Organic Chemistry I & II

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Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

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$301 Hardcover print text only Always up-to-date content, constantly revised by community of professors Content meets standard for Introduction to Organic Chemistry course, and is updated with the latest content In-Book Interactivity Includes embedded multi-media files and integrated software to enhance visual presentation of concepts directly in textbook Only available with supplementary resources at additional cost Only available with supplementary resources at additional cost Only available with supplementary resources at additional cost Customizable Ability to revise, adjust and adapt content to meet needs of course and instructor All-in-one Platform Access to additional questions, test banks, and slides available within one platform Pricing Average price of textbook across most common format Top Hat Steven Forsey, “Organic Chemistry”, Only one edition needed Up to40-60%more affordable Lifetime access on any device McGraw-Hill Carey & Giuliano, “Organic Chemistry”, 10th Edition $219

Hardcover print text only

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

$301 Hardcover print text only Wiley David R. Klein, “Organic Chemistry”, 3rd Edition $301

Hardcover print text only

Always up-to-date content, constantly revised by community of professors

Constantly revised and updated by a community of professors with the latest content

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

In-book Interactivity

Includes embedded multi-media files and integrated software to enhance visual presentation of concepts directly in textbook

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

Customizable

Ability to revise, adjust and adapt content to meet needs of course and instructor

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

All-in-one Platform

Top Hat

Steven Forsey, “Organic Chemistry”, Only one edition needed

McGraw-Hill

Carey & Giuliano, “Organic Chemistry”, 10th Edition

Wiley

Solomons et al., “Organic Chemistry”, 12th Edition

Wiley

David R. Klein, “Organic Chemistry”, 3rd Edition

Dr. Steven Forsey, Ph.D.University of Waterloo

Steven Forsey is currently a Professor at University of Waterloo, teaching a variety of organic chemistry courses to Chemistry, Science, Chemical Engineering, Nanotechnology and distance education students. He received his Ph.D. (2004) for Synthetic Organic Chemistry from University of Waterloo, Ontario. He is a recipient of the Excellence of Science Teaching Award and has acted as the Teaching Fellow for the Department of Chemistry since 2016.

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Chapter 13: Alkynes

Learning Objectives

• Understand the acidity of the acetylide ion.
• Show how alkynes can be synthesized by either addition/substitution of acetylide ions or elimination reactions from alkyl dihalides.
• Understand the mechanism for the addition reaction of hydrogen halides to alkynes.
• Recognize how to synthesize either cis or trans alkenes using either Lindlar’s catalyst or sodium in liquid ammonia.
• Know that alkynes can be converted to aldehydes or ketones, be aware that the mechanism of these reactions involves keto-enol tautomerism.
• Know that the triple bond in alkynes can be cleaved in ozonolysis reactions.
• Develop strategies for the multistep synthesis of compounds with alkynes as reagents, intermediates or products.

13.1 Introduction

Alkynes are hydrocarbons that contain carbon–carbon triple bonds. The simplest alkyne is acetylene or ethyne (HC≡CH). The reactions of alkynes are similar to alkenes, especially addition and oxidation. The unique chemistry of alkynes is associated with the acidity of the acetylenic C≡C−H bond. Even though alkynes are not as common in nature as alkenes, the alkyne functional group is an important part of the drug selegiline, which is used in the treatment of Parkinson’s disease, and ethynyl estradiol, which is a common ingredient in birth control pills.

13.2 Structure and Bonding

The C≡C triple bond consists of a σ bond and two π bonds. The σ bond results from the overlap of sp hybridized orbitals, while each of the π bonds is formed from overlapping p orbitals on carbon. Figure 13.1 shows the linear structure of acetylene, in which the C≡C bond length is shorter than both C=C and C−C bonds. Also, the C−H bond in acetylene is shorter than the C−H bond in alkenes and alkanes. The electrostatic potential map, shown in Figure 13.1, shows the cylindrical region of high electron density (red) that exists in acetylene.

The physical properties of alkynes are very similar to alkanes and alkenes of similar molar mass. They are nonpolar and not very soluble in water. The first four alkynes—ethyne to butyne—are gases at room temperature.

13.3 Occurrence and Uses of Alkynes

Naturally occurring alkynes are relatively rare. Alkynes are not obtained from petroleum but are instead synthesized from other compounds. Acetylene can be produced by heating lime and coke—carbon from coal—to yield calcium carbide. Calcium carbide then reacts with H2O to form acetylene and calcium hydroxide (Figure 13.2). This method was most popular before the 1950s, when coal was cheap and plentiful, and alternate methods are often used today.

One of the major uses of acetylene is as fuel for oxyacetylene welding torches. Acetylene is thermodynamically unstable and will decompose to C and H2, which can then react with O2 in the air producing CO2, H2O, and heat. For welding purposes, the compressed cylinders are filled with crushed firebrick saturated with acetone. Acetylene is soluble in acetone, so the potentially explosive reaction is minimized.

Alkynes

Alkynes are also found in a number of naturally occurring molecules, drugs, and drug candidates. The beastly molecule calicheamicin γ1 is an example of an alkyne-containing therapeutic that serves as an antibiotic and antitumor agent.

How does it work? The enediyne of calicheamicin γ1 undergoes a Bergman cyclization to form a highly reactive 1,4 benzenoid diradical. This resulting intermediate can then cut double-stranded DNA and destroy cells.

Alexander the Great was the king of the Greek kingdom of Macedon from 336–323 BC. He was considered one of history’s most successful commanders as he expanded his empire eastward from present-day Greece to present-day Pakistan.

It has been proposed that he died after he drank poisoned water from the river Styx that contained the beastly enediyne natural product calicheamicin γ1!

13.4 Synthesis of Alkynes

Two approaches are used. The first is nucleophilic substitution between acetylide ions and alkyl halides, or the acetylide ion can add to a carbonyl group (13.4.1). Both of these methods give a product with a longer carbon chain. The second approach is from alkyl dihalides using successive elimination reactions where the product does not gain any additional carbons (13.4.2).

13.4.1 Using Acetylide Ions

Figure 13.3 compares the pKa values for ethane, ethene, and ethyne. Notice that the pKa of ethyne is 1019 times more acidic than ethene! The reason for this increased acidity can be seen in the conjugate bases for ethane, ethene and ethyne (Figure 13.4). In the sp-hybridized orbital of the acetylide ion, the electron density is closer to the positively charged nucleus and is more stable. Figure 13.5 shows why sodium amide in liquid ammonia is used to generate acetylide ions. Note that the hydroxide ion is too weak to produce acetylide ions.

In the laboratory, acetylide ions are commonly produced by the reaction of a terminal alkyne with a strong base such as sodium amide (NaNH2) or butyl lithium (C4H9Li) (Figure 13.6).

Once formed, the acetylide ion can react with an alkyl halide. The acetylide ion acts as a nucleophile displacing the halide and giving the substituted acetylene (Figure 13.7).

The reaction occurs as an SN2 mechanism, and acceptable yields for this reaction are only obtained with methyl and primary alkyl halides. Because the alkynyl anion is a strong base, if sterically hindered secondary or tertiary alkyl halides are used, E2 products are produced as the major products.

Q13.1 - Level 1

What is the major product of the following reaction?

A

a

B

b

C

c

If the reaction is carried out in two steps, dialkylation occurs. For example, the synthesis of 3-heptyne is shown in Figure 13.8. Note that the alkyl groups can be added in any order.

3D Molecule*: hept-3-yne

Q13.2 - Level 2

Match the steps to the reagent.

Premise
Response
1

1

A

CH$_3$CH$_2$Br

2

2

B

epoxyethane (CH$_2$)$_2$O

3

3

C

H$_2$O

4

4

D

NaNH$_2$/ NH$_3$

5

5

E

CH$_3$CH$_2$Li/THF

Q13.3 - Level 2

What is the better way to synthesize 5-methylhex-2-yne?

A

a

B

b

The acetylide ion can add to carbonyl electrophiles such as aldehydes and ketones. As seen in the general reaction below (Figure 13.9), the acetylide nucleophile will add to the partially positively charged electrophilic carbonyl carbon to produce an alkoxide ion. After the addition of dilute acid, an alcohol is produced. The synthesis of 2-propyn-1-ol (propargyl alcohol) is shown in Figure 13.10.

Q13.4 - Level 2

Match the reagent to the step.

Premise
Response
1

1

A

H$_2$O

2

2

B

NaNH$_2$/ NH$_3$

3

3

C

CH$_3$CH$_2$CH$_2$CHO

4

4

D

NaNH$_2$/ NH$_3$

5

5

E

CH$_3$I

13.4.2 Elimination Reactions

Alkynes can be prepared from alkyl dihalides using strong bases such as NaNH2, BuLi, or R2NLi reagents. This is shown in Figure 13.11. A vicinal or geminal dihalide can be used. Vicinal means halogens are connected to adjacent C atoms, and geminal means halogens are connected to the same C atom.

The mechanism is shown in Figure 13.12. The first E2 reaction preferentially occurs through an anti-coplanar conformation, because the anti-coplanar conformation is more stable than syn-coplanar conformation (eclipsed), as discussed in Chapter 8: E2 Reactions. Depending on the stereochemistry of the dialkyl halide, the Z or E alkene can be produced. A second elimination can occur with vinylic bromides. However, the Z isomer undergoes elimination much faster than the E isomer because the E isomer’s C-H and C-Br bonds are syn-coplanar.

The mechanism for the reaction of 1,2-dibromopropane with 3 mol of NaNH2 is shown in Figure 13.13. When 1,2-dibromopropane is reacted with NaNH2, two molar equivalents of the amide participate in two elimination reactions and a terminal alkyne is formed. The third molar equivalent of NaNH2 readily deprotonates the alkyne to form the acetylide ion. The acetylide ion can then be used in further reactions or reprotonated and isolated with the addition of dilute acid.

Q13.5 - Level 2

How can you synthesize propyne starting with 1,1-dichloroethane?

Premise
Response
1

1)

A

1) CH$_3$CH$_2$ Br 2) H$_3$O$^+$

2

2)

B

3 equiv. NaNH$_2$/ NH$_3$

C

1) CH$_3$Br 2) H$_3$O$^+$

D

2 equiv NaNH$_2$/ NH$_3$

13.5 Reactions of Alkynes

Most of the reactions of alkynes are similar to those of alkenes, particularly addition reactions. The main difference is due to the acidic nature of terminal alkynes.

The addition across the triple bond in alkynes is a regioselective reaction and is similar to that in the double bond of alkenes. Markovnikov’s rule applies, as the halide adds to the more substituted carbon. This is shown in Figure 13.14.

A mechanism for the addition of HX is similar to that proposed for alkenes. This is shown in Figure 13.15(a).

Experiments have shown that the alkenyl cation is not very stable. It would be expected that addition of HX to alkynes would be much slower than addition to alkenes, but the difference is not as large as expected.

In contrast, the mechanism in Figure 13.15(b) avoids the formation of the alkenyl cation, and this involves a termolecular transition state, the collision of three molecules in the transition state. In reality, the addition of HX probably occurs through a variety of pathways. Figure 13.16 (a) shows the products that are formed when 2 mol of hydrogen halide are added to an alkyne. The addition of the second halogen to the same carbon can be explained through resonance structures. This is shown in Figure 13.16 (b).

Q13.6 - Level 1

What is the product formed in the following reaction?

A

1)

B

2)

Q13.7 - Level 2

What is the major product formed when 1-heptyne is treated with 2 equivalents of HBr?

A

1, 1-dibromoheptane

B

2, 2-dibromoheptane

C

1, 2-dibromoheptane

D

2,3-dibromo-2-heptene

Bromine and chlorine add to alkynes to produce a tetrahaloalkane (Figure 13.17a). If 1 mol of halogen is added, the product is a dihaloalkane. The addition may be either syn or anti and often a mixture of isomers is produced, E being the major one. For example, the bromination of hex-1-yne produces 72% of the E isomer. It should be noted that it is difficult to stop the reaction at only one addition of the halogen. The tetrahalide product can be produced in a 100% yield, as shown in Figure 13.7c.

Q13.8 - Level 1

What product is formed in the following reaction?

A

a

B

b

C

c

13.5.3 Reduction of Alkynes

Alkynes can be reduced to alkanes using finely divided Pt, Pd, Ni or Rh. The reaction takes place on the surface of the catalyst in two stages through syn additions. The cis-alkene intermediate initially formed is very difficult to isolate and the reaction completely reduces the alkyne to the alkane (Figure 13.18).

One way to stop the reaction at the alkene stage is to use a “poisoned” or partially deactivated catalyst. Lindlar’s catalyst (Figure 13.19 a)) and Nickel boride (Ni2B) are common catalysts used to convert an internal alkyne to a cis-alkene.

This is a stereospecific reaction, and both H atoms are added to the same face of the alkene—syn addition—so that the cis-alkene is the major product. An example of this is shown in Figure 13.19 b).

There is another way to make alkenes. This time, trans-alkenes are produced and the reagents are sodium or lithium in liquid ammonia. This is shown in Figure 13.20. This reaction is also known as dissolving metal reduction.

The mechanism of this stereospecific reaction is very different to the metal catalyzed reaction. The mechanism occurs in four steps: two involve single-electron transfers and two proton transfers. This mechanism is shown in Figure 13.21. The trans isomer is formed in preference due to the lower-energy intermediate anion radical formed as shown in Figure 13.22.

13.5.4 Hydration to Ketones and Aldehydes

Water can add across the triple bond of alkynes in the presence of Hg2+ (from mercuric sulfate, HgSO4) and sulfuric acid (H2SO4) to produce a ketone. This is shown in Figures 13.23a and b.

The initial product of the reaction is called an enol. A possible mechanism to the enol is shown in Figure 13.24.

The enol, however, is not isolated and rapidly isomerizes to a ketone. This conversion is called keto-enol tautomerism. Tautomers are constitutional isomers that interconvert by migration of an atom or group. This is an equilibrium process in which the formation of the thermodynamically more stable ketone is highly favored. The conversion of an enol to a ketone is shown in Figure 13.25. Keto-enol tautomerism will be covered in more detail in Chapter 26: Condensations and Alpha Substitutions of Carbonyl Compounds.

Another reaction that alkynes can undergo is hydroboration-oxidation. This method is used for converting terminal alkynes (1-alkynes) into aldehydes. When an internal alkyne is used, a ketone is produced. Common reagents are dicyclohexylborane, diisoamylborane, and 9-BBN (Figure 13.26). When these reagents are used, only one molar equivalent of the reagent adds to the alkyne. These molecules are so large that it prevents an undesirable second addition from occurring. Their steric bulkiness also helps to direct the addition of boron to the terminal carbon. Oxidation of the vinyl borane with basic hydrogen peroxide produces an unstable enol that readily tautomerizes to an aldehyde (Figure 13.26).

The mechanism for the base-catalyzed keto-enol tautomersim is given in Figure 13.27.

A specific example is the hydroboration–oxidation of hex-1-yne to hexanal.

Q13.9 - Level 1

What is the major product of the following reaction?

A

a

B

b

C

c

D

d

Q13.10 - Level 2

What is the keto tautomer of the following enol?

A

a

B

b

C

c

D

d

Q13.11 - Level 1

What class of organic product is produced when hex-1-yne is treated with a mixture of HgSO$_4$/H$_2$SO$_4$/H$_2$O?

A

Ether

B

Carboxylic acid

C

Aldehyde

D

Ketone

13.5.5 Oxidative Cleavage of Alkynes

Ozonolysis of an alkyne cleaves the triple bond and gives a mixture of carboxylic acids. This is shown in Figure 13.29.

Under mild neutral conditions, potassium permanganate oxidizes an alkyne to a diketone. Terminal alkynes produce a diketo-acid. This is shown in Figure 13.30.

If the reaction mixture becomes too basic, the products become carboxylate salts, which can then be converted to carboxylic acids by adding H+. The formate ion, which is produced by terminal alkynes, is further oxidized to the carbonate ion, which becomes carbonic acid, and then breaks down to CO2 and H2O. Internal alkynes will give a mixture of carboxylic acids. This is shown in Figure 13.31.

Click reactions

One application of alkyne chemistry that has drawn significant attention is ‘click’ chemistry, which involves the reaction of alkynes with azides. ‘Click’ reactions occur very rapidly and can be used for biological purposes.

Keeping it Real Q13.1 - Level 1

Using the image above, follow the arrow-pushing mechanism of the general ‘click reaction’ shown to predict the product formed when Professor Carolyn Bertozzi’s strained alkyne “MOFO” reacts with an azide.

A

a

B

b

C

c

D

No reaction occurs

‘Click’ reactions with strained alkynes are considered to be ‘bioorthogonal reactions,’ meaning they can occur inside living systems without interfering with biochemical processes.

The ‘click’ reaction has now been used in numerous applications, such as biopolymer modifications, drug discover, and biological imaging (e.g., PET, antibody labeling, fluorescence).

One example of imaging using a fluorescently-tagged alkyne referred to as “BARAC” is shown below. After the ‘click’ reaction, the biomolecule is readily observed by fluorescence.

13.6 Multistep Synthesis Using Alkynes

In these types of problems, we are working back from the target molecule to the starting materials. This is called retrosynthetic analysis. One approach to solve these problems is to compare the carbon skeletons of the starting material and product. Often new carbon bonds must be formed in addition to functional group changes. Often the order of adding groups matters: you want to add less reactive groups earlier in the synthesis and reactive groups later.

Let us look at how butanal can be synthesized from two-carbon starting materials. Figure 13.32 shows the retrosynthetic analysis for this reaction. We start with the target molecule, butanal, and then work backwards to get to the starting compounds needed for synthesis. Retrosynthetic analysis: Step 1: Since the given starting material is an alkyne the target molecule could be formed from the oxidation of the alkyne to the aldehyde. Compound B. Step 2: Now disconnect the bond between the sp and sp3 carbon to give the starting material, ethyne plus a 2-carbon chain. However, to couple these compounds together we would need to generate the acetylide ion, C and have a leaving group (LG) on the alkane chain, D. These groups can be joined together through a SN2 reaction. These steps are shown in Figure 13.32.

The acetylide ion is a good starting material; once this is produced, we can increase the length of the carbon chain using an alkyl halide. Then, to produce the aldehyde, hydroboration-oxidation can be done.

Q13.12 - Level 3

Match the reagent to the steps for the synthesis of 2-hexanone from acetylene.

Premise
Response
1

1)

A

NaNH$_2$/ NH$_3$

2

2)

B

H$_2$O/H$_2$SO$_4$/HgSO$_4$

3

3)

C

CH$_3$I

4

4)

D

KMnO$_4$/H$_2$O /OH$^-$