

TABLE 02.1 Common Functional Groups Functional Group A OCO A CP C Cq C F, Cl, Br, or I OOH OOO ONH2 Name Alkane Alkene Alkyne Alkyl halide Alcohol Ether Amine Example CH3CH2CH3 (propane) CH3CHPCH2 (propene) CH3C q CH (propyne) CH3 Br (methyl bromide) CH3CH2OH (ethanol) CH3OCH3 (dimethyl ether) CH3NH2 (methylamine)

The CPO group plays a particularly important role in organic chemistry. This group is called a carbonyl, and some of the functional groups based on a carbonyl are shown in Table O2.2.

TABLE 02.2 Functional Groups That Contain a Carbonyl Functional Group O B O COH O B O CO O B O CO Cl O B O COOH O B O COOO O B O CONH2 Name Example

Aldehyde Ketone Acyl chloride Carboxylic acid Ester Amide

CH3 CHO (acetaldehyde) CH3COCH3 (acetone) CH3COCl (acetyl chloride) CH3CO2H (acetic acid) CH3CO2CH3 (methyl acetate) CH3CONH2 (acetamide)

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Exercise O2.1

Root beer hasn't tasted the same since the use of sassafras oil as a food additive was outlawed because sassafras oil is 80% safrole, which has been shown to cause cancer in rats and mice. Identify the functional groups in the structure of safrole. OOCH2 i O

Safrole

CH2 G CHPCH2 Solution Safrole is an aromatic compound because it contains a benzene ring. It is also an alkene because it contains a CPC double bond. The most difficult functional group to recognize in the molecule might be the two ether linkages (OOO).

Exercise O2.2

The following compounds are the active ingredients in over-the-counter drugs used as analgesics (to relieve pain without decreasing sensibility or consciousness), antipyretics (to reduce the body temperature when it is elevated), and/or anti-inflammatory agents (to counteract swelling or inflammation of the joints, skin, and eyes). Identify the functional groups in each molecule. O B C CH3 G D G CH OH

OH O OH M D O C B OOCOCH3

Aspirin (acetylsalicylic acid)

CH3

NH G D C B Tylenol O (acetaminophen)

CH3

CH G D 2 CH A Advil CH3 (ibuprofen)

Solution All three compounds are aromatic. Aspirin is also a carboxylic acid (OCO2H) and an ester (OCO2CH3). Tylenol is also an alcohol (OOH) and an amide (OCONHO). Ibuprofen contains alkane substituents and a carboxylic acid functional group.

Exercise O2.3

The discovery of penicillin in 1928 marked the beginning of what has been called the "golden age of chemotherapy," in which previously life-threatening bacterial infections

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were transformed into little more than a source of discomfort. For those who are allergic to penicillin, a variety of antibiotics, including tetracycline, are available. Identify the numerous functional groups in the tetracycline molecule. HO CH3 / N(CH3)2 OH

Tetracycline

H

OH

B O

CPO OHB f OH O NH2

Solution The compound contains an aromatic ring fused to three six-membered rings. It is also an alcohol (with five OOH groups), a ketone (with CPO groups at the bottom of the second and fourth rings), an amine [the ON(CH3)2 substituent at the top of the fourth ring], and an amide (the OCONH2 group at the bottom right-hand corner of the fourth ring.)

O2.2 OXIDATION­REDUCTION REACTIONS

Focusing on the functional groups in a molecule allows us to recognize patterns in the behavior of related compounds. Consider what we know about the reaction between sodium metal and water, for example. 2Na(s) 2 H2O(l) H2(g) 2 Na (aq) 2 OH (aq)

We can divide the reaction into two half-reactions. One involves the oxidation of sodium metal to form sodium ions. Oxidation Na Na e

The other involves the reduction of an H ion in water to form a neutral hydrogen atom that combines with another hydrogen atom to form an H2 molecule. O D G

O S

Reduction

2H 2H

H

2H 2 HT

O 2 SO OH Q H2

2e

Once we recognize that water contains an OOH functional group, we can predict what might happen when sodium metal reacts with an alcohol that contains the same functional group. Sodium metal should react with methanol (CH3OH), for example, to give H2 gas and a solution of the Na and CH3O ions dissolved in the alcohol. 2Na(s) 2 CH3OH(l) H2(g) 2 Na (alc) 2 CH3O (alc)

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Because they involve the transfer of electrons, the reactions between sodium metal and either water or an alcohol are examples of oxidation­reduction reactions. But what about the following reaction, in which hydrogen gas reacts with an alkene in the presence of a transition metal catalyst to form an alkane? H H G D C PC G D H H H H H2

Ni

H C

C H

H H

There is no change in the number of valence electrons on any of the atoms in the reaction. Both before and after the reaction, each carbon atom shares a total of eight valence electrons and each hydrogen atom shares two electrons. Instead of electrons, the reaction involves the transfer of atoms--in this case, hydrogen atoms. There are so many atomtransfer reactions that chemists developed the concept of oxidation number (see Chapter 5) to extend the idea of oxidation and reduction to reactions in which electrons aren't necessarily gained or lost. Oxidation involves an increase in the oxidation number of an atom. Reduction occurs when the oxidation number of an atom decreases. During the transformation of ethene into ethane, there is a decrease in the oxidation number of the carbon atom. The reaction therefore involves the reduction of ethene to ethane.

2

H

H G D C PC G D H H

H H H2

Ni

H C

3

C H

H H

Reactions in which none of the atoms undergo a change in oxidation number are called metathesis reactions. Consider the reaction between a carboxylic acid and an amine, for example, CH3CO2H CH3NH2 88n CH3CO2 CH3NH3

or the reaction between an alcohol and hydrogen bromide. CH3CH2OH HBr 88n CH3CH2Br H2O

These are metathesis reactions because there is no change in the oxidation number of any atom in either reaction. The oxidation numbers of the carbon atoms in a variety of compounds are given in Table O2.3. The oxidation numbers can be used to classify organic reactions as either oxidation­reduction reactions or metathesis reactions.

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FUNCTIONAL GROUP CHEMISTRY Typical Oxidation Numbers of Carbon Example CH4 CH3Li H2CPCH2 CH3OH CH3OCH3 CH3Cl CH3NH2 HCqCH H2CO HCO2H CO2 Oxidation Number of the Carbon 4 4 2 2 2 2 2 1 0 2 4

TABLE O2.3

Classes of Compounds Alkane Alkyllithium Alkene Alcohol Ether Alkyl halide Amine Alkyne Aldehyde Carboxylic acid --

Exercise O2.4

Classify the following as either oxidation­reduction or metathesis reactions. (a) 2 CH3OH H CH3OCH3 H2O 8n O O B B 8n (b) HCOH CH3OH H HCOCH3 (c) CO 2 H2 n CH3OH (d) CH3Br 2 Li n CH3Li LiBr

H2O

Solution (a) This is a metathesis reaction because there is no change in the oxidation number of the carbon atoms when an alcohol is converted to an ether. 2 CH3OH 88n CH3OCH3

2 2

H2O

(b) This is a metathesis reaction because there is no change in the oxidation number of any of the carbon atoms when a carboxylic acid reacts with an alcohol to form an ester. HCO2H

2

CH3OH 88n HCO2CH3

2 2 2

H2O

(c) This is an oxidation­reduction reaction because the carbon atom is reduced from the 2 to the 2 oxidation state when CO combines with H2 to form methanol. CO

2

2 H2 88n CH3OH

2

(d) This is an oxidation­reduction reaction because the carbon atom is reduced from the 2 to the 4 oxidation state when CH3Br reacts with lithium metal to form CH3Li. CH3Br

2

2 Li 88n CH3Li

4

LiBr

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Because electrons are neither created nor destroyed, oxidation can't occur in the absence of reduction, and vice versa. It is often useful, however, to focus attention on one component of the reaction and ask, is that substance oxidized or reduced?

Exercise O2.5

Determine whether the following transformations involve the oxidation or the reduction of the carbon atom. H H C H O B H C H O B H C OH O B H C OH OH O B H C H

OPC PO

Solution Each of the transformations involves the oxidation of the carbon atom. The first reaction involves oxidation of the carbon atom from the 2 to the 0 oxidation state. In the second reaction the carbon atom is oxidized to the 2 state, and the third reaction involves oxidation of the carbon atom to the 4 oxidation state.

2

H OH

H C H

0

0 O B H C H

O B H C H

2 O B H C OH 4

O B H C OH

2

OPCPO

Assigning oxidation numbers to the individual carbon atoms in a complex molecule can be difficult. Fortunately, there is another way to recognize oxidation­reduction reactions in organic chemistry: Oxidation occurs when hydrogen atoms are removed from a carbon atom or when an oxygen atom is added to a carbon atom. Reduction occurs when hydrogen atoms are added to a carbon atom or when an oxygen atom is removed from a carbon atom.

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The first reaction in Exercise O2.5 involves oxidation of the carbon atom because a hydrogen atom is removed from that atom when the alcohol is oxidized to an aldehyde. O B CH3OH 8n HCH The second reaction in the exercise is an example of oxidation because an oxygen atom is added to the carbon atom when an aldehyde is oxidized to a carboxylic acid. O B HC H O B HCOH

Reduction, on the other hand, occurs when hydrogen atoms are added to a carbon atom or when an oxygen atom is removed from a carbon atom. An alkene is reduced, for example, when it reacts with H2 to form the corresponding alkane. CH2PCHCH3

Ni H2 88n CH3CH2CH3

Figure O2.1 provides a useful guide to the oxidation­reduction reactions of organic compounds. Each of the arrows in this figure involves a two-electron oxidation of a carbon atom along the path toward carbon dioxide. A line is drawn through the first arrow because it is impossible to achieve this transformation in a single step. O B HCH

0

CH4

­4

CH3OH

­2

O B HCOH

+2

CO2

+4

FIGURE O2.1 The stepwise oxidation of carbon.

O2.3 ALKYL HALIDES

Imagine that a pair of crystallizing dishes are placed on an overhead projector as shown in Figure O2.2. An alkene is added to the dish in the upper left corner of the projector, and an alkane is added to the dish in the upper right corner. A few drops of bromine dissolved in chloroform (CHCl3) are then added to each of the crystallizing dishes.

CH2 = CH(CH2)3CH3

CH3(CH2)4CH3

FIGURE O2.2 Demonstrating the relative rate of bromination reactions.

The characteristic red-orange color of bromine disappears the instant this reagent is added to the alkene in the upper left corner as the Br2 molecules add across the CPC double bond in the alkene.

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CH2PCH(CH2)3CH3

Br A Br2 88n BrCH2CH(CH2)3CH3

The other crystallizing dish picks up the characteristic color of a dilute solution of bromine because the reagent doesn't react with alkanes under normal conditions. If the crystallizing dish in the upper right corner is moved into the center of the projector, however, the color of the bromine slowly disappears. This can be explained by noting that alkanes react with halogens at high temperatures or in the presence of light to form alkyl halides, as noted in Section O1.8. Br A Light Br2 88n CH3CH(CH2)3CH3

CH3(CH2)4CH3

HBr

The light source in an overhead projector is intense enough to initiate the reaction, although the reaction is still much slower than the addition of Br2 to an alkene. The reaction between an alkane and one of the halogens (F2, Cl2, Br2, or I2) can be understood by turning to a simpler example. CH4(g) Cl2(g) 88n CH3Cl(g) HCl(g)

This reaction has the following characteristic properties.

· · · · ·

It doesn't take place in the dark or at low temperatures. It occurs in the presence of ultraviolet light or at temperatures above 250ºC. Once the reaction gets started, it continues after the light is turned off. The products of the reaction include CH2Cl2 (dichloromethane), CHCl3 (chloroform), and CCl4 (carbon tetrachloride), as well as CH3Cl (chloromethane). The reaction also produces some C2H6.

These facts are consistent with a chain reaction mechanism that involves three processes: chain initiation, chain propagation, and chain termination.

Chain Initiation

A Cl2 molecule can dissociate into a pair of chlorine atoms by absorbing energy in the form of either ultraviolet light or heat. Cl2 88n 2 Cl H° 243.4 kJ/molrxn

The chlorine atom produced in the reaction is an example of a free radical--an atom or molecule that contains one or more unpaired electrons.

Chain Propagation

Free radicals, such as the Cl atom, are extremely reactive. When a chlorine atom collides with a methane molecule, it can remove a hydrogen atom to form HCl and a CH3 radical. CH4 Cl 88n CH3 HCl H° 16 kJ/molrxn

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If the CH3 radical then collides with a Cl2 molecule, it can remove a chlorine atom to form CH3Cl and a new Cl radical. CH3 Cl2 88n CH3Cl Cl H° 87 kJ/molrxn

Because a Cl atom is generated in the second reaction for every Cl atom consumed in the first, the reaction continues in a chainlike fashion until the radicals involved in the chain propagation steps are destroyed.

Chain Termination

If a pair of the radicals that keep the chain reaction going collide, they combine in a chain terminating step. Chain termination can occur in three ways. 2 Cl 88n Cl2 CH3 Cl 88n CH3Cl 2 CH3 88n CH3CH3 H° H° H° 243.4 kJ/molrxn 330 kJ/molrxn 350 kJ/molrxn

Because the concentration of the radicals is relatively small, the chain termination reactions are relatively infrequent. The chain reaction mechanism for free radical reactions explains the observations listed for the reaction between CH4 and Cl2.

·

The reaction doesn't occur in the dark or at low temperatures because energy must be absorbed to generate the free radicals that carry the reaction. Cl2 88n 2 Cl H° 243.4 kJ/molrxn

The reaction occurs in the presence of ultraviolet light because a UV photon has enough energy to dissociate a Cl2 molecule to a pair of Cl atoms. The reaction occurs at high temperatures because Cl2 molecules can dissociate to form Cl atoms by absorbing thermal energy. · The reaction continues after the light has been turned off because light is needed only to generate the Cl atoms that start the reaction. The chain reaction then converts CH4 into CH3Cl without consuming the Cl atoms.

·

CH4 CH3

·

Cl 88n CH3 HCl Cl2 88n CH3Cl Cl

The reaction doesn't stop at CH3Cl because the Cl atoms can abstract additional hydrogen atoms to form CH2Cl2, CHCl3, and eventually CCl4. CH3Cl CH2Cl Cl 88n CH2Cl Cl2 88n CH2Cl2 HCl Cl , and so on

·

The formation of C2H6 is a clear indication that the reaction proceeds through a free radical mechanism. When two CH3 radicals collide, they combine to form an ethane molecule.

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2 CH3 88n CH3CH3 Free radical halogenation of alkanes provides us with another example of the role of atom transfer reactions in organic chemistry. The net effect of the reaction is to oxidize a carbon atom by removing a hydrogen from the atom. CH4

4

Cl2

CH3Cl

2

HCl

The reaction, however, doesn't involve the gain or loss of electrons. It occurs by the transfer of a hydrogen atom in one direction and a chlorine atom in the other.

O2.4 ALCOHOLS AND ETHERS

Alcohols contain an OOH group attached to a saturated carbon. The common names for alcohols are based on the name of the alkyl group. CH3OH CH3CH2OH CH3CHOHCH3 Methyl alcohol Ethyl alcohol Isopropyl alcohol

The systematic nomenclature for alcohols adds the ending -ol to the name of the parent alkane and uses a number to identify the carbon that carries the OOH group. The systematic name for isopropyl alcohol, for example, is 2-propanol. CH3OH CH3CH2OH CH3CHOHCH3 Methanol Ethanol 2-Propanol

Exercise O2.6

More than 50 organic compounds have been isolated from the oil that gives rise to the characteristic odor of a rose. One of the most abundant of the compounds is known by the common name citronellol. Use the systematic nomenclature to name this alcohol, which has the following structure. CH3 A CH D G H2C CH2 A A H2C CH2O OH G CH B C D G CH3 CH3 Solution The longest chain of carbon atoms in the compound contains eight atoms.

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CH 2 D G H2C CH2 A A H2C 5 CH2O OH G 1 6 CH B C D7 G CH3 CH3

4 8

3A

CH3

The longest chain contains the OOH group, which means the compound is named as a derivative of octane. Because it is an alcohol, it would be tempting to name it as an octanol. But it contains a CPC double bond, which means it must be an octenol. We now have to indicate that the OOH group is on one end of the chain and the CPC double bond occurs between the sixth and seventh carbon atoms of the chain, which can be done by considering the compound to be a derivative of 6-octen-1-ol. Finally, we have to indicate the presence of a pair of CH3 groups on the third and seventh carbon atoms. The compound is therefore given the systematic name 3,7-dimethyl-6-octen-1-ol.

Methanol, or methyl alcohol, is also known as wood alcohol because it was originally made by heating wood until a liquid distilled. Methanol is highly toxic, and many people have become blind or have died from drinking it. Ethanol, or ethyl alcohol, is the alcohol associated with "alcoholic" beverages. It has been made for at least 6000 years by adding yeast to solutions that are rich in either sugars or starches. The yeast cells obtain energy from enzyme-catalyzed reactions that convert sugar or starch to ethanol and CO2. C6H12O6(aq) 88n 2 CH3CH2OH(aq) 2 CO2(g)

When the alcohol reaches a concentration of 10% to 12% by volume, the yeast cells die. Brandy, rum, gin, and the various whiskeys that have a higher concentration of alcohol are prepared by distilling the alcohol produced by the fermentation reaction. Ethanol isn't as toxic as methanol, but it is still dangerous. Most people are intoxicated at blood-alcohol levels of about 0.1 gram per 100 mL. An increase in the level of alcohol in the blood to between 0.4 and 0.6 g/100 mL can lead to coma or death. The method of choice for determining whether an individual is DUI--driving under the influence--or DWI--driving while intoxicated--is the Breathalyzer, for which a patent was issued to R. F. Borkenstein in 1958. The chemistry behind the Breathalyzer is based on the reaction between alcohol in the breath and the chromate or dichromate ion. 3 CH3CH2OH(g) 2 Cr2O72 (aq) 16 H (aq) 88n 3 CH3CO2H(aq)

4 Cr3 (aq)

11 H2O(l)

The instrument contains two ampules that hold small samples of potassium dichromate dissolved in sulfuric acid. One of the ampules is used as a reference. The other is opened and the breath sample to be analyzed is added. If alcohol is present in the breath, it reduces the yellow-orange Cr2O72 ion to the green Cr3 ion. The extent to which the color balance between the two ampules is disturbed is a direct measure of the amount of alcohol in the breath sample. Measurements of the alcohol on the breath are then converted into

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estimates of the concentration of the alcohol in the blood by assuming that 2100 mL of air exhaled from the lungs contains the same amount of alcohol as 1 mL of blood. Measurements taken with the Breathalyzer are reported in units of percent bloodalcohol concentration (BAC). In most states, a BAC of 0.10% is sufficient for a DUI or DWI conviction. (This corresponds to a blood-alcohol concentration of 0.10 gram of alcohol per 100 mL of blood.) Ethanol is oxidized to CO2 and H2O by the alcohol dehydrogenase enzymes in the body. This reaction gives off 30 kilojoules per gram, which makes ethanol a better source of energy than carbohydrates (17 kJ/g), and almost as good a source of energy as fat (38 kJ/g). An ounce of 80-proof liquor can provide as much as 3% of the average daily caloric intake, and drinking alcohol can contribute to obesity. Many alcoholics are malnourished, however, because of the absence of vitamins in the calories they obtain from alcoholic beverages. As a general rule, polar or ionic substances dissolve in polar solvents; nonpolar substances dissolve in nonpolar solvents. As a result, hydrocarbons don't dissolve in water. They are often said to be immiscible (literally, "not mixable") in water. Alcohols, as might be expected, have properties between the extremes of hydrocarbons and water. When the hydrocarbon chain is short, the alcohol is soluble in water. There is no limit on the amount of methanol (CH3OH) and ethanol (CH3CH2OH), for example, that can dissolve in a given quantity of water. As the hydrocarbon chain becomes longer, the alcohol becomes less soluble in water, as shown in Table O2.4. One end of the alcohol molecules has so much nonpolar character it is said to be hydrophobic (literally, "water-hating"). The other end contains an OOH group that can form hydrogen bonds to neighboring water molecules and is therefore said to be hydrophilic (literally, "water-loving"). As the hydrocarbon chain becomes longer, the hydrophobic character of the molecule increases, and the solubility of the alcohol in water gradually decreases until it becomes essentially insoluble in water.

TABLE O2.4 Formula CH3OH CH3CH2OH CH3(CH2)2OH CH3(CH2)3OH CH3(CH2)4OH CH3(CH2)5OH CH3(CH2)6OH CH3(CH2)7OH CH3(CH2)9OH Solubilities of Alcohols in Water Name Methanol Ethanol Propanol Butanol Pentanol Hexanol Heptanol Octanol Decanol Solubility in Water (g/100 g) Infinitely soluble Infinitely soluble Infinitely soluble 9 2.7 0.6 0.18 0.054 Insoluble in water

Alcohols are classified as either primary (1°), secondary (2°), or tertiary (3°) on the basis of their structures. OH A CH3CHCH3

2

CH3CH2OH

1

OH A CH3CCH3 A CH3

3

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FUNCTIONAL GROUP CHEMISTRY

Ethanol is a primary alcohol because there is only one alkyl group attached to the carbon that carries the OOH substituent. The structure of a primary alcohol can be abbreviated as RCH2OH, where R stands for an alkyl group. The isopropyl alcohol found in rubbing alcohol is a secondary alcohol, which has two alkyl groups on the carbon atom with the OOH substituent (R2CHOH). An example of a tertiary alcohol (R3COH) is tert-butyl (or t-butyl) alcohol or 2-methyl-2-propanol. Another class of alcohols are the phenols, in which an OOH group is attached to an aromatic ring, as shown in Figure O2.3. Phenols are potent disinfectants. When antiseptic techniques were first introduced in the 1860s by Joseph Lister, it was phenol (or carbolic acid, as it was then known) that was used. Phenol derivatives, such as o-phenylphenol, are still used in commercial disinfectants such as Lysol. OH OH

Phenol o-Phenylphenol

FIGURE O2.3 The structures of phenol and o-phenylphenol.

Water has an unusually high boiling point because of the hydrogen bonds between the H2O molecules. Alcohols can form similar hydrogen bonds, as shown in Figure O2.4. CH3 O H ,, O CH3

FIGURE O2.4 A hydrogen bond between a pair of methanol molecules.

H

As a result, alcohols have boiling points that are much higher than alkanes with similar molecular weights. The boiling point of ethanol, for example, is 78.5°C, whereas propane, with about the same molecular weight, boils at 42.1°C. Alcohols are Brønsted acids in aqueous solution. CH3CH2OH(aq) 88n H2O(l) m88 H3O (aq) CH3CH2O (aq)

Alcohols therefore react with sodium metal to produce sodium salts of the corresponding conjugate base, as noted in Section O2.2. 2 Na(s) 2 CH3OH(l) 88n 2 Na (alc) 2 CH3O (alc) H2(g)

The conjugate base of an alcohol is known as an alkoxide. [Na ][CH3O ]

Sodium methoxide

[Na ][CH3CH2O ]

Sodium ethoxide

As we saw in Section O1.8, alcohols can be prepared by adding water to an alkene in the presence of a strong acid such as concentrated sulfuric acid. The reaction involves adding an H2O molecule across a CPC double bond. Because the reactions follow Markovnikov's rule, the product of the reaction is often a highly substituted 2° or 3° alcohol.

FUNCTIONAL GROUP CHEMISTRY

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CH3CHP CHCH3

H2O

H2SO4

OH A CH3CHCH2CH3

Less substituted 1° alcohols can be prepared by substitution reactions that occur when a primary alkyl halide is allowed to react with the OH ion. CH3CH2CH2Br OH 88n CH3CH2CH2OH Br

Alcohols (ROH) can be thought of as derivatives of water in which one of the hydrogen atoms has been replaced by an alkyl group. If both of the hydrogen atoms are replaced by alkyl groups, we get an ether (ROR). These compounds are named by adding the word ether to the names of the alkyl groups. CH3CH2OCH2CH3

diethyl ether

Diethyl ether, often known by the generic name "ether," was once used extensively as an anesthetic. Because mixtures of diethyl ether and air explode in the presence of a spark, ether has been replaced by safer anesthetics. There are important differences between both the physical and chemical properties of alcohols and ethers. Consider diethyl ether and 1-butanol, for example, which are constitutional isomers with the formula C4H10O. CH3CH2OCH2CH3 BP 34.5°C density 0.7138 g/mL Insoluble in water CH3CH2CH2CH2OH BP 117.2°C density 0.8098 g/mL Soluble in water

The shapes of the molecules are remarkably similar, as shown in Figure O2.5. O OH

FIGURE O2.5 The structures of diethyl ether and 1-butanol.

The fundamental difference between the compounds is the presence of OOH groups in the alcohol that are missing in the ether. Because hydrogen bonds can't form between the molecules in the ether, the boiling point of the compound is more than 80°C lower than that of the corresponding alcohol. Because there are no hydrogen bonds to organize the structure of the liquid, the ether is significantly less dense than the corresponding alcohol. Ethers can act as a hydrogen bond acceptor, as shown in Figure O2.6, but they can't act as hydrogen bond donors. As a result, ethers are less soluble in water than alcohols with the same molecular weight. H O H O CH3

FIGURE O2.6 Water acting as a hydrogen bond donor toward an ether.

CH3

The absence of an OOH group in an ether also has important consequences for its chemical properties. Unlike alcohols, ethers are essentially inert to chemical reactions. They

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FUNCTIONAL GROUP CHEMISTRY

don't react with most oxidizing or reducing agents, and they are stable to most acids and bases, except at high temperatures. They are therefore frequently used as solvents for chemical reactions. Compounds that are potential sources of an H ion, or proton, are often described as being protic. Ethanol, for example, is a protic solvent. CH3CH2OH(aq) H2O(l) H3O (aq) CH3CH2O (aq)

Substances that can't act as a source of a proton are said to be aprotic. Because they don't contain an OOH group, ethers are aprotic solvents. Ethers can be synthesized by splitting out a molecule of water between two alcohols in the presence of heat and concentrated sulfuric acid. 2 CH3CH2OH

H

CH3CH2OCH2CH3

They can also be formed by reacting a primary alkyl halide with an alkoxide ion. CH3CH2CH2Br CH3O 88n CH3CH2CH2OCH3 Br

O2.5 ALDEHYDES AND KETONES

The connection between the structures of alkenes and alkanes was established in Section O1.6, which noted that we can transform an alkene into an alkane by adding an H2 molecule across the CPC double bond. H H G D C PC G D H H H H H2

Ni

H C

C H

H H

The driving force behind the reaction is the difference between the strengths of the bonds that must be broken and the bonds that form in the reaction. In the course of the hydrogenation reaction, a relatively strong HOH bond (435 kJ/mol) and a moderately strong carbon­carbon bond (~270 kJ/mol) are broken, but two strong COH bonds (439 kJ/mol) are formed. The reduction of an alkene to an alkane is therefore an exothermic reaction. What about the addition of an H2 molecule across a CPO double bond? H O B H C C H H H OH H2

Pt

H C

C H

H H

Once again, a significant amount of energy has to be invested in the reaction to break the HOH bond (435 kJ/mol) and the carbon­oxygen bond (~375 kJ/mol). The overall reaction is still exothermic, however, because of the strength of the COH bond (439 kJ/mol) and the OOH bond (498 kJ/mol) that are formed. The addition of hydrogen across a CPO double bond raises several important points. First, and perhaps foremost, it shows the connection between the chemistry of primary alcohols and aldehydes. But it also helps us understand the origin of the term aldehyde. If a

FUNCTIONAL GROUP CHEMISTRY

17

reduction reaction in which H2 is added across a double bond is an example of a hydrogenation reaction, then an oxidation reaction in which an H2 molecule is removed to form a double bond might be called dehydrogenation. Thus, using the symbol [O] to represent an oxidizing agent, we see that the product of the oxidation of a primary alcohol is literally an "al-dehyd" or aldehyde. It is an alcohol that has been dehydrogenated. O B CH3CH

CH3CH2OH

[O]

The reaction also illustrates the importance of differentiating between primary, secondary, and tertiary alcohols. Consider the oxidation of isopropyl alcohol, or 2-propanol, for example. OH A CH3CHCH3 O B CH3CCH3

[O]

The product of this particular reaction was originally called aketone, although the name was eventually softened to azetone and finally acetone. Thus, it is not surprising that any substance that exhibited chemistry that resembled "aketone" became known as a ketone. Aldehydes can be formed by oxidizing a primary alcohol; oxidation of a secondary alcohol gives a ketone. What happens when we try to oxidize a tertiary alcohol? The answer is simple: Nothing happens. OH A CH3CCH3 A CH3

[O]

There aren't any hydrogen atoms that can be removed from the carbon atom carrying the OOH group in a 3° alcohol. And any oxidizing agent strong enough to insert an oxygen atom into a COC bond would oxidize the alcohol all the way to CO2 and H2O. A variety of oxidizing agents can be used to transform a secondary alcohol to a ketone. A common reagent for the reaction is some form of chromium(VI)--chromium in the 6 oxidation state--in acidic solution. The reagent can be prepared by adding a salt of the chromate (CrO42 ) or dichromate (Cr2O72 ) ion to sulfuric acid. Or it can be made by adding chromium trioxide (CrO3) to sulfuric acid. Regardless of how it is prepared, the oxidizing agent in the reactions is chromic acid, H2CrO4. OH A CH3CHCH2CH3 O B CH3CCH2CH3

H2CrO4

The choice of oxidizing agents to convert a primary alcohol to an aldehyde is much more limited. Most reagents that can oxidize the alcohol to an aldehyde carry the reaction one step further--they oxidize the aldehyde to the corresponding carboxylic acid. O B CH3CH O B CH3COH

CH3CH2OH

H2CrO4

18

FUNCTIONAL GROUP CHEMISTRY

A weaker oxidizing agent, which is just strong enough to prepare the aldehyde from the primary alcohol, can be obtained by dissolving the complex that forms between CrO3 and pyridine, C6H5N, in a solvent such as dichloromethane that doesn't contain any water.

CrO3 /pyridine CH2Cl2

CH3CH2OH

O B CH3CH

The Nomenclature of Aldehydes and Ketones

The common names of aldehydes are derived from the names of the corresponding carboxylic acids. O B HCOH

Formic acid

O B HCH

Formaldehyde

O B CH3COH

Acetic acid

O B CH3CH

Acetaldehyde

The systematic names for aldehydes are obtained by adding -al to the name of the parent alkane. O B HCH

Methanal

O B CH3CH

Ethanal

The presence of substituents is indicated by numbering the parent alkane chain from the end of the molecule that carries the OCHO functional group. For example, O B BrCH2CH2CH

3-Bromopropanal

The common name for a ketone is constructed by adding ketone to the names of the two alkyl groups on the carbon of the CPO double bond, listed in alphabetical order. O B CH3CCH2CH3

Ethyl methyl ketone

The systematic name is obtained by adding -one to the name of the parent alkane and using numbers to indicate the location of the CPO group. O B CH3CCH2CH3

2-Butanone

Common Aldehydes and Ketones

Formaldehyde has a sharp, somewhat unpleasant odor. The aromatic aldehydes in Figure O2.7, on the other hand, have a very pleasant "flavor." Benzaldehyde has the characteristic

FUNCTIONAL GROUP CHEMISTRY

19

odor of almonds, vanillin is responsible for the flavor of vanilla, and cinnamaldehyde makes an important contribution to the flavor of cinnamon. O B CH

Benzaldehyde

HO CH3O

Vanillin

O B CH

Cinnamaldehyde

O B CH

FIGURE O2.7 Aromatic aldehydes with characteristic odors.

O2.6 REACTIONS AT THE CARBONYL GROUP

It is somewhat misleading to write the carbonyl group as a covalent CPO double bond. The difference between the electronegativities of carbon and oxygen is large enough to make the CPO bond moderately polar. As a result, the carbonyl group is best described as a hybrid of the following resonance structures. O B C D G O SOS A C D G

O S

We can represent the polar nature of the hybrid by indicating the presence of a slight negative charge on the oxygen ( ) and a slight positive charge ( ) on the carbon of the CPO double bond.

O B C D G Reagents that attack the electron-rich end of the CPO bond are called electrophiles (literally, "lovers of electrons"). Electrophiles include ions (such as H and Fe3 ) and neutral molecules (such as AlCl3 and BF3) that are Lewis acids, or electron pair acceptors. Reagents that attack the electron-poor end of the bond are nucleophiles (literally, "lovers of nuclei"). Nucleophiles are Lewis bases (such as NH3 or the OH ion).

O O

Electrophiles O B (H , Fe3 , BF , etc.) 3 C D G Nucleophiles (OH , NH3, etc.) The polarity of the CPO double bond can be used to explain the reactions of carbonyl compounds. Aldehydes and ketones react with a source of the hydride ion (H ) because the H ion is a Lewis base, or nucleophile, that attacks the end of the CPO bond. When this happens, the two valence electrons on the H ion form a covalent bond to the carbon atom. Since carbon is tetravalent, one pair of electrons in the CPO bond is displaced onto the oxygen to form an intermediate with a negative charge on the oxygen atom.

O S

20

FUNCTIONAL GROUP CHEMISTRY

O B C D G CH3 CH3 HS

O SOS A CH3OC OCH3 A H

The alkoxide ion can then remove an H ion from water to form an alcohol. O SOS A CH3OC OCH3 A H O SO OH A CH3OC OCH3 A H

O S

H2O

OH

Common sources of the H ion include lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4). Both compounds are ionic. LiAlH4: NaBH4: [Li ][AlH4 ] [Na ][BH4 ]

The aluminum hydride (AlH4 ) and borohydride (BH4 ) ions act as if they were complexes between an H ion, acting as a Lewis base, and neutral AlH3 or BH3 molecules, acting as a Lewis acid. H A HOAlOH A H H A AlOH A H

HS

LiAlH4 is such a good source of the H ion that it reacts with the H ions in water or other protic solvents to form H2 gas. The first step in the reduction of a carbonyl with LiAlH4 is therefore carried out using an ether as the solvent. The product of the hydride reduction reaction is then allowed to react with water in a second step to form the corresponding alcohol. O B CH3CH2CH

1. LiAlH4 in ether 2. H2O

CH3CH2CH2OH

NaBH4 is less reactive toward protic solvents, which means that borohydride reductions are usually done in a single step, using an alcohol as the solvent. O OH B A NaBH4 CH3CH2CCH3 CH CH OH CH3CH2CHCH3

3 2

O2.7 CARBOXYLIC ACIDS AND CARBOXYLATE IONS

When one of the substituents on a carbonyl group is an OH group, the compound is a carboxylic acid with the generic formula RCO2H. These compounds are acids, as the name suggests, which form carboxylate ions (RCO2 ) by the loss of an H ion.

FUNCTIONAL GROUP CHEMISTRY

21

O J CH3O C G OH

O J CH3O C G O

H

The carboxylate ion formed in the reaction is a hybrid of two resonance structures. O J CH3O C G O O D CH3O C M O

Resonance delocalizes the negative charge in the carboxylate ion, which makes the ion more stable than the alkoxide ion formed when an alcohol loses an H ion. By increasing the stability of the conjugate base, resonance increases the acidity of the acid that forms the base. Carboxylic acids are therefore much stronger acids than the analogous alcohols. The Ka value for a typical carboxylic acid is about 10 5, whereas alcohols have Ka values only 10 16. O J CH3C G OH CH3OH O J CH3C G O CH3O H

H

Ka

1.8

10

5

Ka

8

10

16

Carboxylic acids were among the first organic compounds to be discovered. As a result, they have well-established common names that are often derived from the Latin stems of their sources in nature. Formic acid (Latin formica, "an ant") and acetic acid (Latin acetum, "vinegar") were first obtained by distilling ants and vinegar, respectively. Butyric acid (Latin butyrum, "butter") is found in rancid butter, and caproic, caprylic, and capric acids (Latin caper, "goat") are all obtained from goat fat. A list of common carboxylic acids is given in Table O2.5. The systematic nomenclature of carboxylic acids is easy to understand. The ending -oic acid is added to the name of the parent alkane to indicate the presence of the OCO2H functional group. HCO2H CH3CO2H CH3CH2CO2H Methanoic acid Ethanoic acid Propanoic acid

Unfortunately, because of the long history of carboxylic acids and their importance in biology and biochemistry, you are more likely to encounter these compounds by their common names. Formic acid and acetic acid have sharp, pungent odors. As the length of the alkyl chain increases, the odor of carboxylic acids becomes more unpleasant. Butyric acid, for example, is found in sweat, and the odor of rancid meat is due to carboxylic acids released as the meat spoils. The solubility data in Table O2.5 show that carboxylic acids also become less soluble in water as the length of the alkyl chain increases. The OCO2H end of the molecule is polar and therefore soluble in water. As the alkyl chain gets longer, the molecule becomes more nonpolar and less soluble in water.

22

FUNCTIONAL GROUP CHEMISTRY Common Carboxylic Acids Formula Saturated carboxylic acids and fatty acids Solubility in H2O (g/100 mL)

TABLE O2.5

Common Name

Formic acid Acetic acid Propionic acid Butyric acid Caproic acid Caprylic acid Capric acid Lauric acid Myristic acid Palmitic acid Stearic acid Palmitoleic acid Oleic acid Linoleic acid Linolenic acid

HCO2H CH3CO2H CH3CH2CO2H CH3(CH2)2CO2H CH3(CH2)4CO2H CH3(CH2)6CO2H CH3(CH2)8CO2H CH3(CH2)10CO2H CH3(CH2)12CO2H CH3(CH2)14CO2H CH3(CH2)16CO2H Unsaturated fatty acids CH3(CH2)5CHPCH(CH2)7CO2H CH3(CH2)7CHPCH(CH2)7CO2H CH3(CH2)4CHPCHCH2CHPCH(CH2)7CO2H CH3CH2CHPCHCH2CHPCHCH2CHPCH(CH2)7CO2H

0.968 0.068 0.015 0.0055 0.0020 0.00072 0.00029 -- -- -- --

Compounds that contain two OCO2H functional groups are known as dicarboxylic acids. A number of dicarboxylic acids (see Table O2.6) can be isolated from natural sources. Tartaric acid, for example, is a by-product of the fermentation of wine, and succinic, fumaric, malic, and oxaloacetic acids are intermediates in the metabolic pathway used to oxidize sugars to CO2 and H2O.

TABLE 02.6 Common Dicarboxylic Acids Structure HO2CCO2H HO2CCH2CO2H HO2CCH2CH2CO2H HO 2C CO H G D 2 C PC D G H H H HO 2C G D C PC D G H CO2 H Common Name Oxalic acid Malonic acid Succinic acid Maleic acid Structure OH A HO2CCH2CHCO2H OH OH A A HO2CCHCHCO2H O B HO2CCH2CCO2H Common Name

Malic acid Tartaric acid Oxaloacetic acid

Fumaric acid

Several tricarboxylic acids also play an important role in the metabolism of sugar. The most important example of this class of compounds is the citric acid that gives so many fruit juices their characteristic acidity.

FUNCTIONAL GROUP CHEMISTRY

23

CH2CO2H A HOC OCO2H A CH2CO2H

Citric acid

O2.8 ESTERS

Carboxylic acids (OCO2H) can react with alcohols (ROH) in the presence of either acid or base to form esters (OCO2R). Acetic acid, for example, reacts with ethanol to form ethyl acetate. O B CH3COH O B CH3COCH2CH3

CH3CH2OH

H

H2O

This isn't an efficient way of preparing an ester, however, because the equilibrium constant for the reaction is relatively small (Kc 3). Chemists therefore tend to synthesize esters from carboxylic acids in a two-step process. They start by reacting the acid with a chlorinating agent such as thionyl chloride (SOCl2) to form the corresponding acyl chloride. O B CH3COH O B CH3CCl

SOCl2

SO2

HCl

They then react the acyl chloride with an alcohol in the presence of base to form the ester. O B CH3CCl O B CH3COCH2CH3

CH3CH2OH

B

BH Cl

The base absorbs the HCl given off in the reaction, thereby driving it to completion. As might be expected, esters are named as if they were derivatives of a carboxylic acid and an alcohol. The ending -ate or -oate is added to the name of the parent carboxylic acid, and the alcohol is identified using the "alkyl alcohol" convention. The following ester, for example, can be named as a derivative of acetic acid (CH3CO2H) and ethyl alcohol (CH3CH2OH). O B CH3COCH2CH3

Ethyl acetate

Or it can be named as a derivative of ethanoic acid (CH3CO2H) and ethyl alcohol (CH3CH2OH). O B CH3COCH2CH3

Ethyl ethanoate

The term ester is commonly used to describe the product of the reaction of any strong acid with an alcohol. Sulfuric acid, for example, reacts with methanol to form a diester known as dimethyl sulfate.

24

FUNCTIONAL GROUP CHEMISTRY

O A HO S OH A O

2 CH3OH

O A CH3O S OCH3 A O

2 H2O

Phosphoric acid reacts with alcohols to form triesters such as trimethyl phosphate. O A HO P OH A OH O A CH3O P OCH3 A OCH3

3 CH3OH

3 H2O

Compounds that contain the OCO2R functional group might therefore best be called carboxylic acid esters, to indicate the acid from which they are formed. Carboxylic acid esters with low molecular weights are colorless, volatile liquids that often have a pleasant odor. They are important components of both natural and synthetic flavors (see Figure O2.8). CH3O C O O CH2 CH3

Methyl salicylate (oil of wintergreen)

CH2 CH3 CH2

FIGURE O2.8 Typical carboxylic acid esters with pleasant odors or flavors.

O2.9 AMINES, ALKALOIDS, AND AMIDES

Amines are derivatives of ammonia in which one or more hydrogen atoms are replaced by alkyl groups. We indicate the degree of substitution by labeling the amine as either primary (RNH2), secondary (R2NH), or tertiary (R3N). The common names of the compounds are derived from the names of the alkyl groups. CH3 A CH3CH2NH

Ethylmethylamine

The systematic names of primary amines are derived from the name of the parent alkane by adding the prefix amino- and a number specifying the carbon that carries the ONH2 group. CHP CH NH2 D G D CH2O CH CH3 G CH3

B

OH E

CH2 CH2

CH3 CH CH3

C

CH2

B O

Isoamyl butyrate (chocolate)

O C

B O

CH2 CH3 CH3 C

O

B O

CH2 CH2

CH3 CH CH3

Ethyl butyrate (pineapple)

Isoamyl acetate (apple)

(CH3)2CHNH2

Isopropylamine

CH3 A CH3 NCH3

Trimethylamine

5-Amino-2-hexene

FUNCTIONAL GROUP CHEMISTRY

25

The chemistry of amines mirrors the chemistry of ammonia. Amines are weak bases that pick up a proton to form ammonium salts. Trimethylamine, for example, reacts with acid to form the trimethylammonium ion. CH3 A CH3ONS A CH3 CH3 A CH3ONOH A CH3

H

The salts are more soluble in water than the corresponding amines, and the reaction can be used to dissolve otherwise insoluble amines in aqueous solution. The difference between amines and their ammonium salts plays an important role in both over-the-counter and illicit drugs. Cocaine, for example, is commonly sold as the hydrochloride salt, which is a white, crystalline solid. By extracting the solid into ether, it is possible to obtain the "free base." A glance at the side panel of almost any over-thecounter medicine will provide examples of ammonium salts of amines that are used to ensure that the drug dissolves in water (see Figure O2.9). CH3 CH3O

Dextromethorphan hydrobromide (cough suppressant)

CH3 CH HO CH H CH3

NH2 Cl

N

Br

Pseudoephedrine hydrochloride (decongestant)

FIGURE O2.9 Over-the-counter drugs sold as amine hydrochloride or hydrobromide salts.

Amines that are isolated from natural sources, especially from plants, are known as alkaloids. They include poisons such as nicotine, coniine, and strychnine (shown in Figure O2.10). Nicotine has a pleasant, invigorating effect when taken in minuscule quantities but is extremely toxic in larger amounts. Coniine is the active ingredient in hemlock, a poison that has been used since the time of Socrates. Strychnine is another toxic alkaloid that has been a popular poison in murder mysteries.

N N CH3

Nicotine

N H

Coniine

O N O

Strychnine

N

FIGURE O2.10 The alkaloids are complex amines that can be isolated from plants.

26

FUNCTIONAL GROUP CHEMISTRY

The alkaloids also include a number of drugs, such as morphine, quinine, and cocaine. Morphine is obtained from poppies; quinine can be found in the bark of the chinchona tree; and cocaine is isolated from coca leaves. This family of compounds also includes synthetic analogs of naturally occurring alkaloids, such as heroin and LSD (see Figure O2.11). To illustrate the importance of minor changes in the structure of a molecule, three amines with similar structures are shown in Figure O2.12. One of the compounds is caffeine, which is the pleasantly addictive substance that makes a cup of coffee an important part of the day for so many people. Another is theobromine, which is the pleasantly addictive substance that draws so many people to chocolate. The third compound is theophylline, which is a prescription drug used as a bronchodilator for people with asthma. O B CH3COO

Morphine Heroin

HOH

O NOCH3 E HO CH3H N

Cocaine

O

O

ECH3 N

E CH3CO B O

O

CHPCH2

CO2CH3 HO CH3OH H E CH A N

P O

H OC O

Quinine

N CH3CH2H E CH3CH2 O B NOCO NH N A CH3

FIGURE O2.11 The structures of some alkaloids used as drugs.

Lysergic acid diethylamide (LSD)

O CH3H N O N A CH3

Caffeine

N N

CH3 f

O HH N O N A CH3

CH3 f N N

O CH3H N O N A CH3

Theophylline

H i N N

Theobromine

FIGURE O2.12 The caffeine in coffee, the theobromine in chocolate, and the active ingredient in a common bronchodilator are central nervous system stimulants with very similar structures.

FUNCTIONAL GROUP CHEMISTRY

27

It is tempting to assume that carboxylic acids will react with amines to form the class of compounds known as amides. In practice, when aqueous solutions of carboxylic acids and amines are mixed all we get is an acid­base reaction. O B CH3COH O B CH3CO CH3NH3

CH3NH2

The best way to prepare an amide is to react the appropriate acyl chloride with an amine. O B CH3CCl O B CH3CNHCH3

2 CH3NH2

CH3NH3 Cl

Excess amine is used to drive the reaction to completion by absorbing the HCl given off in the reaction.

O2.10 GRIGNARD REAGENTS

So far, we have built a small repertoire of reactions that can be used to convert one functional group to another. We have briefly discussed converting alkenes to alkanes; alkanes to alkyl halides; alkyl halides to alcohols; alcohols to ethers, aldehydes, and ketones; and aldehydes to carboxylic acids. We have also shown how carboxylic acids can be converted to esters and amides. We have yet to encounter a reaction, however, that addresses a basic question: How do we make COC bonds? One answer resulted from the work that Francois Auguste Victor Grignard started as part of his Ph.D. research at the turn of the twentieth century. Grignard noted that alkyl halides react with magnesium metal in diethyl ether (Et2O) to form compounds that contain a metal­carbon bond. Methyl bromide, for example, forms methylmagnesium bromide. CH3Br

2 Mg 88n CH3MgBr

Et O

Because carbon is considerably more electronegative than magnesium, the metal­carbon bond in the product has a significant amount of ionic character. Grignard reagents such as CH3MgBr are best thought of as hybrids of ionic and covalent Lewis structures. CH3OMgOBr [CH3S ][Mg 2 ][Br ]

Grignard reagents are therefore a potential source of carbanions (literally, "anions of carbon"). The Lewis structure of the CH3 ion suggests that carbanions can be Lewis bases, or electron pair donors. H A HO CS A H

28

FUNCTIONAL GROUP CHEMISTRY

Grignard reagents such as methylmagnesium bromide are therefore sources of a nucleophile that can attack the end of the CPO double bond in aldehydes and ketones. CH3 CH3S G CPO D CH3 A CH3O C O O A CH3

CH3

If we treat the product of the reaction with water, we get a tertiary alcohol. CH3 A CH3OC OO A CH3 CH3 A CH3OC OOH A CH3

H2O

OH

If we wanted to make a secondary alcohol, we could add the Grignard reagent to an aldehyde, instead of a ketone. O B CH3CH

1. CH 3MgBr 2. H2O

OH A CH3CHCH3

By reacting a Grignard reagent with formaldehyde we can add a single carbon atom to form a primary alcohol. CH3 A CH3CCH2MgBr A CH3 CH3 A CH3CCH2CH2O A CH3 CH3 A CH3CCH2CH2OH A CH3

H2CPO

H2O

The alcohol can then be oxidized to the corresponding aldehyde. CH3 A CH3CCH2CH2OH A CH3 CH3 O B A CH3CCH2CH A CH3

CrO3 /pyridine CH2Cl2

The Grignard reagent therefore provides us with a way of performing the following overall transformation. CH3 A CH3CCH2MgBr A CH3

1. H2CO 2. H2O 3. CrO3 /pyridine in CH2Cl2

CH3 O B A CH3CCH2CH A CH3

A single carbon atom can also be added if the Grignard reagent is allowed to react with CO2 to form a carboxylic acid. CH3 A CH3CCH2MgBr A CH3 CH3 O A B CH3CCH2CO A CH3

H2O

CO2

CH3 O A B CH3CCH2 COH A CH3

OH

Perhaps the most important aspect of the chemistry of Grignard reagents is the ease with which the reaction allows us to couple alkyl chains. Isopropylmagnesium bromide, for

FUNCTIONAL GROUP CHEMISTRY

29

example, can be used to graft an isopropyl group onto the hydrocarbon chain of an appropriate ketone, as shown in Figure O2.13.

O

CH3

G ECHMgBr CH3

B CH3CH2CCH3

A CH3CH2CCH3 A CH D G CH3 CH3

H2O

H A CH3CH2CCH3 A CH D G CH3 CH3

FIGURE O2.13 Grignard reagents provide a powerful way to introduce alkyl groups onto a hydrocarbon chain.

Chemistry in the World Around Us

The Chemistry of Garlic

The volatile materials that can be distilled from plants were named essential oils by Paracelsus in the sixteenth century because they were thought to be the quintessence (literally, the "fifth essence," or vital principle) responsible for the odor and flavor of the plants from which they were isolated. The Egyptians extracted essential oils from fragrant herbs more than 5000 years ago by pressing the herb or by extracting the fragrant material with olive or palm oil. Some essential oils are still obtained by pressing. Others are extracted into a nonpolar solvent. The most common method for isolating essential oils, however, is steam distillation. The ground botanical is immersed in water which is heated to boiling, or boiling water is allowed to pass through a sample of the ground botanical. The oil and water vapor pass into a condenser, where the oil separates from the water vapor. The function of the essential oils isn't fully understood. Some act as attractants for the insects involved in pollination. Most are either bacteriostats (which stop the growth of bacteria) or bactericides (which kill bacteria). In some cases, they can be a source of metabolic energy. In other cases, they appear to be waste products of plant metabolism. The essential oils are mixtures of up to 200 organic compounds, many of which are either terpenes (with 10 carbon atoms) or sesquiterpenes (with 15 carbon atoms). Although the three components shown in Figure O2.14 represent almost 60% of the mass of a sample of rose oil, 50 other components of that essential oil have been identified.

CH2OH CH2OH CPO A H

Geraniol (E-3,7-dimethyl2,6-octadien-1-ol) Neral (Z-3,7-dimethyl2,6-octadienal)

Citronellol (3-7-dimethyl6-octen-1-ol)

FIGURE O2.14 The three most abundant components of rose oil.

Garlic, onions, and mustard seed differ from most other sources of essential oils. In each case, the fragrance producing part of the plant must be crushed before the volatile components are released. For more than 100 years, chemists have known that the principal component of the oil that distills from garlic is diallyl disulfide [F. W. Semmler, Archiv der Pharmazie, 230, 434­448 (1892)]. CH2PCHCH2 SSCH2CHPCH2

Diallyl disulfide

30

FUNCTIONAL GROUP CHEMISTRY

Only recently, however, have chemists explained how the compound is produced when a clove of garlic is crushed [E. Block, Angewandte Chemie, International Edition in English, 31, 1101­1264 (1992)]. Before garlic is crushed, the intact cell contains S­2-propenyl-L-cysteine S-oxide--or alliin--which can be found in the cell cytoplasm. O NH3 B A CH2PCHCH2SCH2CHCO2

Alliin

Within the cell there are vacuoles that contain an enzyme known as alliinase. When the cell is crushed, the enzyme is released. The enzyme transforms the natural product alliin into an intermediate that reacts with itself to form a compound known as allicin. O B CH2PCHCH2SSCH2CHPCH2

Allicin

Allicin has been described as an odoriferous, unstable antibacterial substance that polymerizes easily and must be stored at low temperatures. When heated, it breaks down to give a variety of compounds, including the diallyl disulfide obtained when oil of garlic is distilled from the raw material. An alliinase enzyme can also be found in onions, where it converts an isomer of alliin known as S-(E)-1-propenyl-L-cysteine S-oxide into propanethial S-oxide. CH3CH2CHPS OO

Propanethial S-oxide

The product of the reaction is known as the lacrimator factor of onion because it is the substance primarily responsible for the tears generated when onions are cut. A great deal of progress has been made in recent years in identifying the various organosulfur compounds formed when garlic and onion are cut and in understanding the process by which the compounds are formed. The structures of some of the principal organosulfur compounds associated with garlic are shown in Figure O2.15. In spite of the progress made so far, much still has to be learned about the compounds that can be isolated from extracts of the genus Allium, which includes both garlic and onion.

O S SOH S H O S S S

S S O S S

S O

S S S S S S S S

S S

S S S S S S S

S

S

S

S

S

FIGURE O2.15 Some of the organosulfur compounds associated with garlic.

FUNCTIONAL GROUP CHEMISTRY

31

KEY TERMS

Acyl chloride Alcohol Aldehyde Alkaloid Alkoxide Amide Amine Aprotic Carbanion Carbonyl Carboxylate ion Carboxylic acid Carboxylic acid ester Chain initiation Chain propagation Chain reaction Chain termination Dicarboxylic acid Electrophile Ester Ether Free radical Functional group Grignard reagent Hydrophilic Hydrophobic Ketone Nucleophile Oxidation number Protic

PROBLEMS

Functional Groups

1. Give examples of compounds that contain each of the following functional groups. (a) an alcohol (b) an aldehyde (c) an amine (d) an amide (e) an alkyl halide (f) an alkene (g) an alkyne 2. Describe the difference between the members of each of the following pairs of functional groups. (a) an alcohol and an alkoxide ion (b) an alcohol and an aldehyde (c) an amine and an amide (d) an ether and an ester (e) an aldehyde and a ketone 3. Classify the following compounds as an alcohol, an aldehyde, an ether, or a ketone. O O B B (a) CH3CH2CH (b) CH3CH2OH (c) CH3CH2OCH2CH3 (d) CH3CH2CCH3 4. Classify the following compounds as primary, secondary, or tertiary alcohols. CH3 CH3 OH A A A (a) CH3CH2OH (b) CH3CH2CHOH (c) CH3CH2COH (d) CH3CH2CHCH2CH3 A CH3 5. Cortisone is an adrenocortical steroid that is used as an anti-inflammatory agent. Use the fact that carbon is tetravalent to determine the molecular formula of the compound from the following stick structure. Identify the functional groups present in the molecule. CH2OH A CPO CH3A A O OH

O M CH3 A

J O

32

FUNCTIONAL GROUP CHEMISTRY

6. Piperine {(E,E)-1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine} can be extracted from black pepper. Identify the functional groups in the structure of the compound. O O N B O

7. PGE2 is a member of the family of compounds known as prostaglandins, which have very significant physiological effects in even small quantities. They can affect blood pressure, heart rate, body temperature, blood clotting, and conception. Some induce inflammation; others relieve it. Aspirin, which is both an anti-inflammatory and an antipyretic (fever-reducing) drug, acts by blocking the synthesis of prostaglandins. Identify the functional groups in the structure of the PGE2 molecule and calculate its molecular formula. O CO2H OH

OH

8. Pseudoephedrine hydrochloride is the active ingredient in a variety of decongestants, including Sudafed. Use the structure of the compound shown in Figure O2.9 to identify the functional groups in the molecule. 9. Cocaine was once used in Coca Cola. Quinine is still added to tonic water. Use the structures of the alkaloids shown in Figure O2.11 to identify the functional groups in the compounds.

OXIDATION­REDUCTION REACTIONS

10. Arrange the following substances in order of increasing oxidation number of the carbon atom. (a) C (b) HCHO (c) HCO2H (d) CO (e) CO2 (f) CH4 (g) CH3OH 11. Classify the following reactions as examples of either metathesis or oxidation­reduction reactions. (a) CH4 Cl2 n CH3Cl HCl (b) CH3OH n HCHO (c) HCHO n HCO2H (d) CH3OH HBr n CH3Br H2O (e) (CH3)2CO n (CH3)2CHOH 12. Classify the following transformations as examples of either oxidation or reduction. (a) CH3CH2OH n CH3CHO (b) CH3CHO n CH3CO2H (c) (CH3)2CPO n (CH3)2CHOH (d) CH3CHPCHCH3 n CH3CH2CH2CH3 (e) (CH3)2CHCqCH n (CH3)2CHCH2CH3

FUNCTIONAL GROUP CHEMISTRY

33

13. Which of the following compounds can be oxidized to form an aldehyde? (a) CH3CH2OH (b) CH3CHOHCH3 (c) CH3OCH3 (d) (CH3)2CPO 14. Which of the following compounds should be the most difficult to oxidize? (a) CH3CH2OH (b) (CH3)2CHOH (c) (CH3)3COH (d) CH3CHO 15. Which of the following compounds can be prepared by reducing CH3CHO? (a) CH3CH3 (b) CH3CH2OH (c) CH3CO2H (d) CH3CH2CO2H 16. Which of the following compounds can be prepared by oxidizing CH3CHO? (a) CH3CH3 (b) CH3CH2OH (c) CH3CO2H (d) CH3CH2CO2H 17. Predict the product of the oxidation of 2-methyl-3-pentanol. 18. Predict the product of the reduction of 2-methyl-2-pentene with hydrogen gas over a nickel metal catalyst.

Alkyl Halides

19. Use Lewis structures to describe the free radical chain reaction mechanism involved in the bromination of methane to form methyl bromide. Clearly label the chain initiation, chain propagation, and chain termination steps. 20. Use Lewis structures to describe the difference between a CH3 ion, a CH3 radical, and a CH3 ion. Which of these Lewis structures describes a carbanion? Which describes a carbocation? 21. How many different products could be formed by the free radical chlorination of pentane? If attack at the different hydrogen atoms in the compound were more or less random, what would be the relative abundance of the different isomers of chloropentane formed in the reaction? 22. Consider the reaction between a Cl atom and a pentane molecule. Classify the different intermediates that could be produced in the reaction as either primary, secondary, or tertiary free radicals.

Alcohols and Ethers

23. Describe the differences between the structures of water, methyl alcohol, and dimethyl ether. 24. Draw the structures of the seven constitutional isomers that have the formula C4H10O. Classify the isomers as either alcohols or ethers. 25. Ethyl alcohol and dimethyl ether have the same chemical formula, C2H6O. Explain why one of the compounds reacts rapidly with sodium metal but the other does not. 26. Predict the product of the dehydration of ethyl alcohol with sulfuric acid at 130°C. 27. Use examples to explain why it is possible to oxidize either a primary or secondary alcohol, but not a tertiary alcohol. 28. Draw the structure of o-phenylphenol, the active ingredient in Lysol. 29. Explain why alcohols are Brønsted acids in water. 30. Write the structures of the conjugate bases formed when the following alcohols act as a Brønsted acid. (a) CH3CH2OH (ethyl alcohol) (b) C6H5OH (phenol) (c) (CH3)2CHOH (isopropyl alcohol) 31. Use the fact that there are no hydrogen bonds between ether molecules to explain why diethyl ether (C4H10O) boils at 34.5°C, whereas its constitutional isomer-- 1-butanol (C4H10O)--boils at 118°C.

34

FUNCTIONAL GROUP CHEMISTRY

32. Assign a systematic name to the following alcohols. OH OH

A

B

33. Assign a systematic name to the compound known by the common name menthol.

OH

Aldehydes and Ketones

34. At which end of a carbonyl group will each of the following substances react? (a) H (b) H (c) OH (d) NH3 (e) BF3 35. Explain why mild oxidation of a primary alcohol gives an aldehyde, whereas oxidation of a secondary alcohol gives a ketone. 36. Explain why strong oxidizing agents can't be used to convert a primary alcohol to an aldehyde. 37. Assign systematic names to the following compounds. P P H

A B

O

O

38. Assign a systematic name to the compound known by the common name geranial.

O

Carboxylic Acids, Carboxylate Ions, and Carboxylic Acid Esters

39. Explain the difference between a carboxylic acid, a carboxylate ion, and a carboxylic acid ester. 40. What major differences between carboxylic acids (such as butyric acid, CH3CH2CH2CO2H) and esters (such as ethyl butyrate, CH3CH2CH2CO2CH2CH3) help explain why butyric acid gives rise to the odor of rotten meat but ethyl butyrate gives rise to the pleasant odor of pineapple? 41. Explain why fats, which are esters of long-chain carboxylic acids, are insoluble in water. Explain what happens during saponification (see Chapter 8) that makes the resulting compounds marginally soluble in water.

FUNCTIONAL GROUP CHEMISTRY

35

42. Explain the difference between CH3CH2OH and CH3CO2H that makes one of the COOH bonds in the compounds more than 10 orders of magnitude more acidic than the other when values of Ka for the compounds are compared. 43. Use the structures shown in Figure O2.11 to propose a series of reactions that could be used to convert morphine into heroin.

Amines, Alkaloids, and Amides

44. Classify each of the compounds in Figures O2.10 and O2.11 as either a primary amine, a secondary amine, a tertiary amine, and/or an amide. 45. Explain why reacting a complex amine, such as pseudoephedrine, with an acid makes the compounds more soluble in water. 46. Draw the structure of caffeine and label each of the nitrogen atoms in the compound as either an amine or an amide.

Grignard Reagents

47. Use Lewis structures to decide whether the organic component of a Grignard reagent is a nucleophile (Lewis base) or an electrophile (Lewis acid). Predict which end of a CPO bond this portion of the Grignard reagent will attack. 48. If CH3CH2MgBr can be thought of as containing the CH3CH2 , Mg2 , and Br ions, what would be the product of the reaction between the Grignard reagent and dilute hydrochloric acid? 49. Explain why Grignard reagents are prepared in an aprotic solvent, such as an ether, rather than a protic solvent such as an alcohol. 50. Write a step-by-step mechanism for the reaction between CH3MgBr and H2CPO to form CH3CH2OH. 51. Predict the product of the reaction between (CH3)2CHMgBr and 2-pentanone. O B 52. If CH3CH2CCH3 is used as the starting material, show how a tertiary alcohol can be synthesized by a Grignard reaction. 53. Select from the reagents given below to design a sequence of reactions that would lead to the following compound. OH A CH3CHCHCH3 A CH3 (a) (CH3)2CHMgBr (b) CH3CHO (c) CH3MgBr (d) CH3COCH2CH3 (e) CH3COCH3 (f) CH3CH2MgBr (g) CH3COCH3

Qualitative Organic Analysis

54. 55. 56. 57. Describe a way of determining whether a compound is an alkane or an alkene. Describe a way of determining whether a compound is a carboxylic acid or an ester. Describe a way of determining whether a compound is an alcohol or an ether. Describe a way of determining whether a compound is a primary or a tertiary alcohol.

36

FUNCTIONAL GROUP CHEMISTRY

58. 59. 60. 61.

Describe Describe Describe Describe

a way of determining whether a compound is an alcohol or an alkyl halide. a way of determining whether a compound is a carboxylic acid or an amide. a way of determining whether a compound is an alcohol or an amine. a way of determining whether a compound is an aldehyde or ketone.

Integrated Problems

62. Identify the Brønsted acids and the Brønsted bases in the following reaction. CH3CqCH NH2 88n CH3CqC NH3

63. Succinic acid plays an important role in the Krebs cycle, malic acid (apple acid) is found in apples, and tartaric acid ( fruit acid) is found in many fruits. Which of these dicarboxylic acids is chiral? See Table O2.6.

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