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Home , Acyl halide, Addition reaction, Electrophile, Nucleophilic addition, Substitution reaction

SCH 206 SCH 206 Course outline and ; Carboxylic ; Carboxylic Acids derivatives;

Amines R1 N R2 and R3 Structure, Nomenclature, Synthesis and

Dr. Solomon Derese Reactions 1 SCH 206 Dr. Solomon Derese; Department Room 118; [email protected]

Recommended text books

1. , John McMurry 2. Organic Chemistry, Francis Carry 3. Organic Chemistry, Solomons T.W.G.

2 Dr. Solomon Derese SCH 206

Science is the knowledge of consequences and dependence of one fact upon another

Thomas Hobbes (1588–1679)

3 Dr. Solomon Derese O SCH 206 Carbonyl Compounds R Z Two broad classes of compounds contain the : I. Compounds that have only carbon and bonded to the carbonyl group (Aldehydes and Ketones). O

R R' An aldehyde has at least one H bonded to the carbonyl group. A ketone has two or aryl groups bonded to the carbonyl group. 4 Dr. Solomon Derese SCH 206 II. Compounds that contain an electronegative atom bonded to the carbonyl group (Carboxylic acids and their derivatives).

Each of these compounds contains an electronegative atom (Cl, O or N) capable of acting as a . The presence or absence of a leaving group on the carbonyl carbon determines the type of reactions these compounds undergo.

5 Dr. Solomon Derese SCH 206 Nature of the Carbonyl Group The between carbon and oxygen is similar to an C=C double bond. The carbonyl carbon is sp2-hybridized and forms three bonds.

R1 R2

R3 R4 Alkene

6 Dr. Solomon Derese SCH 206 Alkene Carbonyl p-bond p-bond d-bond d-bond C C 120° 120° C O

sp2 orbital sp2 orbital 2p orbital 2p orbital The C=O double bond is similar to a C=C double bond, except that it is shorter, stronger, and polarized. Bond Bond distance Bond energy Dipole moment C=C 134 pm 611 KJ/mol 0.3 D C=O 122 pm 745 KJ/mol 2.5 D

7 Dr. Solomon Derese SCH 206 The difference between the alkene double bond and the carbonyl double bond arises from the different of the elements involved. Oxygen is more electronegative than carbon (3.5 compared with 2.5); therefore, a carbon-oxygen double bond is polar, with oxygen bearing a partial negative charge and carbon bearing a partial positive charge. The carbon carries a partial positive charge, is an electrophilic site, and reacts with . Conversely, oxygen atom carries a partial negative charge, is a nucleophilic site, and reacts with .

8 Dr. Solomon Derese SCH 206 Nucleophilic (electron rich) Reacts with electrophiles, e.g. H+

Electrophilic (electron deficient) Reacts with nucleophiles

Uncrowded SP2 carbon The electrophilicity of a carbonyl group derives from resonance effects as well as inductive effects.

9 Dr. Solomon Derese SCH 206 The reactivity of carbonyl compounds is due to the polarity of the carbonyl group that results from oxygen being more electronegative than carbon. The carbonyl carbon is therefore electron deficient (an ). So we can safely predict that it will be attacked by nucleophiles.

As a result, carbonyl compounds react with nucleophiles.

:Nu

Planar (sp2) Tetrahedral intermediate (sp3)

10 Dr. Solomon Derese SCH 206 When a adds to the carbonyl carbon the weakest bond in the molecule - the carbon- oxygen double bond (p-bond) breaks forming a tetrahedral intermediate. When a carbonyl group is attacked by a nucleophile, the carbon atom undergoes a change in hybridization (sp2 to sp3) and geometry (planar to tetrahedral). The outcome of nucleophilic attack, however, depends on the identity of the carbonyl starting material. It depends on whether Z is a leaving group or not.

11 Dr. Solomon Derese SCH 206 I. Reactions of carbonyl compounds when Z is not a leaving group –

Nucleophilic

Aldehydes (Z = H) and ketones (Z = R) undergo nucleophilic addition as neither H or R are leaving groups.

12 Dr. Solomon Derese SCH 206 Mechanism of Nucleophilic Addition Reaction Step I: Nucleophilic attack

Tetrahedral intermediate The nucleophile (:Nu–H) attacks the electrophilic carbonyl. As the new bond to the nucleophile forms, the p bond is broken, moving an electron pair out on the oxygen atom. This forms an sp3 hybridized intermediate. 13 Dr. Solomon Derese SCH 206 Step II: Proton transfer

OH

R1 H (R2) Nu

Proton (Hydrogen) transfer from the positively charged nucleophile to the negatively charged oxygen forming neutral addition product. The net result is that the p bond is broken, two new d bonds are formed, and the elements of H and Nu are added across the p bond.

14 Dr. Solomon Derese SCH 206 of the Nucleophilic Addition Reaction

H-Nu:

Racemic mixture

H-Nu: The carbonyl carbon is planar and nucleophiles can attack it from either side (bottom as well as top face) equally. As a result, the carbonyl addition product will consist of a racemic mixture.

Dr. Solomon Derese SCH 206 II. Reactions of carbonyl compounds when Z is a leaving group – Nucleophilic Acyl substitution

Z= –OH (carboxylic ), –OR (),

–Cl (acid ), –NH2 (), or –OCOR (acid anhydride) Nucleophilic Acyl Carbonyl compounds that contain leaving groups (electronegative elements) undergo Nucleophilic Acyl Substitution Reaction. 16 Dr. Solomon Derese SCH 206 Mechanism of Nucleophilic Acyl Substitution Reaction Step I: Nucleophilic attack

Tetrahedral intermediate The nucleophile (:Nu–H) attacks the electrophilic carbonyl, forming an sp3 hybridized intermediate. This step is identical to nucleophilic addition. 17 Dr. Solomon Derese Step II: Loss of a leaving group SCH 206

O Z

R1 Z: Nu H

Because the intermediate contains an electronegative atom Z which can act as a leaving group. To do so, an electron pair on oxygen re-forms the p bond, and Z leaves with the electron pair in the C – Z bond. The net result is that Nu replaces Z, a nucleophilic substitution reaction. This reaction is called Nucleophilic Acyl Substitution.

18 Dr. Solomon Derese SCH 206 A compound that has an sp3 carbon bonded to an oxygen atom generally will be unstable if the sp3 carbon is bonded to another electronegative element. The tetrahedral intermediate, therefore, is unstable because Z and Nu are both electronegative atoms. For an aldehyde or ketone to undergo nucleophilic acyl substitution reaction, the tetrahedral intermediate would need to eject a (H:-) or an alkanide ion (R:-). Both are very powerful bases, and both are, therefore, very poor leaving groups.

19 Dr. Solomon Derese SCH 206

Reactions like this do not occur with aldehydes and ketones

20 Dr. Solomon Derese SCH 206 Comparison of Carbonyl Reaction Types I. Nucleophilic addition and nucleophilic acyl substitution involve the same first step— nucleophilic attack on the electrophilic carbonyl carbon to form a tetrahedral intermediate. II. The difference between the two reactions is what then happens to the intermediate. III. Aldehydes and ketones cannot undergo substitution because they do not have a good leaving group bonded to the newly formed sp3 hybridized carbon.

Dr. Solomon Derese 21 SCH 206 Reactivity of carbonyl compounds The reactivity of the carbonyl group towards nucleophiles is dependent on:

I. The electrophilicity of the carbonyl carbon

The relative reactivities of carbonyl O compounds with nucleophiles is mainly attributed to the amount of positive charge R1 Z on the carbonyl carbon. A greater positive charge means higher reactivity. If the partial positive charge is dispersed throughout the molecule, then the carbonyl compound is more stable and less reactive. 22 Dr. Solomon Derese SCH 206 In general electron withdrawing groups increase the electrophilicity of the carbonyl carbon while electron donating groups decrease the electrophilicity of the carbonyl carbon. II. The accessibility of the carbonyl carbon Sterically hindered carbonyl compound react slower with nucleophiles as a result aldehydes (one alkyl group) are more reactive than ketones (two alkyl groups) .

23 Dr. Solomon Derese SCH 206 In general, aldehydes are more reactive than ketones toward nucleophilic attack. This observation can be explained in terms of both steric and electronic effects.

Aldehydes Ketones O

R1 R2

Less steric hindrance Only one R stabilizes Two R’s increase Two R’s stabilizes the with only one R group the positive charge. steric hindrance positive charge. Less crowded Less stable More crowded More stable Aldehydes—more reactive Ketones—less reactive

24 Dr. Solomon Derese SCH 206 Steric effect The two R groups bonded to the ketone carbonyl group make it more crowded, so nucleophilic attack is more difficult. Electronic effect Recall that alkyl groups are electron donating. The two electron-donor R groups stabilize the partial charge on the carbonyl carbon of a ketone, making it more stable and less reactive. The d+ charge of an aldehyde is less stabilized than a ketone. As a result, aldehydes are more electrophilic than ketones and therefore more reactive.

25 Dr. Solomon Derese SCH 206 Thus, carbonyl compounds containing electron- withdrawing groups are the most electrophilic and the most reactive, followed in turn by , other aldehydes, and finally ketones.

Most reactive Least reactive Aromatic carbonyl compounds are less reactive than aliphatic carbonyl compounds, for its delocalized p orbitals can also act as electron source.

26 Dr. Solomon Derese SCH 206

The bulkier the alkyl group the less reactive. > >

This is due to the crowding that results by adding nucleophiles to the carbonyl carbon.

27 Dr. Solomon Derese Assignment 1 SCH 206 Which ones are more reactive towards nucleophilic addition, explain.

a)

b)

28 Dr. Solomon Derese SCH 206 and its derivatives differ greatly in their reactivity towards nucleophilic acyl substitution reaction. They have a generalized structure as follows:

This resonance contribution leads to: a) Partial double bond character on the C-Y bond, and b) Reduced partial positive charge at the carbonyl carbon.

Dr. Solomon Derese 29 SCH 206 The particular extent of the effect depends on the type of derivative. They differ in the degree to which the atom attached to the carbonyl group can stabilize the carbonyl group by electron donation. Electron release from the Z not only stabilizes the carbonyl group, it decreases the positive character of the carbonyl carbon and makes the carbonyl group less electrophilic. The order of reactivity of carboxylic acid derivatives toward nucleophilic acyl substitution can be explained on the basis of the electron-donating properties of substituent Z. The greater the electron-donating powers of Z, the slower the rate.

30 Dr. Solomon Derese SCH 206 a) Acid halide The have considerable electronegativity. Plus, their p-orbitals are 3p, 4p, etc. The carbon p- orbital is 2p. This mismatch will lead to a relatively poor overlap. All in all the resonance contribution (overlap) from halogens is weakest. This would mean that in the carbonyl carbon would have the largest positive charge.

Very small contribution

31 Dr. Solomon Derese SCH 206 b) Acid anhydride

O O

R O R'

The central oxygen (2p) makes a resonance contribution, but the effect is shared between two acyl moieties, so each carbonyl carbon experiences only half of the overall stabilization.

32 Dr. Solomon Derese SCH 206 c) Ester/Carboxylic acid

R’ = H = Carboxylic acid R’ = Alkyl/aryl = Ester The oxygen atoms lone pair conjugates with the carbonyl group, causing a significant reduction of the positive change at the carbonyl carbon.

33 Dr. Solomon Derese SCH 206 d) Amide

Restricted bond rotation Since nitrogen is a better electron-donor than oxygen, the conjugation is more pronounced in . The second resonance structure has such a significant contribution that the C-N bond acquires a considerable double bond character; reflected in the restricted rotation of this bond. 34 Dr. Solomon Derese SCH 206 The amount of positive charge on the carbonyl carbon is directly related to its susceptibility to nucleophilic attack. Due to the above reasons, the following order of reactivity is observed.

> > > > ≈ >

Most Least reactive reactive Least Most stable stable

35 Dr. Solomon Derese SCH 206 Carbonyl compounds will react with nucleophiles without the use of the catalysts only when the carbonyl carbon is very electrophilic or the nucleophile is strong.

Otherwise catalysts must be used that will increase either the electrophilicity of the carbonyl carbon or the nucleophilicity of the nucleophile. This can be achieved by using acid and base catalysts.

36 Dr. Solomon Derese Acid Catalyzed Nucleophilic Addition Reaction SCH 206 Step I: Protonation of the carbonyl oxygen H O H H

In the acid catalyzed mechanism the first step is the protonation of the carbonyl oxygen to give an oxonium. A contributing resonance structure puts the positive charge on the carbonyl carbon. The net effect of protonation is to make the carbonyl carbon even more electron deficient than it was. 37 Dr. Solomon Derese SCH 206 This makes it more susceptible to attack by nucleophiles in this case a weak nucleophile (e.g. /) will suffice. Step II: Nucleophilic attack

38 Dr. Solomon Derese SCH 206 Base Catalyzed Nucleophilic Addition Reaction A base removes a hydrogen from the nucleophile (H-Nu:) and generates a strong nucleophile (:Nu:-).

Step I: Nucleophilic attack O

R1 R2 O

Aldehyde/Ketone R1 R2 Nu

39 Dr. Solomon Derese SCH 206 Step II: Protonation of the oxygen

O

R1 R2 Nu

The same argument also applies for nucleophilic acyl substitution reaction.

40 Dr. Solomon Derese The Acidity of the a of Carbonyl SCH 206 Compounds The a-Hydrogens of b d carbonyl compounds are weakly acidic, (pKa 19 - 20). a c They are unusually acidic for hydrogen atoms attached to carbon. pKa = 16 O pKa = 25 H H H H H H pKa = 20 H H H pKa = 51 41 Dr. Solomon Derese pKa = 44 SCH 206 Why are a-hydrogens of carbonyl compounds acidic?

An a-hydrogen is more acidic because the negative charge formed on the a-carbon when a base abstracts the proton is not localized on this carbon but through resonance is also on the oxygen.

42 Dr. Solomon Derese SCH 206

The greater acidity of a-hydrogens arises because the negative charge on the resulting anion is delocalized by resonance, thus stabilizing it relative to an alkane, alkene, or anion.

43 Dr. Solomon Derese SCH 206

When an enolate anion reacts with a proton donor, it may do so either on oxygen or on the a- carbon. Protonation of the enolate anion on the a- carbon gives the original molecule, called the keto form. Protonation on oxygen gives an (alkene alcohol) form. In this way, the keto form of an aldehyde or ketone can be converted into the enol catalyzed by base.

44 Dr. Solomon Derese SCH 206 Aldehydes and ketones with at least one a- hydrogen are in equilibrium with their enol forms. The keto and enol forms of carbonyl compounds are constitutional isomers, but of a special type. Because they are easily interconverted in the presence of traces of acids and bases, chemists use a special term to describe this type of constitutional isomerism. Interconvertible keto and enol forms are called tautomers, and their interconversion is called tautomerization.

45 Dr. Solomon Derese SCH 206 Tautomers are constitutional isomers that differ in the location of a double bond and a hydrogen atom. Two tautomers are in equilibrium with each other.

A keto tautomer has a C=O and an additional C – H bond. Tautomerization, the process of converting one tautomer into another, is catalyzed by both base and acid.

46 Dr. Solomon Derese SCH 206 Tautomerization under acidic condition.

Tautomerization, the process of converting one tautomer into another, is catalyzed by both acid and base. Tautomerization always requires two steps (protonation and deprotonation), but the order of these steps depends on whether the reaction takes place in acid or base. 47 Dr. Solomon Derese SCH 206 Under most circumstances, we encounter keto– enol tautomers in a state of equilibrium. It is difficult to prevent tautomerization even if care is taken to remove all acids and bases from the solution. Tautomerization can still be catalyzed by the trace amounts of acid or base that are adsorbed to the surface of the glassware. However, the equilibrium favors the keto form largely because a C=O is much stronger than a C=C. Most carbonyl compounds exist almost exclusively in the keto form at equilibrium, and it’s usually difficult to isolate the pure enol.

48 Dr. Solomon Derese SCH 206

0.0001% The percentage of enol tautomer is even less for carboxylic acids, , and amides. Even though are difficult to isolate and are present only to a small extent at equilibrium, they are nevertheless responsible for much of the chemistry of carbonyl compounds because they are so reactive. 49 Dr. Solomon Derese Assignment 2 SCH 206

I. For a long time attempts to prepare compound A were thwarted by its ready isomerization to compound B. The isomerization is efficiently catalyzed by traces of base. Write a reasonable mechanism for this isomerization.

O OH KOH

H H2O H

OH O A B

50 Dr. Solomon Derese SCH 206 II. Consider the ketones piperitone, menthone, and isomenthone.

Suggest reasonable explanations for each of the following observations: a) Optically active piperitone ([a]D=32) is converted to racemic piperitone on standing in a solution of ethoxide in . b) Menthone is converted to a mixture of menthone and isomenthone on treatment with 90% .

51 Dr. Solomon Derese