Materials preparation to the practical classes
for the students of pharmaceutical faculty
LESSON № 12
Theme 16. Aldehydes and ketones of the aliphatic row.
Theme 17. Aldehydes and ketones of the aromatic row.
AdehydeS and KetOneS
Aldehydes and ketones are simple compounds which contain a carbonyl group – a carbon-oxygen double bond. They are simple in the sense that they don’t have other reactive groups like -OH or -Cl attached directly to the carbon atom in the carbonyl group – as you might find, for example, in carboxylic acids containing -COOH.
The connection between the structures of alkenes and alkanes was previously established, which noted that we can transform an alkene into an alkane by adding an H2 molecule across the C=C double bond.
The driving force behind this 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 this hydrogenation reaction, a relatively strong HH bond (435 kJ/mol) and a moderately strong carbon-carbon bond (270 kJ/mol) are broken, but two strong CH 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 C=O double bond?
Once again, a significant amount of energy has to be invested in this reaction to break the HH bond (435 kJ/mol) and the carbon-oxygen bond (375 kJ/mol). The overall reaction is still exothermic, however, because of the strength of the CH bond (439 kJ/mol) and the OH bond (498 kJ/mol) that are formed. The addition of hydrogen across a C=O 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 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.
This reaction also illustrates the importance of differentiating between primary, secondary, and tertiary alcohols. Consider the oxidation of isopropyl alcohol, or 2-propanol, for example.
The product of this reaction was originally called ketone, although the name was eventually softened to azetone and finally acetone. Thus, it is not surprising that any substance that exhibited chemistry that resembled “ketone” 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.
There aren’t any hydrogen atoms that can be removed from the carbon atom carrying the OH group in a tetriary alcohol. And any oxidizing agent strong enough to insert an oxygen atom into a CC 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 this reaction is some form of chromium(VI)chromium in the +6 oxidation state in acidic solution. This reagent can be prepared by adding a salt of the chromate (CrO42-) or dichromate (Cr2O72-) ions 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 these reactions is chromic acid, 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.
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.
Examples of aldehydes
In aldehydes, the carbonyl group has a hydrogen atom attached to it together with either a second hydrogen atom or, more commonly, a hydrocarbon group which might be an alkyl group or one containing a benzene ring.
For the purposes of this section, we shall ignore those containing benzene rings.
Note: There is no very significant reason for this. It is just that if you are fairly new to organic chemistry you might not have come across any compounds with benzene rings in them yet.
Notice that these all have exactly the same end to the molecule. All that differs is the complexity of the other group attached.
When you are writing formulae for these, the aldehyde group (the carbonyl group with the hydrogen atom attached) is always written as -CHO – never as COH. That could easily be confused with an alcohol. Ethanal, for example, is written as CH3CHO; methanal as HCHO.
The name counts the total number of carbon atoms in the longest chain – including the one in the carbonyl group. If you have side groups attached to the chain, notice that you always count from the carbon atom in the carbonyl group as being number 1.
Examples of ketones
In ketones, the carbonyl group has two hydrocarbon groups attached. Again, these can be either alkyl groups or ones containing benzene rings. Again, we’ll concentrate on those containing alkyl groups just to keep things simple.
Notice that ketones never have a hydrogen atom attached to the carbonyl group.
Propanone is normally written CH3COCH3. Notice the need for numbering in the longer ketones. In pentanone, the carbonyl group could be in the middle of the chain or next to the end – giving either pentan-3-one or pentan-2-one.
Bonding and reactivity
Bonding in the carbonyl group
Oxygen is far more electronegative than carbon and so has a strong tendency to pull electrons in a carbon-oxygen bond towards itself. One of the two pairs of electrons that make up a carbon-oxygen double bond is even more easily pulled towards the oxygen. That makes the carbon-oxygen double bond very highly polar.
Aldehyde – а carbonyl compound containing two hydrogen atoms or hydrogen and alkyl group.
Example:
Acetaldehyde
Propionaldehyde
Butyraidehyde
Benzaldehyde
phenylethanal
Ketone – а carbonyl compound containing а pair of cumulative double bonds of which one is the carbonyl group, or ketone is а carbonyl compound containing two alkyl groups.
Example:
1-phenylethanone
diphenylmethanon
5–methylhexan-3-one
Structure. Aldehydes and ketones are compounds containing the carbonyl group, С=О.
When two alkyl groups are attached to the carbonyl, the compound is а ketone.
When two hydrogen atoms, or one hydrogen and one alkyl group are attached to the carbonyl, the compound is an aldehyde.
Lewis structure Kekule structure Condensed structure
R, R’ = Н or alkyl
The structure of formaldehyde, the simplest member of the class, is depicted below, along with its experimental bond lengths and bond angles.
Bond lengths, А Bond Angles, deg
The polarity of the carbonyl group also has a profound effect on its chemical reactivity, compared with the non-polar double bonds of alkenes. Thus, reversible addition of water to the carbonyl function is fast, whereas water addition to alkenes is immeasurably slow in the absence of a strong acid catalyst. Curiously, relative bond energies influence the thermodynamics of such addition reactions in the opposite sense.
The C=C of alkenes has an average bond energy of 146 kcal/mole. Since a C–C σ-bond has bond energy of 83 kcal/mole, the π-bond energy may be estimated at 63 kcal/mole (i.e. less than the energy of the sigma bond). The C=O bond energy of a carbonyl group, on the other hand, varies with its location, as follows:
The C–O σ-bond is found to have average bond energy of 86 kcal/mole. Consequently, with the exception of formaldehyde, the carbonyl function of aldehydes and ketones has a π-bond energy greater than that of the sigma-bond, in contrast to the pi-sigma relationship in C=C. This suggests that addition reactions to carbonyl groups should be thermodynamically disfavored, as is the case for the addition of water. All of this is summarized in the following diagram (ΔHº values are for the addition reaction).
Although the addition of water to an alkene is exothermic and gives a stable product (an alcohol), the uncatalyzed reaction is extremely slow due to a high activation energy. The reverse reaction (dehydration of an alcohol) is even slower, and because of the kinetic barrier, both reactions are practical only in the presence of a strong acid. The microscopically reversible mechanism for both reactions was described earlier.
In contrast, both the endothermic addition of water to a carbonyl function, and the exothermic elimination of water from the resulting geminal-diol are fast. The inherent polarity of the carbonyl group, together with its increased basicity (compared with alkenes), lowers the transition state energy for both reactions, with a resulting increase in rate. Acids and bases catalyze both the addition and elimination of water. Proof that rapid and reversible addition of water to carbonyl compounds occurs is provided by experiments using isotopically labeled water. If a carbonyl reactant composed of 16O (colored blue above) is treated with water incorporating the 18O isotope (colored red above), a rapid exchange of the oxygen isotope occurs. This can only be explained by the addition-elimination mechanism shown here.
Bond lengths Bond angles
С = O 1.203 Н — С — O 121.8
С — Н 1.101 Н — С — Н 116.6
The carbon atom is approximately sp2 hybridized and forms o bonds to two hydrogen atoms and one oxygen. The molecule is planar and the Н-С-O and Н-С-Н bond angles are close to 1200, the idealized sp2 angles. The remaining carbon p orbital overlaps with the oxygen р, orbital, giving rise to а p-bond between these atoms. The oxygen atom also has two nonbonding electron pairs (the lone pairs) that occupy the remaining orbitals. Note the planarity of the carbonyl group. Also note that one С-Н bond of the methyl group is eclipsed with the С-O bond and that the carbonyl С-Н is staggered with respect to the other two С–Н bonds.
A comparison of the properties and reactivity of aldehydes and ketones with those of the alkenes is warranted, since both have a double bond functional group. Because of the greater electronegativity of oxygen, the carbonyl group is polar, and aldehydes and ketones have larger molecular dipole moments (D) than do alkenes. The resonance structures on the right illustrate this polarity, and the relative dipole moments of formaldehyde, other aldehydes and ketones confirm the stabilizing influence that alkyl substituents have on carbocations (the larger the dipole moment the greater the polar character of the carbonyl group). We expect, therefore, that aldehydes and ketones will have higher boiling points than similar sized alkenes. Furthermore, the presence of oxygen with its non-bonding electron pairs makes aldehydes and ketones hydrogen-bond acceptors, and should increase their water solubility relative to hydrocarbons. Specific examples of these relationships are provided in the following table.
For a review of the intermolecular forces that influence boiling points and water solubility.
The small aldehydes and ketones are freely soluble in water but solubility falls with chain length. For example, methanal, ethanal and propanone – the common small aldehydes and ketones – are miscible with water in all proportions.
The reason for the solubility is that although aldehydes and ketones can’t hydrogen bond with themselves, they can hydrogen bond with water molecules.
One of the slightly positive hydrogen atoms in a water molecule can be sufficiently attracted to one of the lone pairs on the oxygen atom of an aldehyde or ketone for a hydrogen bond to be formed.
There will also, of course, be dispersion forces and dipole-dipole attractions between the aldehyde or ketone and the water molecules.
Forming these attractions releases energy which helps to supply the energy needed to separate the water molecules and aldehyde or ketone molecules from each other before they can mix together.
As chain lengths increase, the hydrocarbon “tails” of the molecules (all the hydrocarbon bits apart from the carbonyl group) start to get in the way.
By forcing themselves between water molecules, they break the relatively strong hydrogen bonds between water molecules without replacing them by anything as good. This makes the process energetically less profitable, and so solubility decreases.
Oxygen is more electronegative than carbon and attracts the bonding electrons more strongly; that is, the higher nuclear charge on oxygen provides а greater attractive force than carbon. Accordingly, the С – О bond is polarized in the direction С+ – О-. This effect is especially pronounced for the p electrons. А perspective plot of the p electron density shows the higher concentration of electron density around the oxygen atom.
This effect can be represented by the resonance structures for formaldehyde.
The actual structure is а composite of the normal octet structure, СН2 =О and the polarized structure +СН2 – O–, which corresponds to а carbonium oxide. The composite structure may be represented with dotted line symbоlism which shows the partial charges in carbon and oxygen and the partial single bond character of the C –O bond.
One physical consequence of this bond polarity is that carbonyl compounds generally have rather high dipole moments. The experimental dipole moments of formaldehyde and acetone are 2.27 D and 2.85 D, respectively.
The chemical consequences of this bond polarity will be are become apparent during our discussions of the reactions of carbonyl groups. We shall find that the positive carbon can react with bases and that much of the chemistry оf the carbonyl function corresponds to that of а relatively stable carbonium ion.
The ione pair electrons in the carbonyl oxygen have weakly basic properties. In acidic solution, acetone acts as а Lewis base and is protonated to а small but significant extent.
In fact, acetone is а much weaker Lewis base than is water. The material is one half protonated only in 82% sulphuric acid. This corresponds to an approximate pKa for the conjugate acid of acetone of – 7.2 (the approximate рKa of НО+ is – 1.7). Even though the carbonyl group has only weakly basic properties, we shall find that this basicity plays an important role in the chemistry of aldehydes, ketones, and related compounds.
Nomenclature: COMMON (trivial) names
Traditionally, aldehyde names were derived from the name of the corresponding acid by dropping the suffix –ic (or – oic) and adding in its place the suffix – aldehyde. These commoames are still widely used for simpler aldehydes.
formic acid
formaldehyde
benzoic acid
benzaldehyde
Appendage groups are designated by the appropriate prefixes. The chain is labelled by using the Greek letters a, b, g, and so on, beginning with the carboext to the carbonyl group.
a–chloropropionaldehyde
b–bromobutyraldehyde
The commoames of ketones are derived by prefixing the word ketone by they names of the two alkyl-radical-groups; the separate parts are separate words.
methylethyl ketone
di-sec-butyl ketone
Dimethyl ketone has the additional trivial name acetone, which is universally used.
acetone
As with aldehydes, appendages may be designated by а prefix using the Greek letter notational system.
methyl-b–chloroethyl ketone
b) IUPAC nomenclature
Aldehydes and ketones are organic compounds which incorporate a carbonyl functional group, C=O. The carbon atom of this group has two remaining bonds that may be occupied by hydrogen or alkyl or aryl substituents. If at least one of these substituents is hydrogen, the compound is an aldehyde. If neither is hydrogen, the compound is a ketone.
The IUPAC system of nomenclature assigns a characteristic suffix to these classes, al to aldehydes and one to ketones. For example, H2C=O is methanal, more commonly called formaldehyde. Since an aldehyde carbonyl group must always lie at the end of a carbon chain, it is by default position #1, and therefore defines the numbering direction. A ketone carbonyl function may be located anywhere within a chain or ring, and its position is given by a locator number. Chaiumbering normally starts from the end nearest the carbonyl group. In cyclic ketones the carbonyl group is assigned position #1, and this number is not cited in the name, unless more than one carbonyl group is present. If you are uncertain about the IUPAC rules for nomenclature you should review them now.
Examples of IUPAC names are provided (in blue) in the following diagram. Common names are in red and derived names in black. In commoames carbon atoms near the carbonyl group are often designated by Greek letters. The atom adjacent to the function is alpha, the next removed is beta and so on. Since ketones have two sets of neighbouring atoms, one set is labelled α, β etc., and the other α’, β’ etc.
The IUPAC rules for naming aldehydes are as follows:
1. Select as the parent carbon chain the longest chain that includes the carbon atom of the carbonyl group.
2. Name the parent chain by changing the -е ending of the corresponding alkane name to -al.
3. Number the parent chain by assigning the number 1 to the carbonyl carbon atom of the aldehyde group.
4. Determine the identity and location of any substituents, and append this information to the front of the parent chaiame.
propanal
5-methylhexanal
Nomenclature for Ketones. Assigning IUPAC names to ketones is similar to naming aldehydes except that the ending -one is used instead of -al. The rules for IUPAC ketone nomenclature follow.
1. Select as the parent carbon chain the longest carbon chain that includes the carbon atom of the carbonyl group.
2. Name the parent chain by changing the -е ending of the corresponding alkane name to -one.
3. Number the carbon chain such that the carbonyl carbon atom receives the lowest possible number. The position of the carbonyl carbon atom is noted by placing а number immediately before the parent chain name.
4. Determine the identity and location of any substituents, and append this information to the front of the parent chaiame.
5. Cyclic ketones are named by assigning the number 1 to the carbon atom of the carbonyl group. The ring is theumbered to give the lowest number(s) to the atom(s) bearing substituents.
5-ethyl-3-heptanone 3-methylcyclohexanone
Occasionally, it is necessary to name а molecule containing а carbonyl group as а derivative of а more important function. In such а case, the prefix oxo– is used, along with а number, to indicate the position and nature of the group. One such example is shown below.
2-methyl-4-oxohexanal
It is generally desirable that the common and IUPAC nomenclature systems not be mixed. Ambiguity can result because counting by Greek letters in the common system starts from the carboext to the carbonyl group, whereas the numbers in the IUPAC system always include the carbonyl group.
Very simple ketones, such as propanone and phenylethanone (first two examples in the left column), do not require a locator number, since there is only one possible site for a ketone carbonyl function. Likewise, locator numbers are omitted for the simple dialdehyde at the bottom left, since aldehyde functions must occupy the ends of carbon chains. The hydroxy butanal and propenal examples (2nd & 3rd from the top of column) and the oxopropanal example (bottom right) illustrate the nomenclature priority of IUPAC suffixes. In all cases the aldehyde function has a higher status than alcohol, alkene or ketone and provides the nomenclature suffix. The other functional groups are treated as substituents. Because ketones are just below aldehydes iomenclature suffix priority, the “oxo” substituent terminology is seldom needed.
Simple substituents incorporating a carbonyl group are often encountered. The generic name for such groups is acyl. Three examples of acyl groups having specific names are shown below.
Physical properties: The boiling points at 1 atm. for straight chain aldehydes and methyl n-alkyl ketones are plotted, along with the corresponding data for straight chain alkanes. As in other homologous series, there is а smooth increase in boiling point with increasing molecular weight. Aldehydes and ketones boil higher than alkanes of comparable molecular weights. This boiling point elevation results from the interaction between dipoles.
Synthesis of aldehydes and ketones. The carbonyl group in aldehydes and ketones is one of the most important functional groups. In this section, we shall review several reactions that are good methods for the synthesis of aldehydes and ketones.
Aldehydes and ketones are widespread iature, often combined with other functional groups. Examples are shown in the following diagram. The compounds in the top row are found chiefly in plants or microorganisms; those in the bottom row have animal origins. With the exception of the first three compounds (top row) these molecular structures are all chiral. When chiral compounds are found iature they are usually enantiomerically pure, although different sources may yield different enantiomers. For example, carvone is found as its levorotatory (R)-enantiomer in spearmint oil, whereas, caraway seeds contain the dextrorotatory (S)-enantiomer.
Note that the aldehyde function is often written as –CHO in condensed or complex formulas.
Oxidation of alcohol. As discussed, aldehydes and ketones may be obtained by the oxidation of primary and secondary alcohols, respectively.
In the latter case, the product is not easily oxidized further, so there is no special problem in controlling the reaction to obtain the ketone in good yield. Although many oxidants have been used, the most commonly employed ones are chromium (VI) compounds. However, in aqueous solution, the product aldehyde forms а hydrate, which is oxidized even more rapidly than the primary alcohol.
Oxidation of alkenes. Aldehydes and ketones may also be prepared by oxidative cleavage of С -С multiple bonds. А particularly useful reagent for this purpose is ozone. Hydrolysis of the ozonide, usually under reductive conditions, results in the production of two carbonyl compounds.
Friedel-Crafts acylation
With the exception of Friedel-Crafts acylation, these methods do not increase the size or complexity of molecules. In the following sections of this chapter we shall find that one of the most useful characteristics of aldehydes and ketones is their reactivity toward carbon nucleophiles, and the resulting elaboration of molecular structure that results. In short, aldehydes and ketones are important intermediates for the assembly or synthesis of complex organic molecules.
Hydration of alkynes. As was discussed, alkynes undergo hydration to yield an unstable vinyl alcohol, which immediately rearranges to the corresponding ketone. The reaction is usually catalyzed by mercuric ion and sulphuric acid.
Aldehydes may be prepared by the partial reduction of acyl halides or nitriles.
Several important methods for preparing ketones involve reactions of carboxylic acids, acyl halides, anhydrides, and nitriles with organometallic compounds.
The reactions of aldehydes and ketones can be divided into the following types:
Keto – enol equilibrium. Aldehydes and ketones exist in solution as an equilibrium mixture of two isomeric forms, the keto form and the enol (from –ene + –ol, unsaturated alcohol) form. For simple aliphatic ketones, there is very little of the enol form present at equilibrium, as shown by the following examples.
This type isomerism, where the isomers differ only by the placement of а proton and the corresponding location of а double bond, is commonly referred to as tautomerism. The isomers are known as tautomers.
Even though the percentage of enol form at equilibrium is quite small, the enol is important in many reactions. As we shall soon see, many reactions of aldehydes and ketones occur by way of the unstable enol form.
Nucleophilic addition reaction of Aldehydes and Ketones. Many different substances can add to the carbon – oxygen double bond of а carbonyl group. In fact, because of its polarity, а carbon – oxygen double bond is even more susceptible to addition reactions than а carbon – carbon double bond.
Polarity is used to predict locations for the entering groups from addition. In а carbon-oxygen double bond, due to electronegativity differences, the carbon atom possesses а partial positive charge (d+), and the oxygen atom possesses а partial negative charge (d–).
An unsymmetrical addition agent also has partial charges.
The atom (or group of atoms) ш the addition agent with the positive partial charge (d+), bonds to the carbonyl oxygen atom (d–), and the atom (or group of atoms) with the partial negative charge (d–) bonds to the carbonyl carbon atom (d+).
Hemiacetals and Hemiketals. When an alcohol molecule adds across the carbon – oxygen double bond of an aldehyde or ketone, the Н atom from the alcohol adds to the carbonyl oxygen atom, and the R – О portion of the alcohol adds to the carbonyl carbon atom.
The product of the addition of one molecule of an alcohol to an aldehyde is called а hemiacetal. Similarly, the addition of one molecule of alcohol to а ketone produces а hemiketal.
aldehyde alcohol hemiacetal
ketone alcohol hemiketal
For example:
Hemiacetals and hemiketals both contain an alcohol group (hydroxyl group) and an ether group (alkoxy group) on the same carbon atom. What differentiates them is the presence or lack of а hydrogen atom on this same carbon atom. In а hemiacetal а hydrogen atom is present. In а bcmiketal no hydrogen atom is present.
Formally defined, а hemiacetal is а compound that has а carbon atom to which а hydroxyl group (-ОН), an alkoxy group (-OR), and а hydrogen atom (-Н) are attached. А hemiketal differs from а hemiacetal in that an R group has replaced the Н atom. А hemiketal is а compound that has а carbon atom to which а hydroxyl group (-ОН) and an alkoxy group (-OR), but no hydrogen atom (-Н) are attached.
Reaction mixtures containing hemiacetals and hemiketals are always in equilibrium with the alcohol and carbonyl compounds from which they are made, and the equilibrium lies to the carbonyl compound side of the reaction.
Alcohol + aldehyde = hemiacetal
Alcohol + ketone = hemiketal
This situation makes isolation of the hemiacetal or hemiketal difficult; in practice, it usually cannot be done.
An important exception to this isolation dif5culty is the case where the -ОН and -С=О functional groups that react to form the hemiacetal or hemiketal come from the same molecule. This produces а cyclic hemiacetal or cyclic hemiketal rather than а noncyclic one, and the cyclic species are more stable than the noncyclic ones and can be isolated.
Illustrative of intramolecular hemiacetal formation is the reaction
Cyclic hemiacetals are very important compounds in carbohydrate chemistry.
Acetals and Ketals. If а small amount of acid catalyst is added to а hemiacetal reaction mixture, then the hemiacetal reacts with а second alcohol molecule to form an acetal.
For example:
acetal
An acetal is а compound that has а carbon atom to which two alkoxy groups (-OR) and а hydrogen atom (-Н) are attached.
Similarly, in the presence of an acid catalyst, the reaction of а second alcohol molecule with а hemiketal produces а ketal.
For example:
ketal
А ketal is а compound that has а carbon atom to which two alkoxy groups (-OR) and no hydrogen atom (Н) are attached.
Acetals and ketals, unlike hemiacetals and hemiketals, are easily isolated from reaction mixtures. They are stable in basic solution but undergo hydrolysis in acidic solution. А hydrolysis reaction is the reaction of а compound with water, in which the compound splits into two or more fragments as the elements of water (Н- and -ОН) are added. The products of such hydrolysis are the aldehyde or ketone and alcohols that originally reacted to form the acetal or ketal.
Both acetals and ketals have two alkoxy groups (-OR) attached to the same carbon atom. What differentiates them is the presence or lack of а hydrogen atom on this same carbon atom. In an acetal, а hydrogen atom.
Some examples of acetal formation are presented in the following diagram. As noted, p-toluenesulfonic acid (pKa = -2) is often the catalyst for such reactions. Two equivalents of the alcohol reactant are needed, but these may be provided by one equivalent of a diol (example #2). Intramolecular involvement of a gamma or delta hydroxyl group (as in examples #3 and 4) may occur, and is often more facile than the intermolecular reaction. Thiols (sulfur analogs of alcohols) give thioacetals (example #5). In this case the carbonyl functions are relatively hindered, but by using excess ethanedithiol as the solvent and the Lewis acid BF3 as catalyst a good yield of the bis-thioacetal is obtained. Thioacetals are generally more difficult to hydrolyze than are acetals.
The importance of acetals as carbonyl derivatives lies chiefly in their stability and lack of reactivity ieutral to strongly basic environments. As long as they are not treated by acids, especially aqueous acid, acetals exhibit all the lack of reactivity associated with ethers in general.
Among of the most useful and characteristic reactions of aldehydes and ketones is their reactivity toward strongly nucleophilic (and basic) metallo-hydride, alkyl and aryl reagents (to be discussed shortly). If the carbonyl functional group is converted to an acetal these powerful reagents have no effect; thus, acetals are excellent protective groups, when these irreversible addition reactions must be prevented.
Addition of Organometallic reagents
The two most commonly used compounds of this kind are alkyl lithium reagents and Grignard reagents. They are prepared from alkyl and aryl halides, as discussed earlier. These reagents are powerful nucleophiles and very strong bases (pKa’s of saturated hydrocarbons range from 42 to 50), so they bond readily to carbonyl carbon atoms, giving alkoxide salts of lithium or magnesium. Because of their ring strain, epoxides undergo many carbonyl-like reactions, as noted previously. Reactions of this kind are among the most important synthetic methods available to chemists, because they permit simple starting compounds to be joined to form more complex structures. Examples are shown in the following diagram.
A common pattern, shown in the shaded box at the top, is observed in all these reactions. The organometallic reagent is a source of a nucleophilic alkyl or aryl group (colored blue), which bonds to the electrophilic carbon of the carbonyl group (colored magenta). The product of this addition is a metal alkoxide salt, and the alcohol product is generated by weak acid hydrolysis of the salt. The first two examples show that water soluble magnesium or lithium salts are also formed in the hydrolysis, but these are seldom listed among the products, as in the last four reactions. Ketones react with organometallic reagents to give 3º-alcohols; most aldehydes react to produce 2º-alcohols; and formaldehyde and ethylene oxide react to form 1º-alcohols (examples #5 & 6). When a chiral center is formed from achiral reactants (examples #1, 3 & 4) the product is always a racemic mixture of enantiomers.
Two additional examples of the addition of organometallic reagents to carbonyl compounds are informative. The first demonstrates that active metal derivatives of terminal alkynes function in the same fashion as alkyl lithium and Grignard reagents. The second example again illustrates the use of acetal protective groups in reactions with powerful nucleophiles. Following acid-catalyzed hydrolysis of the acetal, the resulting 4-hydroxyaldehyde is in equilibrium with its cyclic hemiacetal.
Reaction with the ammonia and its derivatives.
(a)Ammonia will react with aldehydes and ketones to form а compound containing the nitrogen analog of а carbonyl group. These compounds are called imines.
(b) Amines will react with aldehydes and ketones to form compounds containing the nitrogen analog of а carbonyl group. These compounds are called imines.
(c) Hydroxylamine will react with aldehydes and ketones to form а compound containing the nitrogen analog of а carbonyl group. These compounds are called oxymes.
(d) Hydrazine will react with aldehydes and ketones to form а compound containing the nitrogen analog of а carbonyl group. These compounds are called hydrazone.
(i) Derivative of hydrazine will react with aldehydes and ketones to form а compound containing the nitrogen analog of а carbonyl group. These compounds are called alkyl- or arylhydrazone.
For example: reaction formaldehyde with 2,4,-dinitrophenylhydrazine:
2,4,-dinitrophenylhydrazone
Methyl ketones undergo base-catalyzed halogenation to give the trihalo ketone, which is normally not isolated.
Instead, the a, a, a – trihaloketone reacts further with hydroxyde ion to give а carboxylate salt and the corresponding trihalomethane:
The overall reaction is known as the haloform reaction. The probable mechanism for the cleavage reaction is:
Furthermore, the addition-elimination mechanism is important in the chemistry of carboxylic acid derivatives. In the present case, the trihalomethyl anion is far more stable than methyl anion itself. (The рKa of chloroform, СНС13, is about 25, and the other haloforms have comparable acidities.) Most of the time when hydroxyde ion adds to the carbonyl group it comes right back off again, but sometimes the less stable СХ3– ion comes off instead. This ion immediately becomes protonated so that the cleavage of the trihalomethyl ion, when it does occur, is irreversible.
(a) Oxidation of Aldehydes and Ketones. Aldehydes readily undergo oxidation to carboxylic acids, and ketones are resistant to oxidation.
Aldehyde Carboxylic acid
Ketone
Because both aldehydes and ketones contain carbonyl groups, we might expect similar reactions for the two types of compounds. Oxidation of an aldehyde involves breaking а carbon – hydrogen bond, and oxidation of а ketone involves breaking а carbon – carbon bond. The former is much easier to accomplish than the latter. For ketones to be oxidized, strenuous reaction conditions must be employed.
The difference in the tendency of aldehydes and ketones to undergo oxidation enables us to use simple tests to distinguish between these two types of compounds. To determine whether а compound is an aldehyde or а ketone, we treat it with а mild oxidizing agent: If oxidation occurs, it is an aldehyde; if no oxidation occurs, it is а ketone. Two tests commonly used for this purpose are the Tollens test and Benedict’s test. These tests are particularly important in carbohydrate chemistry.
The Tollens test, also called the silver mirror test, involves а solution that contains silver nitrate (AgNO3) and ammonia (NH3) in water. When Tollens solution is added to an aldehyde, Ag+ ion (the oxidizing agent) is reduced to silver metal, which deposits on the inside of the test tube, forming а silver mirror. The appearance of this silver mirror is а positive test for the presence of the aldehyde group.
The Ag+ ion will not oxidize ketones.
Benedict’s test is similar to the Tollens test in that а metal ion is the oxidizing agent. With this test, Cu2+ ion is reduced to Cu+ ion, which precipitates from solution as Cu2O (Benedict’s solution is made by dissolving copper sulfate, sodium citrate and sodium carbonate in water).
(b) Reduction of Aldehydes and Ketones. Aldehydes and ketones are easily reduced by hydrogen gas (H2), in the presence of а catalyst (Ni, Pt, or Cu), to form alcohols. The reduction of aldehydes produces primary alcohols, and the reduction of ketones yields secondary alcohols. Aldehyde and ketone reductions by H2 gas involve the addition of the H2 to the carbon-oxygen double bond, а process that is similar to the addition of H2 to а carbon — carbon double bond.
Addition of a hydride anion to an aldehyde or ketone would produce an alkoxide anion, which on protonation should yield the corresponding alcohol. Aldehydes would give primary alcohols (as shown) and ketones would give secondary alcohols.
RCH=O + H:(–) RCH2O(–) + H3O(–) RCH2OH
Two practical sources of hydride-like reactivity are the complex metal hydrides lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4). These are both white (or near white) solids, which are prepared from lithium or sodium hydrides by reaction with aluminum or boron halides and esters. Lithium aluminum hydride is by far the more reactive of the two compounds, reacting violently with water, alcohols and other acidic groups with the evolution of hydrogen gas. The following table summarizes some important characteristics of these useful reagents.
Formaldehyde, the simplest aldehyde, with only one carbon atom, is manufactured on а large scale by the oxidation of methanol. Its major use is in the manufacture of polymers. At room temperature and pressure, formaldehyde is an irritating gas. When this colorless gas is bubbled through water, а highly concentrated aqueous formaldehyde solution called formal in is produced. Formal in is used as а germicide for disinfecting surgical instruments and as а preservative that hardens tissues. Anyone who has experience in а biology laboratory is familiar with the pungent odour of formalin.
The ketone used in the largest volume is acetone, the simplest ketone. Acetone is an excellent solvent because it is miscible with both water and nonpolar solvents. Acetone is the main ingredient in gasoline treatments that are designed to solubilize water in the gas tank and allow it to pass through the engine in miscible form. Acetone can also be used to remove water from glassware in the laboratory. And it is а major component of some nail polish removers.
Acetone is normally present in the human body in small amounts; it is а product of the synthesis of ketone bodies in the liver. Abnormal metabolic conditions, such as those associated with diabetes, can result ш elevated blood acetone levels. Such excess acetone is excreted ш the urine, and its presence in urine is used as а diagnostic test for diabetes. The sweetish odour of acetone can also often be detected on the breath of an untreated diabetic.
Aldehydes and ketones occur widely iature. Naturally occurring compounds of these types, with higher molecular masses, usually have pleasant odours and flavours and are often used for these properties in consumer products (perfumes, air fresheners, and the like)
Many important steroid hormones are ketones, including testosterone, the hormone that controls the development of male sex characteristics; progesterone, the hormone secreted at the time of ovulation in females; and cortisone, а hormone from the adrenal glands that is used medicinally to relieve inflammation.
Some examples of aldehyde and ketone reductions, using the reagents described above, are presented in the following diagram. The first three reactions illustrate that all four hydrogens of the complex metal hydrides may function as hydride anion equivalents which bond to the carbonyl carbon atom. In the LiAlH4 reduction, the resulting alkoxide salts are insoluble and need to be hydrolyzed (with care) before the alcohol product can be isolated. In the borohydride reduction the hydroxylic solvent system achieves this hydrolysis automatically. The lithium, sodium, boron and aluminum end up as soluble inorganic salts. The last reaction shows how an acetal derivative may be used to prevent reduction of a carbonyl function (in this case a ketone). Remember, with the exception of epoxides, ethers are generally unreactive with strong bases or nucleophiles. The acid catalyzed hydrolysis of the aluminum salts also effects the removal of the acetal. This equation is typical iot being balanced (i.e. it does not specify the stoichiometry of the reagent).
Reduction of α,β-unsaturated ketones by metal hydride reagents sometimes leads to a saturated alcohol, especially with sodium borohydride. This product is formed by an initial conjugate addition of hydride to the β-carbon atom, followed by ketonization of the enol product and reduction of the resulting saturated ketone (equation 1 below). If the saturated alcohol is the desired product, catalytic hydrogenation prior to (or following) the hydride reduction may be necessary. To avoid reduction of the double bond, cerium(III) chloride is added to the reaction and it is normally carried out below 0 ºC, as shown in equation 2.
Before leaving this topic it should be noted that diborane, B2H6, a gas that was used in ether solution to prepare alkyl boranes from alkenes, also reduces many carbonyl groups. Consequently, selective reactions with substrates having both functional groups may not be possible. In contrast to the metal hydride reagents, diborane is a relatively electrophilic reagent, as witnessed by its ability to reduce alkenes. This difference also influences the rate of reduction observed for the two aldehydes shown below. The first, 2,2-dimethylpropanal, is less electrophilic than the second, which is activated by the electron withdrawing chlorine substituents.
References:
1. Clayden Jonathan. Organic Chemistry. Jonathan Clayden, Nick Geeves, Stuart Warren // Paperback, 2nd Edition. – 2012. – 1234 p.
2. Bruice Paula Y. Organic Chemistry / Paula Y. Bruice // Hardcover, 6th Edition. – 2010. – 1440 p.
3. Brückner Reinhard. Organic Mechanisms – Reactions, Stereochemistry and Synthesis / Reinhard Brückner // Hardcover, First Edition. – 2010. – 856 p.
4. Moloney Mark G. Structure and Reactivity in Organic Chemistry / Mark G. Moloney // Softcover, First Edition. – 2008. – 306 p.
5. Carrea Giacomo. Organic Synthesis with Enzymes in Non-Aqueous Media / Giacomo Carrea, Sergio Riva // Hardcover, First Edition. – 2008. – 328 p.
6. Smith Michael B. March’s Advanced Organic Chemistry. Reactions, mechanisms, and structure / Michael B. Smith, Jerry March // Hardcover, 6th Edition. – 2007. – 2384 p.
7. Carey Francis A. Advanced Organic Chemistry / Francis A. Carey, Richard A. Sundberg // Paperback, 5th Edition. – 2007. – 1199 p.
Additional:
1. Francotte Eric. Chirality in Drug Research / Eric Francotte, Wolfgang Lindner //
Hardcover, First Edition. – 2006. – 351 p.
2. Quin Louis D. Fundamentals of Heterocyclic Chemistry: Importance in Nature and in the Synthesis of Pharmaceuticals / Louis D. Quin, John Tyrell // Hardcover, 1st Edition. – 2010. – 327 p.
3. Zweifel George S. Modern Organic Synthesis – An Introduction / George S. Zweifel, Michael H. Nantz // Softcover, 1st Edition. – 2007. – 504 p.
4. K. C. Nicolaou. Molecules that changed the World / Nicolaou K. C., Tamsyn Montagnon // Hardcover, First Edition. – 2008. – 385 p.
5. Mundy Bradford P. Name Reactions and Reagents in Organic Synthesis / Bradford P. Mundy, Michael G. Ellerd, Frank G. Favaloro // Hardcover, 2nd Edition. – 2005. – 886 p.
6. Li Jie Jack. Name Reactions. A Collection of Detailed Reaction Mechanisms / Jie Jack Li // Hardcover, 4th Edition. – 2009. – 621 p.
7. Gallego M. Gomez. Organic Reaction Mechanisms / M. Gomez Gallego, M. A. Sierra // Hardcover, First Edition. – 2004. – 290 p.
8. Sankararaman Sethuraman. Pericyclic Reactions – A Textbook / Sethuraman Sankararaman // Softcover, First Edition. – 2005. – 418 p.
9. Tietze Lutz F. Reactions and Syntheses / Lutz F. Tietze, Theophil Eicher, Ulf Diederichsen // Paperback, First Edition. – 2007. – 598 p.
10. Olah George A. Superelectrophiles and Their Chemistry / George A. Olah, Douglas A. Klumpp // Hardcover, First Edition. – 2007. – 301 p.
11. Grossmann Robert B. The Art of Writing Reasonable Organic Reaction Mechanisms / Robert B. Grossmann // Hardcover, 2nd Edition. – 2003. – 355 p.
12. Cole Theodor C.H. Wörterbuch Labor – Laboratory Dictionary / Theodor C.H. Cole // Hardcover, 2nd Edition. – 2009. – 453 p.
