CHAPTER 8

Hydroxy Functional Group: Alcohols

Properties, Preparation, and Strategy of Synthesis

Ethanol is the alcohol contained in alcoholic beverages.

Alcohols can be thought of as a derivative of water in which a hydrogen atom has been replaced by an alkyl group.

Replacement of the 2nd hydrogen on the water molecule leads to an ether.

Naming the Alcohols 8-1 The systematic nomenclature of alcohols treats them as derivatives of alkanes. The –e is dropped from the alkane name and is replaced by –ol.

Alkane à Alkanol

In complicated, branched alkanes, the name of the alcohol is based on the longest chain containing the –OH group. Other substituents are then named using the IUPAC rules for hydrocarbons.

The number of the chain is from the end closest to the OH group.

Cyclic alcohols are called cycloalkanols and the carbon carrying the –OH group is the 1 carbon.

Alcohols can be classified as primary, secondary or tertiary:

In common notation (non-IUPAC), the word alcohol directly follows the name of the alkane.

• Methyl alcohol

• Isopropyl alcohol

• Tert-Butyl alcohol

Structural and Physical Properties of Alcohols 8-2

The structure of alcohols resembles that of water. In the structures of water, methanol, and methoxymethane, the oxygen atoms are all sp3+ hybridized and their bond angles are all nearly tetrahedral.

The O-H bond is shorter than the C-H bonds.

The bond strength of the O-H bond is greater than that of the C-H bonds:

• DHoO-H = 104 kcal mol-1

• DHoC-H = 98 kcal mol-1

Due to the electronegativity difference between oxygen and hydrogen, the O-H bond is polar.

Hydrogen bonding raises the boiling points and water solubilities of alcohols.

Alcohols have unusually high boiling points compared to the corresponding alkanes and haloalkanes.

Hydrogen bonding between alcohol molecules is much stronger than the London forces and dipole-dipole interactions in alkanes and haloalkanes, although much weaker than O-H covalent bonds.

• O···H-O DHo ~ 5-6 kcal mol-1

• Covalent O-H DHo = 104 kcal mol-1.

The extensive network of H-bonds between neighboring alcohol molecules makes it difficult for a molecule to leave the surface of the liquid.

An alcohol molecule makes slightly less than 2 hydrogen bonds to other alcohol molecules on the average. A water molecule, on the other hand, forms hydrogen bonds to slightly less than 4 other water molecules. Water has an abnormally high boiling point for a molecule of its size due to this hydrogen bonding.

Many alcohols are appreciably soluble in water whereas their parent alkanes are not.

• Alkanes and most alkyl chains are said to be hydrophobic (water-hating).

In order to dissolve, alkanes must interrupt the strong hydrogen bonding between water molecules which is then replaced by weaker dipole-induced dipole forces (ΔH > 0).

In addition, long hydrocarbon chains force water molecules to form a cage-like (or clathrate) structure about the non-polar chain which greatly reduces the entropy of the water molecules involved (ΔS < 0).

The –OH groups of alcohols (as well as groups like –COOH and –NH2) are said to be hydrophilic (water-loving) and enhance solubility.

The longer the alkyl chain of an alcohol, the lower its solubility in water (it looks more and more like an alkane).

Alcohols are popular protic solvents for SN2 reactions.

Alcohols as Acids and Bases 8-3

The acidity of alcohols resembles that of water. The acidity constant for an alcohol can be defined as:

Alcohols are acidic compared to alkanes and haloalkanes because the electronegative oxygen atom is able to stabilize the negative charge of the alkoxide ion.

To drive the alcohol/alkoxide equilibrium towards the conjugate base, a base stronger than alkoxide must be used to remove the proton:

The equilibrium constant for this reaction is about 1019.5.

Alkoxides in less that stoichiometric equilibrium concentrations can be generated by adding a metal hydroxide to an alcohol:

At equimolar starting concentrations, about ½ of the alcohol is converted to alkoxide. If the alcohol is the solvent, all of the base is in the alkoxide form (Le Châtelier’s principle).

Steric disruption and inductive effects control the acidity of alcohols.

The acidity of an alcohol varies (relative pKa in solution):

Strongest acid Weakest acid

CH3OH < primary < secondary < tertiary

This ordering is due to solvation and hydrogen bonding in the more sterically hindered alcohols.

The presence of halogens in the alcohol increases the acidity of the alcohol due to an inductive effect.

The electronegative halogen atom polarizes the X-C bond producing a partial positive charge on the carbon atom. This charge is further transmitted through the C-O σ bond to the oxygen atom which is then better able to stabilize the negative charge on the alkoxide oxygen.

Inductive effects increase with the number of electronegative groups and decreases with the distance from the oxygen.

The lone electron pairs on oxygen make alcohols basic.

Alcohols may be weakly basic as well as being acidic. Molecules that can be both acidic and basic are called amphoteric.

Very strong acids are required to protonate alcohols.

Industrial Sources of Alcohols: Carbon Monoxide and Ethene

8-4

Methanol is commercially synthesized from synthesis gas, a mixture of CO and H2:

A change of catalyst leads to the production of 1,2-ethanediol:

Synthesis gas itself can be prepared from coal:

Ethanol can be prepared by the fermentation of sugars or the hydration of ethene:

Synthesis of Alcohols by Nucleophilic Substitution 8-5

If the required halides are available, the corresponding alcohols can be prepared by SN2 and SN1 processes using hydroxide and water respectively as nucleophiles.

These methods have some drawbacks: • Bimolecular elimination is possible in hindered systems

• Tertiary halides form carbocations which may undergo E1 reactions.

The use of polar, aprotic solvents alleviates some of these problems.

The problem of elimination in SN2 reactions of oxygen nucleophiles with secondary or sterically encumbered, branched primary substrates is the use of acetate as a less basic nucleophile.

Step 1: Acetate formation (SN2 reaction)

Step 2: Conversion to alcohol (hydrolysis)

Synthesis of Alcohols: Oxidation-Reduction Relation between Alcohols and Carbonyl Compounds

8-6

Oxidation and reduction have special meanings in organic chemistry.

A process that adds electronegative atoms such as halogen or oxygen to a molecule constitutes an oxidation.

A process that removes hydrogen from a molecule also constitutes an oxidation.

The reversal of either of these two steps constitutes a reduction.

Step-by-Step Oxidation of CH4 to CO2:

Aldehydes and primary alcohols, ketones and secondary alcohols can be interconverted using reduction and oxidation reactions involving 2 atoms of hydrogen:

Reduction of carbonyl compounds is carried out using hydride reagents.

Alcohols can form by hydride reduction of the carbonyl group

The carbonyl functional group is polarized due to the high electronegativity of the carbonyl oxygen atom:

The carbonyl carbon can be attacked by a nucleophilic hydride ion, H-, furnished by a hydride reagent.

Sodium borohydride, NaBH4, and lithium aluminum hydride, LiAlH4, are commonly used for hydride reductions because their solubilities are higher in common organic solvents than LiH and NaH.

These reductions are achieved by the addition of a H- ion to the electropositive carbon and a proton to the electronegative oxygen.

The reactivity of NaBH4 is much lower than a free hydride ion, and NaBH4 can be used in protic solvents such as ethanol.

The mechanism of a sodium borohydride reduction involves:

• Donation of H- to the carbonyl carbon

• Simultaneous protonation of the carbonyl oxygen by a solvent molecule

• Combination of the boron fragment with the ethoxide ion to yield sodium ethoxyborohydride

The resulting sodium ethoxyborohydride is capable of another three reductions, thus four equivalents of aldehyde or ketone can be reduced to alcohol.

The reactivity of LiAlH4 is much greater than that of NaBH4 and is less selective in its reactions.

LiAlH4 reacts vigorously with water and ethanol and must be used in an aprotic solvent such as diethyl ether.

All four hydrogens in a LiAlH4 molecule are available for reductions, thus lithium aluminum hydride can reduce four aldehyde or ketone molecules to alcohols.

After the reaction is carried out, aqueous acid is added to consume the excess reagent and release the product alcohol from the tetraalkoxyaluminate.

Alcohol synthesis by reduction can be reversed: chromium reagents.

Alcohols can be oxidized back to aldehydes and ketones using chromium (VI) compounds.

During this process, the yellow-orange Cr(VI) species is reduced to a deep green Cr(III) species. K2Cr2O7 or Na2Cr2O7, or CrO3 are commonly used Cr(VI) reagents.

Secondary alcohols can be oxidized to ketones in aqueous solution:

Primary alcohols tend to overoxidize to carboxylic acids when oxidized in aqueous solution:

Overoxidation of primary alcohols is not a problem in the absence of water. The oxidizing agent, pyridinium chlorochromate (pyH+CrO3Cl-) can be used in dichloromethane to successfully oxidize these alcohols:

PCC oxidation is also used with secondary alcohols instead of the aqueous chromate method to minimize side reactions and improve yields.

Tertiary alcohols cannot be oxidized by chromium reagents since the alcoholic carbon atom carries no hydrogen atoms and cannot readily form a double bond with the oxygen.

Chromic esters are intermediates in alcohol oxidation.

The mechanism of chromium(VI) oxidations involves two steps:

• Formation of a chromic ester

• E2 elimination of a proton and a HCrO3- ion.

The Cr(IV) species disproportionates into Cr(III) and Cr(V).

The Cr(V) may also function as an oxidizing agent.

Organometallic Reagents: Sources of Nucleophilic Carbon for Alcohol Synthesis

8-7

If the carbonyl carbon of an aldehyde or ketone could be attacked by a nucleophilic carbon atom, R:-, instead of a hydride ion, both an alcohol and a new carbon-carbon bond would be formed.

The class of compounds called organometallic reagents are strong bases and good nucleophiles and are useful in this kind of synthesis.

Alkyllithium and alkylmagnesium reagents are prepared from haloalkanes.

Alkyllithium and alkylmagnesium compounds can be prepared by reaction of alkyl halides with lithium or magnesium in ethoxyethane (diethylether) or oxacyclopentane (THF).

The order of reactivity of the haloalkane is:

Cl < Br < I

Grignard reagents, RMgX, can be formed from primary, secondary, and tertiary haloalkane, as well as from haloalkenes and halobenzenes.

Grignard reagents are very sensitive to moisture and air and are formed in solution and used immediately.

The metal atoms in a Grignard reagent are electron-deficient and become coordinated to two solvent molecules:

The alkylmetal bond is strongly polar. The carbon-lithium bond in CH3Li has about 40% ionic character, and the carbon-magnesium bond in CH3MgCl has about 35% ionic character.

The metal atom is strongly electropositive and is at the positive end of the dipole.

The formation of a Grignard reagent is an example of reverse polarization. In the haloalkane, the carbon atom attached to the halogen was electrophilic. In the Grignard reagent, the carbon atom has become nucleophilic.

The alkyl group in alkylmetals is strongly basic. Carbocations are the conjugate bases of alkanes (estimated pKa’s of about 50), and as a result are extremely basic, much more so than amines or alkoxides.

Because of their basicity, carbocations are extremely sensitive to moisture or other acidic functional groups.

This reaction is one method which can be used to convert alkylhalides into alkanes.

A more direct way of producing an alkane from a haloalkane is by an SN2 displacement of the halide by a hydride ion from LiAlH4.

NaBH4 is not reactive enough to carry out this displacement.

A deuterium atom can be introduced into an alkane by the reaction of D2O with an organometallic reagent:

Organometallic Reagents in the Synthesis of Alcohols

8-8

One of the most useful reactions of organometallic reagents is the reaction with aldehydes and ketones to produce an alcohol containing a new C-C bond.

Reaction with formaldehyde produces a primary alcohol.

Aldehydes other than formaldehyde form secondary alcohols.

Ketones react to form tertiary alcohols.

Alkyllithium and Grignard reagents cannot be used to displace halide ions from haloalkanes as the reaction is too slow.

Complex Alcohols: An Introduction to Synthetic Strategy

8-9

Mechanisms help in predicting the outcome of a reaction.

Bromide is a better leaving group than fluoride.

The negatively polarized alkyl group in the organometallic reagent attacks the positively polarized carbonyl carbon in the carbonyl group.

Example 2: How does a Grignard reagent add to a carbonyl group?

The tertiary bond is weaker than a primary or secondary C-H bond. Br2 is very selective in radical halogenations.

Example 3: What is the product of the radical halogenation of methylcyclohexane?

New reactions lead to new synthetic methods. We now have several synthetic methods at our disposal:

Each of the products formed by these reactions can be altered by further chemical reactions leading to more and more complicated molecules.

Finding suitable starting materials and an efficient synthetic path to a desired target molecule is a problem called total synthesis.

A successful synthesis is characterized by:

• Brevity

• High overall yield

• Readily available starting materials (commercially available and inexpensive)

• Reagents should be relatively nontoxic and easy to handle.

Retrosynthetic analysis simplifies synthesis problems.

The most frequent synthetic task is building up larger, more complicated molecules from smaller simple fragments.

The best approach in designing a synthetic route to a desired product is to work the synthesis backwards on paper.

This approach is called retrosynthetic analysis.

In this approach, strategic C-C bonds in the target molecule are broken at points where bond formation seems possible.

The reason that retrosynthetic analysis is useful is that fewer possible reactions need to be considered compared to an analysis starting with large numbers of possible starting materials and chemical reactions.

An analogy would be to start at the tip of a branch of a tree and work backwards to the main trunk. If you started at the trunk and tried to find a particular branch, you would encounter many dead end paths and would have to constantly backtrack.

Consider the retrosynthetic analysis of 3-hexanol:

The double-shafted arrow indicates a strategic disconnection.

Two inferior retrosynthetic analyses are:

These strategies are inferior to the first because they do not simplify the target structure: no C-C bonds are broken.

Retrosynthetic analysis aids in alcohol construction. Consider the retrosynthetic analysis of the preparation of 4-ethyl-4-nonanol.

The strategic bonds are around the functional group.

Of the three paths, a,b, and c, is best:

The building blocks are almost equal in size (5 and 6 carbon fragments), providing the greatest simplification in structure.

The 3-hexanone can also be subjected to retrosynthetic analysis:

The 3-hexanol was subjected to an earlier retrosynthetic analysis. The complete synthetic scheme will be:

Watch out for pitfalls in planning syntheses. Try to minimize the total number of transformations required to convert the initial starting material into the desired product.

A seven-step synthesis with a yield of 85% at each step gives an overall efficiency of conversion of 32%.

A four-step synthesis with three yields at 95% and one at 45% gives an overall efficiency of conversion of 39%.

A convergent synthesis of the same number of steps is preferable to a linear synthesis.

Do not use reagents having functional groups that would interfere with the desired reaction.

This problem could be overcome by using two equivalents of a Grignard reagent, or by protecting the hydroxy functionality in the form of an ether.

Do not try to make a Grignard reagent from a bromoketone. It will react with its own or another molecule’s ketone group.

It is possible to protect the ketone group in this case.

Take into account any mechanistic and structural constraints affecting the reactions under consideration:

• Radical brominations are more selective than chlorinations.

• Remember the structural limitations on nucleophilic reactions.

• Remember the lack of reactivity of the 2,2-dimethyl-1-halopropanes.

• These hindered systems form organometallic reagents and may be modified in this manner.

• Tertiary haloalkanes do not undergo SN2 reactions, but eliminate in the presence of bases:

Important Concepts 8

1.  Alcohols are alkanols (IUPAC) – Names derived from stem prefixed by alkyl and halo substituents

2.  Alcohols Have Polar and Short O-H Bond – •  Hydroxy group is hydrophilic (hydrogen bonding) •  Unusually high boiling points •  Appreciable water solubility •  Alkyl part is hydrophobic

3.  Alcohols Are Amphoteric – •  Deprotonation by bases whose conjugate acids are

weaker than the alcohol •  Protonation yields alkyloxonium ions •  Acidity: primary > secondary > tertiary alcohol •  Electron-withdrawing substituents increase acidity

Important Concepts 8

4.  Reverse Polarization – i.e., conversion of the alkyl group in a haloalkane, Cδ+-Xδ-, into its nucleophilic analog in an organometallic compound, Cδ--Mδ+.

5.  Aldehyde and Ketone Carbonyl Carbons are Electrophilic – C=O carbon is subject to attack by hydride hydrogens or organometallic alkyl groups. Aqueous workup yields alcohols.

6.  Oxidation of Alcohols – Yields aldehydes and ketones (Chromium IV reagents).

7.  Retrosynthetic Analysis – Identifies efficient sequence of reactions by identifying strategic bonds.