Organic Chemistry I & II
Organic Chemistry I & II

Organic Chemistry I & II

Lead Author(s): Steven Forsey

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Pricing

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Top Hat

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

Up to 40-60% 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

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

$301

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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

Access to additional questions, test banks, and slides available within 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

About this textbook

Lead Authors

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.

Contributing Authors

Felix NgassaGrand Valley State University

Neil GargUCLA

Jennifer ChaytorSaginaw Valley State University

Greg DomskiAugustana College

Christian E. MaduCollin Community College

Christopher NicholsonUniversity of West Florida

Franklin OwEast Los Angeles College, UCLA

Robert S. PhillipsUniversity of Georgia

Grigoriy SeredaUniversity of South Dakota

Simon E. LopezUniversity of Florida

Brannon McCulloughNorthern Arizona University

Jason JonesKennesaw State University

José BoquinAugustana College

Stephanie BrouetSaginaw Valley State University

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Chapter 14: Alcohols and Oxiranes

The most common industrial use of alcohols is in beverages. The beer industry in America alone is worth hundreds of billions of dollars. [1]

Contents

14.1 Definitions
14.2 Carbocation Stability
     14.2.1 Hyperconjugation
     14.2.2 Adjacent Lone Pairs
     14.2.3 Adjacent π Bonds
     14.2.4 Inductive Effects
14.3 Oxidation States of Carbon - Review from Chapter 12.10: Alkenes
     14.3.1 Calculation of the Oxidation States
14.4 Introduction to Alcohols
Keeping it Real
14.5 Synthesis of Alcohols
     14.5.1 Review: SN1, SN2, Acid-Catalyzed Hydration, Hydroboronation-Oxidation, Oxymercuration-Demercuration and Halohydrin Reactions
     14.5.2 Synthesis of Alcohols with the Grignard and Organolithium Reagents: Nucleophilic Additions to Carbonyl Compounds
          14.5.2.1 Reaction with Carbonyl Groups to Form Alcohols
          14.5.2.2 Grignard and Organolithium Reagents as Strong Bases
          14.5.2.3 Limitations of Grignard and Organolithium Reagents
     14.5.3 Synthesis of Acetylenic Alcohols
     14.5.4 Alcohols by Reduction of Carbonyl Compounds with LiAlH4 and NaBH4
          14.5.4.1 Mechanism: Reduction of Aldehydes and Ketones with Sodium Borohydride
          14.5.4.2 Mechanism: Reduction of Aldehydes and Ketones with Lithium Aluminum Hydride
          14.5.4.3 Mechanism: Reduction of Esters and Carboxylic Acids with Lithium Aluminum Hydride
     14.5.5 Nucleophilic Ring-Opening of Oxiranes to Produce Alcohols
Keeping it Real
          14.5.5.1 Ring-Opening of an Asymmetrical Oxirane: Regioselective and Stereospecific
          14.5.5.2 Acid-Catalyzed Ring-Opening of Oxiranes to Produce Alcohols
          14.5.5.3 Acid-Catalyzed Ring-Opening of Asymmetrical Oxiranes: Regioselective and Stereospecific
          14.5.5.4 Ring-Opening of Oxiranes: Strong nucleophile Versus Acid-Catalyzed
14.6 Oxidation of Alcohols to Ketones and Carboxylic Acids
     14.6.1 Oxidation Mechanism
     14.6.2 Oxidation of Primary Alcohols to Aldehydes
14.7 Conversion of Alcohols into Better Leaving Groups
     14.7.1 SN2 and SN1 Reactions
     14.7.2 Phosphorus Halides (PBr3, P/I2, PCl3, PCl5)
     14.7.3 Thionyl Chloride (SOCl2)
     14.7.4 Sulfonates: Retention of Configuration
14.8 Dehydration of Alcohols
14.9 Chapter Summary 

Learning Objectives

  • Recognize the reagents needed to convert carboxylic acids, ketones, aldehydes, esters and alkenes into 1°, 2° and 3° alcohols.
  • Understand the mechanism and predict the products produced in the nucleophilic addition to carbonyl compounds (RCOR, RCHO, RCO2R) to produce alcohols. (Grignard reagents, alkyl lithium reagents, LiAlH4, NaBH4).
  • Determine the relative base strength of Grignard and lithium reagents and predict the products produced in acid-base reactions.
  • Recognize limitations of Grignard and alkyl lithium reagents.
  • Understand and write the mechanism for the nucleophilic ring-opening of oxiranes to produce alcohols and predict the regiochemistry and stereochemistry of the products in both basic and acidic conditions.
  • Recognize reagents needed to oxidize alcohols to ketones, aldehydes and carboxylic acids.
  • Predict the products formed from the oxidation of 1° and 2° alcohols using different oxidizing reagents: K2Cr2O7/H2SO4, KMnO4/NaOH, PCC/CHCl3.
  • Identify reagents used to convert alcohols into better leaving groups, such as Cl, Br, I, and sulfonates.
  • Understand the limitation of using reagents SOCl2, PCl3, PIand PBr3 in converting alcohols to alkyl halides and predict the stereochemical changes when using these reagents.
  • Predict the intermediates and the final product in multi-stepped synthesis questions.

14.1 Definitions

Hofmann Rule: This rule refers to a special β-elimination reaction in which the alkene having the smallest number of alkyl groups attached to the double bonded carbon atoms will be the predominant product (less stable alkene forms as the major product). The Hofmann rule is observed in elimination reactions with leaving groups like quaternary ammonium salts, tertiary sulfonium salts, and with bulky strong bases (NaOC(CH3)3) reacting with tertiary alkyl halides.

Figure 14.1.Elimination of 2-bromo-2-methylbutane with a bulky strong base to produce major (Hofmann) product and minor (Zaitsev) product​

Markovnikov’s Rule: In the ionic addition of a polar reagent to an asymmetrical alkene, the positive portion of the reagent being added attaches itself to a carbon atom of the double bond forming the more stable carbocation as an intermediate. Older definition: the hydrogen becomes attached to the carbon atom of the double bond with the greater number of hydrogens (for addition of HX). It can also be stated; the hydrogen adds to the less substituted carbon.

Figure 14.2. Markovnikov Rule: Ionic addition of a polar reagent to an unsymmetrical alkene​


Regiochemistry: A reaction that can occur with different regions on a molecule to produce different products. A region is defined as a site on a molecule where a reaction can occur. Regiochemistry is the difference in the reactivity of the various sites.

Regioselective reaction: When there is more than one reactive site a regioselective reaction can occur. A regioselective reaction is one that produces one major product when many possible products are possible. For example, the molecule 2-bromo-2-methylbutane has eight hydrogens on β carbons that can undergo elimination reaction in the presence of a base such as sodium ethoxide. Removal of a Ha hydrogen produces the minor product 2-methylbut-1-ene while removal of a Hb hydrogen produces the major product.

Figure 14.3. Regioselective outcomes of elimination of 2-bromo-2-methylbutane​​

Stereoselective reaction: A reaction in which a single reactant can produce two or more stereoisomeric products and one of these products is preferred over another. For example, the reaction of either enantiomer of 2-bromobutane will stereoselectively produce (E)-but-2-ene as the major product. Notice that it does not matter which enantiomer the starting material is; the product ratio is the same.

Figure 14.4 Stereoselectivity in elimination reactions of enantiomers of 2-bromobutane​

Stereospecific reaction: A reaction in which a single reactant can produce two or more stereoisomeric products and one of these products is exclusively formed over the other(s). For example; the elimination reaction of (1R,2R)-1-bromo-1,2-diphenylpropane with a strong base produces the (Z) stereoisomer whereas the elimination of the (1R,2S) diastereomer produces the (E) stereoisomer.

Figure 14.5. Stereospecificity in elimination reactions of diastereomers of 1-bromo-1,2-diphenylpropane​

Similarly, a SN2 reaction with 2-bromobutane and sodium methanethiolate (CH3SNa) will produce either (S)-sec-butyl(methyl)sulfane or (R)-sec-butyl(methyl)sulfane depending on which enantiomer you start with. This is another example of a stereospecific reaction.

Figure 14.6. Stereospecificity in SN2 reactions of enantiomers of 2-bromobutane​

Zaitsev’s Rule: An empirical rule that states; when two or more alkenes can be produced in an elimination reaction, the thermodynamically most stable alkene will predominate. The most thermodynamically stable alkene will be the alkene that has the most alkyl groups attached to the alkene carbons.

Figure 14.7. Elimination of 2-bromo-2-methylbutane with a strong base to produce major (Zaitsev) product and minor product​

14.2 Carbocation Stability

Before examining reactions with alkenes, we need to review carbocation stability because carbocation intermediates play an important role in determining the regiochemistry of the products.

Neighboring functional groups can stabilize carbocations through hyperconjugation, adjacent lone pairs and adjacent π bonds. Carbocations can also be destabilized by nearby partial positive charges.

14.2.1 Hyperconjugation

The stability of a carbocation increases as the number of alkyl groups attached to the electron deficient carbon increases. Review: Substitution-elimination chapters: Effect of structure on the rate of reaction.

Figure 14.8. Carbocation substitution and relative stability

This can be explained by the electron donation of the adjacent C-C or C-H sigma bonds into the empty carbocation’s p orbital, which stabilizes the electron deficient carbon. Alkyl groups donate electron density inductively through σ bond conjugation or hyperconjugation.

Figure 14.9. Stabilization of alkenes by hyperconjugation

14.2.2 Adjacent Lone Pairs

Atoms adjacent to a carbocation that have a lone pair (N,O, S, and halogen) will stabilize the carbocation through resonance.

Figure 14.10​. Carbocation stabilization through resonance from adjacent lone pairs​

You may be thinking that electronegative atoms such as oxygen and chlorine would destabilize the carbocation, but in most cases, resonance with the heteroatom has a greater influence than inductive effects.

14.2.3 Adjacent π Bonds

Carbocations that are adjacent to π bonds (allyl, benzyl and cyano) are stabilized through resonance, which delocalizes the charge onto different atoms.

Figure 14.11​. Carbocation stabilization through resonance from adjacent pi bonds

14.2.4 Inductive Effects

Carbocations are destabilized by electronegative atoms that inductively create a partial positive charge adjacent to the carbocation.

Figure 14.12. Carbocation destabilization through nearby electronegative atoms

14.3 Oxidation States of Carbon - Review from Chapter 12.10 

In the next sections, we will be looking at specific reactions involving the oxidation and reduction of carbon atoms using various oxidizing and reducing reagents.

When a carbon is oxidized, it 'loses electrons' by gaining bonds to atoms that are more electronegative than itself, such as oxygen or other electronegative atoms like nitrogen. When a carbon is reduced it 'gains electrons' by being bonded to an atom that is less electronegative than itself such as hydrogen or silicon.

However, generally speaking, the reduction of a molecule increases its hydrogen content, and oxidation increases its oxygen content. Or, if you think about the oxidation or reduction of a specific carbon, the oxidation state changes with the number of times it is bonded to an oxygen or a hydrogen as shown below.

Figure 14.13. Oxidations states of carbon arranged lowest to highest​

As mentioned above, the oxidation state of carbon does not only change with the number of times it is bonded to oxygen or hydrogen. The oxidation state changes when carbon is bonded to any element that is more or less electronegative than it. For example, the chlorination of methylcyclohexane is an oxidation of methylcyclohexane.

Figure 14.14. Oxidation of methylcyclohexane by chlorination

14.3.1 Calculation of the Oxidation States

The oxidation state of an atom is the number of electrons that an atom gains or loses, or appears to gain or lose, in bonding with other atoms in compounds. This is not a formal charge; it is another way of electron bookkeeping.

To calculate the oxidation state of a single carbon atom, proceed as follows:

  • Assign -1 to a carbon bonded to each hydrogen or anything less electronegative than carbon
  • Assign +1 to a carbon bonded to each nitrogen, oxygen or anything more electronegative than carbon
  • Assign 0 to a carbon bonded to each carbon.

You can also artificially treat each sigma bond as an ionic bond by heterolytically breaking each bond, giving the more electronegative atom the electrons from the sigma bond.

For example, methane is bonded to four hydrogens. Since carbon is more electronegative than hydrogen, assign -1 to the carbon for each hydrogen. Thus, this carbon would have an oxidation state of -4. Go through the examples below.

Figure 14.15. Calculating carbons oxidation state in various organic molecules​

To determine if a molecule is being oxidized or reduced, you calculate the oxidation states of the products and reactants. If there is a decrease in a molecule's oxidation state in going from reactant to product, the molecule is gaining electrons or being reduced. If the oxidation state becomes more positive, the molecule has been oxidized. For example, the oxidation state for each carbon in ethene is -2. When ethene is treated with hydrogen gas and a catalyst, ethane is produced. The oxidation state of each carbon has decreased from -2 to -3. Thus each carbon has gained one electron and the molecule has been reduced. 

Figure 14.16. Reduction of ethene to ethane​

If there is an increase in a molecule's oxidation state, the molecule is losing electrons or being oxidized.

Figure 14.17. Oxidation of ethanol to ethanoic acid

14.4 Introduction to Alcohols

Alcohols are weak bases and weak acids. Molecules that are both acidic and basic are called amphoteric.

Figure 14.18. pKa's of protonated alcohols, alcohols and deprotonated alcohols.

Alcohols are weak bases, and strong acids such as sulfuric acid (H2SO4) are needed to protonate the alcohol. Once formed, alkoxonium ions are strong acids as seen by their small pKa values. 

To deprotonate alcohols, strong bases such as sodium hydride (NaH) or sodium amide (NaNH2) must be used because alkoxide ions are themselves strong bases.

Alkoxides can also be produced through an oxidation-reduction reaction with a metal such as Na, K or Li.

Figure 14.19. Production of alkoxides through reaction of an alcohol with metal (M)​

We have looked at the acid/base properties of alcohols in Chapter 4: Acids and Bases. Can you answer the following question?

Q14.1 - Level 1

Which of the following equilibria would be shifted to the left?

question description
A

a

B

b

C

c


Alcohol Chemistry & Breaking Bad

Although organic synthesis is used to prepare the majority of medicines used to benefit humanity, regrettably, illegal drugs can also be made.

One example of illegal drug synthesis from pop culture is the synthesis of methamphetamine (aka “meth”), as shown in the hit TV show “Breaking Bad”. Methamphetamine is a very dangerous, highly addictive drug that systematically destroys the body and causes memory loss and psychotic behavior.

It is estimated that nearly 500 metric tons of amphetamine-type stimulants are produced each year with over 24 million abusers worldwide. 

Have you ever been “carded” when purchasing the popular over-the-counter decongestant Sudafed? Or, if you watched “Breaking Bad”, you’ll recall several references to Sudafed in the earlier episodes.

Sudafed, and several other major brand-named medicines, all contain pseudoephedrine, which is structurally very similar to methamphetamine. In fact, pseudoephedrine can be converted to methamphetamine, which is why sales of Sudafed are now monitored. 

Keeping it Real Q14.1

Would you classify this transformation involving the removal of an alcohol as an oxidation process, a reduction process, or neither?

question description
A

Oxidation

B

Reduction

C

Neither

14.5 Synthesis of Alcohols

You have learned a number of ways to synthesize alcohols in previous chapters. How much do you remember?

14.5.1: Review of SN1, SN2, Acid-Catalyzed Hydration, Hydroboronation-Oxidation, Oxymercuration-Demercuration and Halohydrin Reactions

SN2 and SN1 Reactions: Chapter 7, Chapter 9 and Chapter 11

Q14.2 - Level 1

Match the appropriate reagent and mechanism to the following substitution reactions.

question description
Premise
Response
1

1)

A

Reagent: NaOH; Reaction mechanism: SN_N2

2

2)

B

Reagent: NaOH; Reaction mechanism: SN_N1

C

Reagent: H2_2O; Reaction mechanism: SN_N1

D

Reagent: H2_2O; Reaction mechanism: SN_N2


Hydroboronation-Oxidation: Chapter 12.5

Q14.3 - Level 2

What are the major products produced in the following reaction?

question description
A

1) and 2)

B

3) and 4)

C

1) and 3)

D

2) and 4)

E

All are produced


Oxymercuration-demercuration: Chapter 12.6

Q14.4 - Level 2

What is the major product formed in the following reaction?

question description
A

1)

B

2)

C

3)

D

4)


Halohydrins: Chapter 12.7

Q14.5 - Level 2

What are the major products formed in the following reaction?

question description
A

All products are produced equally

B

1) and 2) are the major products

C

3) and 4) are the major products

D

1) and 3) are the major products

E

2) and 4) are the major products


Diols: Chapter 12.12

Q14.6 - Level 2

Which of the given compounds are produced in the oxidation reaction?

question description
Premise
Response
1

1)

A

Not produced

2

2)

B

Produced

3

3)

C

Not produced

4

4)

D

Produced

5

5)

E

Not produced

6

6)

F

Not produced


Here is a question to make sure you know the differences between the above reactions.

Q14.7 - Level 2

Match the reagent needed to accomplish the following transformations.

question description
Premise
Response
1

1)

A

Reagent b

2

2)

B

Reagent d

3

3)

C

Reagent a

4

4)

D

Reagent c


14.5.2 Synthesis of Alcohols with Grignard and Organolithium Reagents: Nucleophilic Additions to Carbonyl Compounds

When an alkyl halide is added to magnesium or lithium metal in an ether solvent, an organometallic reagent is formed. If magnesium is used, the reagent is called a Grignard reagent. The reagent was named after Victor Grignard (1871-1935) who extensively determined the chemistry of the reagent. Grignard and organolithium reagents can be made from alkyl halides, aryl halides, and vinyl halides.

Figure 14.20. Generation of several Grignard and organolithium reagents​

Grignard and organolithium reagents are not simple structures. In the case of Grignard reagents, the ether solvent is essential and incorporates two solvent molecules into its structure.

Figure 14.21​. Formation of Grignard reagent and interaction with diethyl ether

It is generally accepted that the mechanism follows a series of single electron transfers.

Figure 14.22. General reaction mechanism for the formation of a Grignard reagent​

Grignard reagents can be made with chloro, bromo, and iodoalkyl halides but not fluroalkyl halides. 

Organolithium reagents are more complex than Grignard reagents. Organolithium reagents form oligomeric structures, which consist of a few monomer units. Depending on the size of the alkyl group, aggregates are formed.

Figure 14.23. Formation of generic Organolithium reagent oligomers from alkyl halide and lithium

However, when thinking about the chemical reactivity of these reagents, the structures can be simplified to RMgX and RLi. The most important feature about these reagents is that the bond between carbon and the metals is a highly polarized bond that is slightly ionic in character. This is because carbon is far more electronegative than Mg or Li and carbon withdraws electron density from the metals. The carbon-lithium bond has about 40% ionic character and the magnesium-carbon bond 35%. We can characterize this strongly polarized bond by the resonance structures given below.

Figure 14.24. Strongly polarized carbon-metal bond represented with resonance form.

Thus Grignard and organolithium reagents are essentially carbanions and are very strong bases.

For comparison, the structure of a carbocation, carbon radical, and a carbanion are given below. Because of charge repulsion, carbanions are tetrahedral in structure.

Figure 14.25. Structure and geometry of a carbocation, carbon radical and carbanion​

They are also strong nucleophiles that are capable of attacking electrophiles, including the carbonyl group of aldehydes, ketones, and esters.

14.5.2.1 Reaction with Carbonyl Groups to Form Alcohols

The carbonyl group contains a short, strong and very polar bond. The hybridization of the C and O atoms of the carbonyl group is sp2 hybridized. The C, O and the two atoms attached to the carbon all lie in the same plane. The bond angles about the carbonyl are about 120°. The π bond of the carbonyl is created by the sideways overlap of the p orbitals on the carbon and oxygen.

Figure 14.26. a) Bond angles about carbonyl group showing the pi bond on the plane of the page (left). Bond angles with sigma bond on the plane of the page (right). b) Large dipole moment because of the more electronegative oxygen atom (left). Resonance forms to represent unequal sharing of pi electrons (right)​

Carbonyl groups are susceptible to attack by both electrophiles and nucleophiles.

Question 14.8

Q14.8 - Level 1

Click on the atom that would be attacked by a nucleophile.

Click here to see the answer to Question 14.8.

What is the mechanism of a Grignard Reagent attacking a carbonyl group?

Q14.9 - Level 1

Grignard reagents react as carbanions (negatively charged carbons) and are strong nucleophiles. Click on the arrows that represent the first step in the mechanism of a Grignard reagent reacting with a ketone.


As seen from the question above, the first step in the mechanism is a nucleophilic attack by the negatively charged carbon of the Grignard (or organolithium) reagent on the partially positive carbonyl carbon (negative goes to positive) to form a halomagnesium alkoxide. To complete the synthesis and produce the alcohol, diluted acid or water is added to the halomagnesium alkoxide.

Figure 14.27​. Synthesis of an alcohol from halomagnesium alkoxide by addition of dilute acid

General Reactions to Produce 1°, 2° and 3° Alcohols and Carboxylic Acids

When a Grignard or organolithium reagent is reacted with formaldehyde, a primary alcohol is produced.

Figure 14.28. Reaction of generic Grignard reagent with formaldehyde to form a primary alcohol

When a Grignard or organolithium reagent is reacted with an aldehyde a secondary alcohol is produced.

F14.29.png
Figure 14.29. Reaction of generic Grignard reagent with an aldehyde to form a secondary alcohol​

When a Grignard or organolithium reagent is reacted with a ketone, a tertiary alcohol is produced.

F14.30.png
Figure 14.30. Reaction of generic Grignard reagent with ketone to form a tertiary alcohol​

When a Grignard or organolithium reagent is reacted with carbon dioxide, a carboxylic acid is produced. This is not an alcohol but is included here to show the full scope of the organometallic reagent.

Figure 14.31. Reaction of generic Grignard reagent with carbon dioxide to form a carboxylic acid​

When a Grignard or organolithium reagent is reacted with an ester, a tertiary alcohol is formed and interestingly the tertiary alcohol produced has the alkyl group of the reagent added twice to it. The reason for this is that a ketone is generated as an intermediate that then reacts with a second equivalence of the Grignard reagent, as shown in the mechanism below.

The first step is the nucleophilic addition of the reagent to form a tetrahedral intermediate.

Figure 14.32. Reaction of generic Grignard reagent with ester to form tetrahedral intermediate​

In the second step, an alkoxide leaves to form a ketone. Typically, alkoxides are not good leaving groups, however the tetrahedral intermediate itself is an alkoxide and loss of RO- produces a more thermodynamically stable carbonyl compound.

Figure 14.33. Loss of leaving group from tetrahdral intermediate to form ketone intermediate​

The above reaction is in equilibrium and the alkoxide can act as a nucleophile and reverse the process. However, once the ketone is formed, the stronger nucleophile, which is the Grignard reagent, will preferentially react with the ketone to form a new C-C bond and convert the ketone into a tertiary alcohol.

Figure 14.34. Reaction of generic Grignard reagent with a ketone intermediate to form a tertiary alcohol​

The final step is not in equilibrium since a leaving group is not present.

Simplifying the Mechanism (Nucleophilic Addition to a Carbonyl Carbon)

Notice that all of the reactions involve a nucleophilic attack on the carbonyl carbon to form an alkoxide.

Figure 14.35. Nucleophilic attack on carbonyl carbon followed by proton transfer​

Thus for all Grignard and organolithium reactions follow the simplified mechanism.

  • Identify the carbanion of the reagent. It is the carbon bonded to the metal.
  • Draw an arrow from the carbanion to the carbonyl’s electrophilic carbon. This forms the new carbon–carbon bond.
  • Draw another arrow from the π bond to the oxygen. This forms a negatively charged alkoxide ion.
  • Step 2 protonates the alkoxide to form the desired alcohol.

If the carbonyl is an ester, the nucleophile adds twice.

Figure 14.36. Mechanism of nucleophilic attack on ester carbonyl carbon. Two nucleophilic additions occur.​
  • Identify the carbanion of the reagent. It is the carbon bonded to the metal.
  • Draw an arrow from carbanion to the carbonyl’s electrophilic carbon.This forms the new carbon-carbon bond,
  • Draw another arrow from the π bond to the oxygen.This forms a negatively charged alkoxide ion.
  • The alkoxide leaving group leaves to form a ketone.
  • Draw an arrow from carbanion to the carbonyl’s electrophilic carbon.This adds the alkyl group for the second time.
  • Draw another arrow from the π bond to the oxygen.This forms a negatively charged alkoxide ion.
  • Step 2 protonates the alkoxide to form a tertiary alcohol with the alkyl group from the reagent added twice.


Q14.10 - Level 2

What is the major product produced in the given reactions?

question description
A

1)

B

2)

C

3)

D

4)


Q14.11 - Level 1

What type of alcohol is produced in the given reactions?

question description
Premise
Response
1

1)

A

Secondary alcohol

2

2)

B

Primary alcohol

3

3)

C

Tertiary alcohol

D

Primary alcohol

E

Tertiary alcohol

F

Secondary alcohol


Q14.12 - Level 2

What is the major product produced in the given reaction?

question description
A

1)

B

2)

C

3)

D

4)


14.5.2.2 Grignard and Organolithium Reagents as Strong Bases

Grignard and organolithium reagents behave like carbanions and are much more basic than amides and alkoxides, because carbon is less electronegative than either nitrogen or oxygen. Because alkylmetals are strong bases, organometallic reagents are sensitive to moisture and react rapidly with water. It is very important that all reagents are dry when using organometallic reagents. If water is present in the reaction vessel, the yield of the desired alcohol will be dramatically decreased because the reagent will react as a Brønsted-Lowry base and abstract a proton from water to generate an undesired alkane. The example below depicts the undesirable side reaction with water that would decrease the yield of 1-phenylethanol.

Figure 14.37. Reactions of Grignard reagent phenylmagnesiumbromide. a ) With water present an undesired proton transfer occurs (top). b) With ethanaldehyde to produce the desired product, 1-phenylethanol​ (bottom).​

This can be turned into a useful reaction if the desired product is a deuterated compound.

Figure 14.38. Deuteration by reaction of a Grignard reagent with D2O​


Question 14.13

Q14.13 - Level 2

What is the major product produced in the given reactions?

question description
A

1)

B

2)

C

3)

D

4)

Click here to see the answer to Question 14.13.

14.5.2.3 Limitations of Grignard and Organolithium Reagents

Grignard and organolithium reagents are strong bases. Because of this, they cannot be prepared from compounds that contain acidic groups (-OH, -NH2, -NHR, -SH, -C≡CH, RCO2H) or compounds that have carbonyl groups.

Question 14.14

Q14.14 - Level 1

Which of the following compounds could be used successfully to prepare a Grignard reagent for alcohol synthesis by subsequent reaction with an aldehyde or ketone?

question description
A

A)

B

B)

C

C)

D

D)

Click here to see the answer to Question 14.14.

Q14.15 - Level 1

Which of the given syntheses of a Grignard reagent would fail to form as written?

question description
A

1)

B

2)

C

3)

D

4) all would succeed


14.5.3 Synthesis of Acetylenic Alcohols

Magnesium acetylides can be readily made by using an alkyl Grignard reagent because the sp hybridized ≡C-H bond is more acidic than the sp2 hybridized C-H bond, Chapter 4.2.7.

Figure 14.39. Generation of magnesium acetylides using an alkyl Grignard reagent.

Lithium acetylides can be made by the addition of lithium metal or using strong bases such as butyllithium (LiCH2(CH2)2CH3).

Figure 14.40. Generation of lithium acetylides using butyl lithium

Acetylides can also be made using sodium amide.

Figure 14.41. Generation of sodium acetylides using sodium amide

Acetylides are nucleophilic and will react with carbonyl groups. Again, the attack of an acetylide follows the simplified general mechanism where the nucleophile is RC≡C.

Figure 14.42. Mechanism of an acetylide nucleophile reacting with a carbonyl group


Q14.16 - Level 2

What is the final product produced in the following reactions?

question description
A

1)

B