Chemistry Department of Pharmaceutical Faculty II Course 3 Semester LESSON 1

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Chemistry department of pharmaceutical faculty II course 3th semester LESSON 1 Benzene and AromaticityIn the early days of organic chemistry, the word aromatic was used to describe such fragrant substances as benzaldehyde (from cherries, peaches, and almonds), toluene (from Tolu balsam), and benzene (from coal distillate). It was soon realized, however, that substances grouped as aromatic differed from most other organic compounds in their chemical behavior.

Today, we use the word aromatic to refer to benzene and its structural relatives. We'll see in this and the next lectures that aromatic compounds show chemical behavior quite different from that of the aliphatic compounds we've studied to this point. Thus, chemists of the early nineteenth century were correct about there being a chemical difference between aromatic compounds and others, but the association of aromaticity with fragrance has long been lost. Many compounds isolated from natural sources are aromatic in part. In addition to benzene, benzaldehyde, and toluene, such compounds as the steroidal hormone estrone and the well-known analgesic morphine have aromatic rings. Many synthetic drugs are also aromatic in part; the tranquilizer diazepam (Valium) is an example.

Benzene itself has been found to cause bone-marrow depression and consequent leukopenia (depressed white blood cell count) on prolonged exposure. Benzene should therefore be used cautiously as a laboratory solvent.Structure of Benzene: The Kekule Proposal

By the mid-1800s, benzene was known to have the molecular formula C6H6 and its chemistry was being actively explored. The results, though, were puzzling. Although benzene is clearly "unsaturated"—the formula C6H6 requires

1 a combination of four double bonds/rings—it nevertheless fails to undergo reactions characteristic of alkenes. For example, benzene reacts slowly with Br2 in the presence of iron to give the substitution product C6H5Br, rather than the possible addition product C6H6Br2. Furthermore, only one monobromo substitution product was known; no isomers of C6H5Br had been prepared. Fe C6H6 + Br2 C6H5Br + HBr C6H6Br2

Benzene Brombenzene (Addition product - (substitution product) NOT FORMED

On further reaction of C6H5Br with Br2, disubstitution products are obtained, and three isomeric С6Н4Вг2 compounds had been prepared. On the basis of these and similar results, August Kekule proposed in 1865 that benzene consists of a ring of carbon atoms and can be formulated as 1,3,5-cyclohexatriene. Kekule reasoned that this structure would readily account for the isolation of only a single monobromo substitution product, because all six carbon atoms and all six hydrogens in 1,3,5-cyclohexatriene are equivalent.

H Br

All six hydrogens Only one possible monobromo substitution product are equivalent The observation that only three isomeric dibromo substitution products were known was more difficult to explain because four structures can be written:

Although there is only one 1,3 derivative and one 1,4 derivative, there appear to be two 1,2-dibromo substitution products, which differ in the positions of the double bonds. One isomer has a single bond between the bromine- bearing carbons, and the other isomer has a double bond. Kekule accounted for the formation of only three isomers by proposing that the double bonds in benzene "oscillate" rapidly between two positions. Thus, the two 1,2- dibromo-cyclohexatrienes can't be separated, according to Kekule, because they interconvert too rapidly.

Kekule's proposed structure for benzene was widely criticized at the time. Although it satisfactorily accounts for the correct number of mono-and disubstituted benzene isomers, it fails to answer two critical questions: Why is benzene unreactive compared with other alkenes, and why does benzene give a substitution product rather than an addition product on reaction with Br2? PROBLEM.

How many tribromo benzene derivatives are possible according to Kekule's theory? Draw and name them.

PROBLEM. 2 The following structures with formula C6H6 were considered for benzene at one time. If we assume that bromine can be substituted for hydrogen, how many monobromo derivatives are possible for each? How many dibromo derivatives?

Stability of Benzene

The unusual stability of benzene was a great puzzle to early chemists. Although its formula, C6H6, indicates that multiple bonds must be present, benzene shows none of the behavior characteristic of alkenes or alkynes. For example, alkenes react readily with KMnO4 to give cleavage product they react with aqueous acid to give alcohols, and they react with HCl to give saturated chloroalkanes. Benzene does none of these things. Benzene does not undergo electrophilic addition reactions.

No reaction

We can get a quantitative idea of benzene's unusual stability from data on heats of hydrogenation. Cyclohexene, an o isolated alkene, has ΔH hydrog = -118 kJ/mol (-28.2 kcal/mol), and 1,3-cyclohexadiene, a conjugated diene, has o ΔH hydrog = -230 kJ/mol (-55.0 kcal/mol). As expected, the value for 1,3-cyclohexadiene is a bit less than twice the cyclohexene value because conjugated dienes are unusually stable. Carrying the analogy one step further, we might o expect the ΔH hydrog for "cyclohexatriene" (benzene) to be a bit less than -356 kJ/mol, or to times the cyclohexene value. The actual value is —206 kJ/mol, some 150 kJ/mol (36 kcal/mol) less than expected. Since 150 kJ/mol less heat thai expected is released during hydrogenation of benzene, benzene must have 150 kJ/mol less energy than expected. In other words, benzene has 150 kJ/mol "extra" stability.

Figure 1.5 Reaction energy diagram for the hydrogenation of benzene compared with a hypothetical cyclohexatriene. Benzene is 150 kJ/mol (36 kcal/mol) more stable than "cyclohexatriene." 3

Further evidence for the unusual nature of benzene is that all carbon-carbon bonds in benzene have the same length, intermediate between typical single and double bonds. Most C-C single bonds are 1.54 A long and most C=C double bonds are 1.34 A long, but all C-C bonds in benzene are 1.39 A long. Representations of Benzene: The Resonance Approach How can we account for benzene's properties, and how can we best represent its structure? Resonance theory answers this question by saying that benzene can be described as a hybrid of two equivalent Kekule structures in which each C-C connection averages 1.5 bonds—midway between single and double.

Resonance theory says the following:

1. Resonance forms are imaginary, not real. Benzene has a single, unchanging hybrid structure, which combines the characteristics of both resonance forms. 2. Resonance structures differ only in the positions of their electrons. Neither the position nor the hybridization of atoms changes from one resonance structure to another. In benzene, the six carbon atoms form a regular hexagon with the  electrons shared equally between neighboring nuclei. Each C-C connection averages 1.5 bonds, and all bonds are equivalent. 3. Different resonance forms don't have to be equivalent. The more nearly equivalent the forms are, however, the more stable the molecule. 4. The more resonance structures there are, the more stable the molecule. Benzene can't be represented accurately by either individual Kekule structure and does not oscillate back and forth between the two. The true structure is somewhere in between the two extremes but is impossible to draw with our usual conventions. We might try to represent benzene by drawing it with either a full or a dotted circle to indicate the equivalence of the C-C bonds, but these representations have to be used very carefully because they don't indicate the number of  electrons in the ring: How many electrons does a circle represent? In this lecture, benzene and other aromatic compounds will be represented by a single Kekule structure. We'll be able to keep count of  electrons this way, but we must be aware of the limitations of the drawings.

Some alternative representations of benzene. Such structures must be used carefully, since they don't indicate the number of  electrons.

There is a subtle yet important difference between Kekule's representation of benzene and the resonance representation. Kekule considered benzene as rapidly oscillating back and forth between two cyclohexatriene structures, whereas resonance theory considers benzene to be a single "resonance hybrid" structure:

At any given instant, Kekule's oscillating structures have different carbon-carbon bond lengths—three bonds are short and three are long. This difference in bond length implies that the carbon atoms must change position in oscillating from one structure to another, and thus the two structures are not the same as resonance forms. The same resonance argument that explains benzene's stability also explains why there is only one o- dibromobenzene rather than two. The two Kekule structures of o-dibromobenzene are simply resonance forms of a single compound, whose true structure is intermediate between the forms.

Molecular Orbital Description of Benzene Having just seen a resonance description of benzene, let's now see the alternative molecular orbital description. An orbital view of benzene emphasizes the cyclic conjugation of the benzene molecule and the equivalence of the six C-C bonds. Benzene is a planar molecule with the shape of a regular hexagon. All C-C-C bond angles are 120°, all six carbon atoms are sp2-hybridized, and each carbon has a p orbital perpendicular to the plane of the six-membered ring. Since all six carbon atoms and all six p orbitals in benzene are equivalent, it's impossible to define three localized  bonds in which a given p orbital overlaps only one neighboring p orbital. Rather, each p orbital overlaps equally well with both neighboring p orbitals, leading to a picture of benzene in which the six  electrons are completely delocalized around the ring. Benzene therefore has two doughnut-shaped clouds of electrons, one above and one below the ring:

We can construct molecular orbitals for benzene just as we did for hydrogen molecule earlier. If six p atomic orbitals combine in a cyclic manner, six benzene molecular orbitals result, as shown in Figure 1.6. The three low-energy molecular orbitals, denoted ѱ1, ѱ2, and ѱ3, are bonding combinations, and the three high-energy orbitals are antibonding Note that two of the bonding orbitals, ѱ2 and ѱ3, have the same energy, as do the antibonding orbitals

ѱ4* and ѱ5*. Such orbitals are said to be degenerate. The six p electrons of benzene occupy the three bonding molecular orbitals and are delocalized over the entire conjugated system, leading to the observed 150 kJ/mol stabilization of benzene.

Figure 1.6 Energy levels of the six benzene molecular orbitals. The bonding orbitals ѱ 2 and ѱ 3 have the same energy and are

said to be degenerate, as are the antibonding orbitals ѱ 4* and ѱ 5*.

LESSON 2

Aromaticity and the Huckel 4n + 2 Rule

Let's review what we've learned thus far about benzene and, by extension, about other benzene-like aromatic molecules:

1. Benzene is a cyclic conjugated molecule. 2. Benzene is unusually stable, having a heat of hydrogenation 150 kJ/mol less negative than we might expect for a cyclic triene. 3. Benzene is planar and has the shape of a regular hexagon. All bond angles are 120°, and all C-C bond lengths are 1.39 A. 4. Benzene undergoes substitution reactions that retain the cyclic conjugation rather than electrophilic addition reactions that would destroy the conjugation. 5. Benzene is a resonance hybrid whose structure is intermediate between two Kekule structures:

Although these facts would seem to provide a good description of benzene and other aromatic molecules, they aren't enough. Something else is needed to complete a description of aromaticity. According to a theory devised by the German physicist Erich Huckel in 1931, a molecule is aromatic only if it has a planar, monocyclic system of conjugation with a p orbital on each atom and only if the p orbital system contains 4n + 2  electrons, where n is an integer (n = 0, 1, 2, 3, . . .). In other words, only molecules with 2, 6, 10, 14, 18, . . .  electrons can be aromatic. Molecules with 4n  electrons (4, 8, 12, 16, . . .) can't be aromatic, even though they may be cyclic and apparently conjugated. In fact, planar, conjugated molecules with in  electrons are said to be antiaromatic, because derealization of their  electrons leads to an increase in energy.

6 Let's look at some examples to see how the Huckel 4n + 2 rule work 1. Cyclobutadiene has four  electrons and is antiaromatic:

Cyclobutadiene Two double bonds four electrons 2. Cyclobutadiene is a highly reactive substance that shows none of the properties associated with aromaticity. A long history of attempts to synthesize the compound culminated in 1965 when Rowland Pettit of the University of Texas prepared cyclobutadiene at low temperature but was unable to isolate it. Even at — 78°C, cyclobutadiene dimerizes by a Diels-Alder reaction with itself. One molecule behaves as a diene and the other as a dienophile:

3. Benzene has six  electrons (4n + 2 = 6 when n = 1) and is aromatic:

Benzene Three double bonds six electrons 4. Cyclooctatetraene has eight  electrons and is not aromatic:

Cyclooctatetraene Four double bonds eight electrons

Chemists in the early 1900s believed that the only requirement for aromaticity was the presence of a cyclic conjugated system. It was therefore expected that cyclooctatetraene, as a close analog of benzene, would also prove to be unusually stable. The facts proved otherwise. When cyclooctatetraene was first prepared in 1911 by the German chemist Richard Willstatter, it was found to resemble open-chain polyenes in its reactivity.

Cyclooctatetraene reacts readily with Br2, КМnО4, and HCl, just as other alkenes do. We now know, in fact, that cyclooctatetraene is not even conjugated. It is tub-shaped rather than planar and has no cyclic conjugation because neighboring p orbitals don't have the proper alignment for overlap (Figure 1.7). The  electrons are localized in four discrete C=C bonds rather than delocalized as in benzene. X-ray studies show that the C-C single bonds are 1.47 A long, and the double bonds are 1.34 A long. In addition, the 1H NMR spectrum shows a single sharp resonance line at 5.7 δ, a value characteristic of an alkene rather than an aromatic molecule.

Figure 1.7 Cyclooctatetraene is a tub-shaped molecule that has no cyclic conjugation because its p orbitals are not aligned properly for overlap.

PROBLEM To be aromatic, a molecule must be flat, so that p-orbital overlap can occur, and it must have 4n + 2  electrons. Cyclodecapentaene fulfills one of these criteria but not the other and is therefore nonaromatic. Explain.

Aromatic Ions Look back at the Huckel criteria for aromaticity in the preceding section. To be aromatic, a molecule must be cyclic, conjugated (that is, have a p orbital on each carbon), and have 4n + 2  electrons. Nothing in this definition says that the numbers of p orbitals and  electrons must be the same. In fact, they can be different. The 4n + 2 rule is broadly applicable to many kinds of molecules, not just to neutral hydrocarbons. For example, both the cyclopentadienyl anion and the cycloheptatrienyl cation are aromatic. H

H H + H - H H H H

H H H H Cyclopentadienyl anion Cycloheptatrienyl cantion

six electrons, aromatic ions

Let's look first at the cyclopentadienyl anion. Cyclopentadiene itself is not aromatic because it is not fully 3 conjugated. The -CH2- carbon in the ring is sp -hybridized, thus preventing complete cyclic conjugation. Imagine, 2 though, that we remove one hydrogen from the saturated CH2 group and let that carbon become sp -hybridized. The resultant species would have five p orbitals, one on each of the five carbons, and would be fully conjugated. There are three ways, shown in Figure 1.8, we might imagine removing the hydrogen: 1. We could remove the hydrogen atom and both electrons (H:-)from the C-H bond. Since the hydrogen would have two electrons and a negative charge, the cyclopentadienyl group that remains is positively charged. 2. We could remove the hydrogen and one electron (H.) from the C-H bond, leaving a cyclopentadienyl radical. 3. We could remove a hydrogen ion with no electrons (H+), leaving a cyclopentadienyl anion.

Figure 1.8 Generating the cyclopentadienyl cation, radical, and anion by removing a hydrogen from cyclopentadiene.

Although five equivalent resonance structures can be drawn for all three species, Huckel's rule predicts that only the anion—with six  electrons—should be aromatic. The cyclopentadienyl carbocation—with four  electrons—and the cyclopentadienyl radical—with five  electrons—are predicted to be unstable and antiaromatic. In practice, both the cyclopentadienyl cation and the radical are highly reactive and difficult to prepare. Neither shows any sign of the unusual stability expected of an aromatic system. The cyclopentadienyl anion (with six  electrons), by contrast, is easily prepared and remarkably stable. In fact, cyclopentadiene is one of the most acidic hydrocarbons known. Although most hydrocarbons have а pKa > 45, cyclopentadiene has pKa = 16, a value comparable to that of water! Cyclopentadiene is acidic because the anion formed by dissociation is so stable. It doesn't matter that the cyclopentadienyl anion has only five p orbitals; all that matters is that there are six  electrons, a Huckel number (Figure 1.9).

Figure 1.9 An orbital view of the aromatic cyclopentadienyl anion, showing the cyclic conjugation and six 7r electrons in five p orbitals

Similar arguments can be used to predict the relative stabilities of the cycloheptatrienyl cation, radical, and anion. Removal of a hydrogen from cycloheptatriene can generate the cation (six  electrons), the radical (seven  electrons), or the anion (eight  electrons), as shown in Figure 1.10. Once again, all three species have numerous resonance forms, but Huckel's rule predicts that only the cycloheptatrienyl cation (six  electrons) should be aromatic. The cycloheptatrienyl radical (seven  electrons) and the anion (eight  electrons) are antiaromatic. Both the cycloheptatrienyl radical and the anion are reactive and difficult to prepare. The cation (with six  electrons), however, is extraordinarily stable. In fact, the cycloheptatrienyl cation was first prepared in 1891 by reaction of Br2 with cycloheptatriene (Figure 1.11), although its structure was not recognized at the time. 9

Figure 1.10 Generation of the cycloheptatrienyl cation, radical, and anion. Only the cation (six  electrons) is aromatic.

Figure 1.11 Reaction of cycloheptatriene with bromine yields cycloheptatrienylium bromide, a salt-like material containing the cycloheptatrienyl cation. PROBLEM 2- Cyclooctatetraene readily reacts with potassium metal to form the cyclooctatetraene dianion, C8H8 . Why do you suppose this reaction occurs so easily? What geometry do you expect for the cyclooctatetraene dianion?

Pyridine and Pyrrole: Two Aromatic Heterocycles

Look back once again at the definition of aromaticity: ... a cyclic conjugated molecule containing 4n + 2  electrons. Nothing in this definition says that the atoms in the ring must be carbon. In fact, heterocyclic compounds can also be aromatic. A heterocycle is a compound with a ring that has one or more atoms other than carbon. The heteroatom is often nitrogen or oxygen, but sulfur, phosphorus, and other elements are also found. Pyridine, for example, is a six-membered heterocycle with a nitrogen atom in its ring. Pyridine is much like benzene in its  electron structure. Each of the five sp2-hybridized carbons has a p orbital perpendicular to the plane of the ring, and each p orbital contains one  electron. The nitrogen atom is also sp2-

10 hybridized and has one electron in a p orbital, bringing the total to six  electrons. The nitrogen lone-pair electrons are in an sp2 orbital in the plane of the ring perpendicular to the  system and are not involved with the aromatic  system because they don't have the correct alignment for overlap (Figure 1.12).

Figure 1.12 Pyridine, an aromatic heterocycle, has а  electron arrangement much like that of benzene.

The five-membered heterocycle, pyrrole, another example of an aromatic substance with six  electrons, has a  electron system similar to that of the cyclopentadienyl anion. Each of the four sp2-hybridized carbons has a p orbital perpendicular to the ring, and each contributes one  electron. The nitrogen atom is sp2-hybridized, with its lone pair of electrons also occupying a p orbital. Thus, there are a total of six  electrons, making pyrrole an aromatic molecule. An orbital picture of pyrrole is shown in Figure 1.13.

Figure 1.13 Pyrrole, a five-membered aromatic heterocycle, has a  electron arrangement much like that of the cyclopentadienyl anion.

Note that the nitrogen atoms have different roles in pyridine and pyrrole even though both compounds are aromatic. The nitrogen atom in pyridine is in a double bond and therefore contributes only one  electron to the aromatic sextet, just as a carbon atom in benzene does. The nitrogen atom in pyrrole, however, is not in a double bond. Like one of the carbons in the cyclopentadienyl anion, the pyrrole nitrogen atom contributes two  electrons (the lone pair) to the aromatic sextet. Pyridine, pyrrole, and other aromatic heterocycles are crucial to many biochemical processes. Their chemistry will be discussed in more detail during next lessons.

PROBLEM The aromatic five-membered heterocycle imidazole is important in many biological processes. One of its nitrogen atoms is pyridine-like in that it contributes one  electron to the aromatic sextet, and the other nitrogen is pyrrole- like in that it contributes two  electrons. Draw an orbital picture of imidazole, and account for its aromaticity. Which atom is pyridine-like and which is pyrrole-like?

H N N Imidazole

11 PROBLEM Assuming that the oxygen atom in furan is sp2-hybridized, draw an orbital picture to show how the molecule is aromatic.

Naphthalene: A Polycyclic Aromatic Compound The Huckel rule is strictly applicable only to monocyclic aromatic compounds, but the general concept of aromaticity can be extended beyond simple monocyclic compounds to include polycyclic aromatic compounds. Naphthalene, with two benzene-like rings fused together, anthracene, 1,2-benzpyrene, and coronene are all well known. Benzo[a]pyrene is particularly interesting because it is one of the cancer-causing substances that has been isolated from tobacco smoke.

All polycyclic aromatic hydrocarbons can be represented by a number of different resonance forms. Naphthalene, for instance, has three:

As was true for benzene with its two equivalent resonance forms, no individual Kekule structure is a true representation of naphthalene. The true structure of naphthalene is a hybrid of the three resonance forms. Naphthalene and other polycyclic aromatic hydrocarbons show many of the chemical properties associated with aromaticity. Thus, heat of hydrogenation measurements show an aromatic stabilization energy of approximately 250 kJ/mol (60 kcal/mol). Furthermore, naphthalene reacts slowly with electrophiles such as Br2 to give substitution products rather than double-bond addition products.

How can we explain the aromaticity of naphthalene? The orbital picture of naphthalene in Figure 1.14 shows a fully conjugated cyclic  electron system, with p-orbital overlap both around the ten-carbon periphery of the molecule and across the central bond. Since ten  electrons is a Huckel number, there is a high degree of  electron derealization and consequent aromaticity in naphthalene.

Figure 1.14 An orbital picture of naphthalene, showing that the ten - electrons are fully delocalized throughout both rings.

PROBLEM

Azulene, a beautiful blue hydrocarbon, is an isomer of naphthalene. Is azulene aromatic? Draw a second resonance form of azulene in addition to that shown,

PROBLEM

Naphthalene is sometimes represented with circles in each ring to represent aromaticity:

The difficulty with this representation is that it's not immediately apparent how many  electrons are present. How many  electrons are in each circle?

13 LESSON 3 Structures of aromatic heterocycles This lesson describes the structures of aromatic heterocycles and gives a brief summary of some physical properties. The treatment we use is the valence-bond description, which we believe is sufficient for the understanding of all heterocyclic reactivity, perhaps save some very subtle effects, and is certainly sufficient for a general text-book on the subject. The more fundamental, molecular-orbital description of aromatic systems, is still not so relevant to the day-to-day interpretation of heterocyclic reactivity, though it is necessary in some cases to utilize frontier orbital considerations, however such situations do not fall within the scope of this lesson.

2.1 Carbocyclic aromatic systems 2.1.1 Structures of benzene and naphthalene The concept of aromaticity as represented by benzene is a familiar and relatively simple one. The difference between benzene on the one hand and alkenes on the other is well known: the latter react by addition with electrophiles, such as bromine, whereas benzene reacts only under much more forcing conditions and then nearly always by substitution. The difference is due to the cyclic arrangement of six -electrons in benzene: this forms a conjugated molecular orbital system which is thermodynamically much more stable than a corresponding non- cyclically conjugated system. The additional stabilization results in a diminished tendency to react by addition and a greater tendency to react by substitution for, in the latter manner, survival of the original cyclic conjugated system of electrons is ensured in the product. A general rule proposed by Hückel in 1931 states that aromaticity is observed in cyclically conjugated systems of 4n + 2 electrons, that is with 2, 6, 10, 14, etc., -electrons; by far the majority of monocyclic aromatic, and heteroaromatic systems are those with 6  electrons. In this lesson we use the pictorial valence-bond resonance description of structure and reactivity. Even though this treatment is not rigorous it is still the standard means for the understanding and learning of organic chemistry, which can at a more advanced level give way naturally to the much more complex, and mathematical, quantum mechanical approach. We begin by recalling the structure of benzene in these terms. In benzene, the geometry of the ring, with angles of 120°, precisely fits the geometry of a planar trigonally hybridised carbon atom, and allows the assembly of a -skeleton of six sp2 hybridised carbon atoms in a strainless planar ring. Each carbon then has one extra electron which occupies an atomic p orbital orthogonal to the plane of the ring. The p orbitals interact to generate -molecular orbitals associated with the aromatic system. Benzene is described as a resonance hybrid of the two extreme forms which correspond, in terms of orbital interactions, to the two possible spin-coupled pairings of adjacent p electrons - structures 1 and 2. These are known as canonical structures, have no existence in their own right, but serve to illustrate two extremes which contribute to the “real” structure of benzene.

Sometimes, benzenoid compounds are represented using a circle inside a hexagon; although this emphasises their delocalised nature and the close similarity of the ring bond lengths (all exactly identical only in benzene itself), it is not helpful in interpreting reactions, and we do not use this method here.

Treating naphthalene comparably reveals three canonical structures, 3, 4, and 5. Note the standard use of a 14 double-headed arrow to interrelate resonance contributors. This must never be confused with the use of opposing straight 'fish-hook' arrows which are used to designate an equilibrium between two species: resonance contributors have no separate existence; they are not in equilibrium one with the other. This valence bond treatment predicts quite well the non-equivalence of the bond lengths in naphthalene: in two of the three contributing structures, C-l-C-2 is double and in one it is single, whereas C-2-C-3 is single in two and double in one. Statistically, then, the former may be looked on as 0.67 of a double bond and the latter as 0.33 of a double bond: the measured bond lengths confirm that there indeed is this degree of bond fixation, with values closely consistent with statistical prediction.

2.1.2 Aromatic resonance energy The difference between the ground-state energy of benzene and that of hypothetical, non-aromatic, 1, 3, 5- cyclohexatriene corresponds to the degree of stabilization conferred to benzene by the special cyclical interaction of the six -electrons. This difference is known as aromatic resonance energy. Of course, quantification depends on the assumptions made in estimating the energy of the “non-aromatic” structure, and for this reason and others, a variety of values have been calculated for the various heteroaromatic systems; perhaps their absolute values are less important than their relative values. What one can say with certainty is that the resonance energy of bicyclic aromatics, like naphthalene, is considerably less than twice that of the corresponding monocyclic system, implying a smaller loss of stabilization energy on conversion to a reaction intermediate which still retains a complete benzene ring, for example during electrophilic substitution. The resonance energy of pyridine is of the same order as that of benzene, that of thiophene is lower, with pyrrole and lastly furan of lower stabilisation energy still. Actual values for the stabilizations of these systems vary according to assumptions made, but are in the same relative order (kJ mol-1): benzene (150), pyridine (117), thiophene (122), pyrrole, (90), and furan (68).

2.2 Structure of six-membered heteroaromatic systems

2.2.1 Structure of pyridine The structure of pyridine is completely analogous to that of benzene, being related by replacement of CH by N. The key differences are: (i) the departure from perfectly regular hexagonal geometry caused by the presence of the hetero atom, in particular the shorter carbon-nitrogen bonds, (ii) the replacement of a hydrogen in the plane of the ring with an unshared electron pair, likewise in the plane of the ring, located in an sp2 hybrid orbital, and not at all involved in the aromatic -electron sextet; it is this nitrogen lone pair which is responsible for the basic properties of pyridines, and (iii) a strong permanent dipole, traceable to the greater electronegativity of the nitrogen compared with carbon.

It is important to realize that the electronegative nitrogen causes inductive polarization, mainly in the -bond framework, and additionally, stabilizes those polarized canonical structures in which nitrogen is negatively charged - 8, 9, and 10 -which, together with contributors 6 and 7, which are strictly analogous to the Kekule contributors to benzene, represent pyridine. The polarized contributors imply a permanent polarization of the -electron system too (these 15 equate, in the more rigorous molecular orbital treatment, to a consideration of the relative magnitudes of orbital coefficients in the HOMO and LUMO).

Because inductive and mesomeric effects work in the same sense in pyridine, there results a permanent dipole towards the nitrogen atom. It also means that there are fractional positive charges on the carbons of the ring, located mainly on the α- and γ-positions. It is because of this general electron-deficiency at carbon that pyridine and similar heterocycles are referred to as 'electron-poor', or sometimes “-deficient”. A comparison with the dipole moment of piperidine, which is due wholly to the induced polarization of the -skeleton, gives an idea of the additional polarization associated with distortion of the -electron system.

2.2.2 Structure of diazines The structures of the diazines (six-membered systems with two nitrogen atoms in the ring) are analogous, but now there are two nitrogen atoms and a corresponding two lone pairs; as an illustration, the main canonical contributors (11-18) to pyrimidine are shown below.

2.2.3 Structures of pyridinium and related cations Electrophilic addition to the pyridine nitrogen generates pyridinium ions, the simplest being 1 H-pyridinium formed by addition of a proton. 1H-Pyridinium is actually isoelectronic with benzene, the only difference being the nuclear charge of nitrogen, which makes the system, as a whole, positively charged. Thus pyridinium cations are still aromatic, the diagram making clear that the system of six p orbitals required to generate the aromatic molecular orbitals is still present, though the formal positive charge on the nitrogen atom severely distorts the -system, making the α- and γ-carbons in these cations carry fractional positive charges which are higher than in pyridine, with a consequence for their reactivity towards nucleophiles. Electron density at the pyridinium β-carbons is also reduced relative to these carbons in pyridines.

In the pyrylium cation, the positively charged oxygen also has an unshared electron pair, in an sp2 orbital in the plane of the ring, exactly as in pyridine. Once again, a set of resonance contributors, 19-23, makes clear that this ion 16 is strongly positively charged at the 2-, 4- and 6-positions, in fact, because the more electronegative oxygen tolerates positive charge much less well than nitrogen, the pyrylium cation is certainly a less stabilised system than a pyridinium cation.

2.2.4 Structures of pyridones and pyrones Pyridines with an oxygen at either the 2- or 4-position exist predominantly as carbonyl tautomers, which are therefore known as pyridones. In the analogous oxygen systems, no alternative tautomer is possible; the systems are known as pyrones. The extent to which such molecules are aromatic has been a subject for considerable speculation and experimentation, and estimates have varied considerably. The degree of aromaticity depends on the contribution which dipolar structures, 25 and 27, with a 'complete' pyridinium (pyrylium) ring make to the overall structure. Pyrones are less aromatic than pyridones, as can be seen from their tendency to undergo addition reactions, and as would be expected from a consideration of the 'aromatic' contributors, 25 and 27, which have a positively charged ring hetero atom, oxygen being less easily able to accommodate this requirement.

2.3 Structure of five-membered heteroaromatic systems 2.3.1 Structure of pyrrole Before discussing pyrrole it is necessary to recall the structure of the cyclopentadienyl anion, which is a 6--electron aromatic system produced by the removal of a proton from cyclopentadiene. This system serves to illustrate nicely the difference between aromatic stabilization and reactivity, for it is a very reactive, fully negatively charged entity, and yet is 'resonance stabilized' - everything is relative. Cyclopentadiene, with a pKa of about 14, is much more acidic than a simple diene, just because the resulting anion is resonance stabilised. Five equivalent contributing structures, 28-32, show each carbon atom to be equivalent and hence to carry one fifth of the negative charge.

Pyrrole is isoelectronic with the cyclopentadienyl anion, but is electrically neutral because of the higher nuclear charge on nitrogen. The other consequence of the presence of nitrogen in the ring is the loss of radial symmetry, so that pyrrole does not have five equivalent canonical forms: it has one with no charge separation, 33, and two pairs of equivalent forms in which there is charge separation, indicating electron density drift away from the nitrogen. These forms do not contribute equally; the order of importance is: 33 > 35,37 > 34,36.

Resonance leads, then, to the establishment of partial negative charges on the carbons and a partial positive charge on the nitrogen. Of course the inductive effect of the nitrogen is, as usual, towards the hetero atom and away 17 from carbon, so that the electronic distribution in pyrrole is a balance of two opposing effects, of which the mesomeric effect is probably the more significant. The lengths of the bonds in pyrrole are in accord with this exposition, thus the 3,4-bond is very much longer than the 2,3-/4,5-bonds, but appreciably shorter than a normal single bond between sp2 hybridised carbons, in accord with contributions from the polarised structures 34-37. It is because of this electronic drift away from nitrogen and towards the ring carbons that five-membered heterocycles of the pyrrole type are referred to as 'electron-rich', or sometimes 'π-excessive'.

It is most important to recognise that the nitrogen lone pair in pyrrole forms part of the aromatic six-electron system.

2.3.2 Structures of thiophene and furan

The structures of thiophene and furan are closely analogous to that discussed in detail for pyrrole above, except that the NH is replaced by S and O respectively. A consequence is that the hetero atom in each has one lone pair as part of the aromatic sextet, as in pyrrole, but also has a second lone pair which is not involved, and is located in an sp2 hybrid orbital in the plane of the ring. Canonical forms exactly analogous to those (above) for pyrrole can be written for each, but the higher electronegativity of both sulfur and oxygen means that the polarised forms, with positive charges on the hetero atoms, make a smaller contribution. The decreased mesomeric electron drift away from the hetero atoms is insufficient, in these two cases, to overcome the inductive polarisation towards the hetero atom (the dipole moments of tetrahydrothiophene and tetrahydrofuran, 1.87D and 1.68D, respectively, both towards the hetero atom, are in any case larger) and the net effect is to give dipoles directed towards the hetero atoms in thiophene and furan.

The larger bonding radius of sulfur is one of the influences making thiophene more stable (more aromatic) than pyrrole or furan - the bonding angles are larger and angle strain is somewhat relieved, but in addition, a contribution to the stabilization involving sulfur d orbital participation may be significant.

2.3.3 Structures of azoles The 1,3- and 1,2-azoles, five-membered rings with two hetero atoms, present a fascinating combination of hetero atom types - in all cases, one hetero atom must be of the five-membered heterocycle (pyrrole, thiophene, furan) type and one of the imine type, as in pyridine; imidazole with two nitrogen atoms illustrates this best. Contributor 39 is a particularly favorable one.

2.4 Structures of bicyclic heteroaromatic compounds Once the ideas of the structures of benzene, naphthalene, pyridine and pyrrole, as prototypes, have been assimilated it is straightforward to extrapolate to those systems which combine two (or more) of these types, thus quinoline is like naphthalene, only with one of the rings a pyridine, and indole is like pyrrole, but with a benzene ring attached.

Resonance representations must take account of the pattern established for benzene and the relevant heterocycle. Contributors in which both aromatic rings are disrupted make a very much smaller contribution and are shown in parentheses.

2.5 Tautomerism in heterocyclic systems A topic which has attracted an inordinately large research effort over the years is the determination of precise structure of heterocyclic molecules which are potentially tautomeric - the pyridinol/pyridone relationship is one such situation. In principle, when an oxygen is located on a carbon α or γ to nitrogen, two tautomeric forms can exist; the same is true of amino groups.

Early attempts to use the results of chemical reactions to assess, the form of a particular compound were misguided, since these can give entirely the wrong answer: the minor partner in such a tautomeric equilibrium may be the one which is the more reactive, so a major product may be actually derived from the minor component in the tautomeric equilibrium. Most secure evidence on these questions has come from comparisons of spectroscopic data for the compound in question with unambiguous models - often N- and O-methyl derivatives.

After all the effort that has been expended on this area, the picture which emerges is fairly straightforward: α and γ oxy-heterocycles generally prefer the carbonyl form; amino-heterocycles nearly always exist as amino tautomers. Sulfur analogues -potentially thiol or thione - tend to exist as thione in six-membered situtations, but as thiol in five-membered rings. The establishment of tautomeric form is perhaps of most importance in connection with the purine and pyrimidine bases which form part of DNA and RNA, and, through H-bonding involving carbonyl oxygen, provide the mechanism for base pairing.

LESSON 4

Reactivity of Aromatic Heterocycles

3.1 Electrophilic addition at nitrogen Heterocycles which contain an imine unit (C = N) as part of their ring structure -pyridines, quinolines, isoquinolines, 1,2- and 1,3-azoles, etc. - do not utilize the nitrogen lone pair in their aromatic -system and therefore it is available for donation to electrophiles, just Reactivity of Aromatic Heterocycles as in any simpler amine. In other words, such heterocycles are basic and will react with protons, or other electrophilic species, at nitrogen, by addition. In many instances the product salts, from such additions, are isolable.

For reversible additions, for example of a proton, the position of equilibrium depends on the pKa of the 20 heterocycle, and this in turn is influenced by the substituents present on the ring: electron-releasing groups enhance the basicity and electron-withdrawing substituents reduce the basic strength. The pKa of simple pyridines is of the order of 5, while those for 1,2- and 1,3-azoles depends on the character of the other heteroatom: pyrazole and imidazole, with two nitrogen atoms, have values of 2.5 and 7.1 respectively. Related to basicity, but certainly not always mirroring it, is the N-nucleophilicity of imine-containing heterocycles. Here, the presence of substituents adjacent to the nitrogen can have a considerable effect on how easily reaction with alkyl halides takes place and indeed whether nitrogen attacks at carbon, forming N+-alkyl salts, or by deprotonation, bringing about a 1,2-dehydrohalogenation of, the halide, the heterocycle then being converted into an N+ -hydrogen salt. The classical study of the slowing of N-alkylation by the introduction of steric interference at α-positions of pyridines showed one methyl to slow the rate by about threefold, whereas 2,6-dimethyl substitution slowed the rate between 12 and 40 times. Taking this to an extreme, 2,6-di-t-butylpyridine will not react at all with iodomethane, even under high pressure; the very reactive methyl fluorosulfonate will N-methylate it, but only under high pressure. The quantitative assessment of reactivity at nitrogen must always take into account both steric (especially at the α-positions) and electronic effects: 3-methylpyridine reacts faster ( 1.6) but 3-chloropyridine reacts slower ( 0.14) than pyridine. Other factors can influence the rate of quaternisation: all the diazines react with iodomethane more slowly than does pyridine. Pyridazine, much more weakly basic (pKa 2.3) than pyridine, reacts with iodomethane faster than the other diazines, a result which is ascribed to the 'α effect', i.e. the increased nucleophilicity is deemed to be due to electron repulsion between the two immediately adjacent lone pairs. Reaction rates for iodomethane with pyridazine, pyrimidine and pyrazine are respectively 0.25, 0.044, and 0.036 relative to the rate with pyridine.

3.2 Electrophilic substitution at carbon The study of aromatic heterocyclic reactivity can be said to have begun with the results of electrophilic substitution processes - these were traditionally the means for the introduction of substitutents onto heterocylic rings. To a considerable extent that methodology has been superseded, especially for the introduction of carbon substituents, by methods relying on the formation of heteroaryllithium nucleophiles and on palladium-catalysed processes. Nonetheless the reaction of heterocycles with electrophilic reagents is still extremely useful in many cases, particularly for electron-rich, five-membered heterocycles.

3.2.1 Aromatic electrophilic substitution - mechanism Electrophilic substitution of aromatic (and heteroaromatic) molecules proceeds via a two-step sequence, initial addition (of X+) giving a positively charged intermediate (a -complex, or Wheland intermediate), then elimination (normally of H+), of which the former is usually the slower (rate-determining) step. Under most circumstances such substitutions are irreversible and the product ratio is determined by kinetic control.

3.2.2 Six-membered heterocycles An initial broad division must be made in considering heteroaromatic electrophilic substitution, into those heterocycles which are basic and those which are not, for in the case of the former the interaction of nitrogen lone pair with the electrophile, or indeed with any other electrophilic species in the proposed reaction mixture (protons in a nitrating mixture, or aluminium chloride in a Friedel-Crafts combination) will take place far faster than any C- substitution, thus converting the substrate into a positively charged salt and therefore hugely reducing its susceptibility to attack by X+ at carbon. It is worth recalling the rate reduction attendant upon the change from benzene to N, N, N- 21 + 8 trimethylanilinium cation (PhN Me3) where the electrophilic substitution rate goes down by a factor of 10 even though in this instance the charged atom is only attached to, and not a component of, the aromatic ring. Thus all heterocycles with a pyridine-type nitrogen (i.e. those containing C=N) do not easily undergo C-electrophilic substitution, unless (a) there are other substituents on the ring which 'activate' it for attack, or (b) the molecule has another, fused benzene ring in which substitution can take place, or (c) there is a second hetero atom in a five-membered ring, which can release electrons to the attacking electrophile. For example, simple pyridines do not undergo many useful electrophilic substitutions, but quinolines and isoquinolines undergo substitution in the benzene ring. It has been estimated that the intrinsic reactivity of a pyridine (i.e. not protonated) to electrophilic substitution is around 107 times less than that of benzene, that is to say, about the same as that of nitrobenzene. When quinoline or isoquinoline undergo nitration in the benzene ring the actual species attacked is the N- protonated heterocycle, and even though substitution is taking place in the benzene ring, it must necessarily proceed through a doubly charged intermediate: this results in a much slower rate of substitution than for the obvious comparison, naphthalene - the 5- and 8-positions of quinolinium are attacked at about a 1010 slower rate than the 1- position of naphthalene, and it was estimated that the nitration of pyridinium cation is at least 105 slower still.

'Activating' substitutents, i.e. groups which can release electrons either inductively or mesomerically, make the electrophilic substitution of pyridine rings to which they are attached faster, for example 4-pyridone nitrates at the 3- position via the O-protonated salt. In order to understand the activation, it is helpful to view the species attacked as a (protonated) phenol-like substrate. Electrophilic attack on neutral pyridones is best visualised as attack on an enamide. Dimethoxypyridines also undergo nitration via their cations, but the balance is often delicate, for example 2- aminopyridine brominates at C-5, in acidic solution, via the free base.

Pyridines carrying activating substituents at C-2 are attacked at C-3/C-5, those with such groups at C-3 are attacked at C-2, and not at C-4, whilst those with substituents at C-4 undergo attack at C-3.

Substituents which reduce the basicity of a pyridine nitrogen can also influence the susceptibility of the heterocycle to electrophilic susbtitution, in these cases by increasing the proportion of neutral (more reactive) pyridine present at equilibrium: 2,6-dichloropyridine nitrates at C-3, as the free base, and only 103 times more slowly than 1,3-dichlorobenzene. It has been suggested that:

22 (i) pyridines with a pKa > 1 will nitrate as cations, slowly unless strongly activated, and at an a or β position depending on the position of the substituent,

(ii) weakly basic pyridines, pKa < -2.5, nitrate as free bases, and at an α or β position depending on the position of the substituent. (iii) Pyridines carrying strongly electron-withdrawing substituents, or heterocycles with additional heteroatoms, diazines for example, are so deactivated that electrophilic substitutions do not take place.

3.2.3 Five-membered heterocycles For five-membered, electron-rich heterocycles the utility of electrophilic substitutions is much greater. Heterocycles such as pyrrole, thiophene and furan undergo a range of electrophilic substitutions with great ease, at either type of ring position, but with a preference for attack adjacent to the hetero atom - at their α- positions. These substitutions are facilitated by electron-release from the hetero atom and, as a consequence, pyrroles are more reactive than furans which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole:furan:thiophene ratio is: 5  107:1.5  102:l; in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeprotonation) the partial rate factors for the α and β positions of N-methylpyrrole are 3.9  1010 and 2.0  1010 respectively; for this same process, the values for furan are 1.6  108 and 3.2  104 and for thiophene, 3.9  108 and 1.0  105 respectively, and in a study of thiophene, α:β ratios ranging from 100:1 to 1000:1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the α:β ratio decreases in the order furan > thiophene > pyrrole. Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together.

Indoles are only slightly less reactive than pyrroles, electrophilic substitution taking place in the heterocyclic ring, at a β-position: in acetylation using a Vilsmeier combination (N,N- dimethylacetamide/phosgene), the rate ratio compared with pyrrole is 1:3. In contrast to pyrrole there is a very large difference in reactivity between the two hetero-ring position in indoles: 2600:1, β:α, in Vilsmeier acetylation. With reference to benzene, indole reacts at its β-position around 5 x 1013 times as fast. Again, these differences can be illustrated conveniently using an example which contains two types of system linked together.

The reactivity of an indole is very comparable to that of a phenol: typical of phenols is their ability to be substituted even by weak electrophiles, like benzenediazonium cations, and indeed indoles (and pyrroles) also undergo such couplings; depending on pH, indoles can undergo such processes via a small equilibrium concentration of anion formed by loss of N-proton; of course this is an even more rapid process, 8 + shown to be 10 faster than for the neutral heterocycle. The Mannich substitution (electrophile: CH2 = N Me2) of 5- and 6-hydroxyindoles, takes place ortho to the phenolic activating group on the benzene ring, and not at the indole β-position. Comparisons of the rates of substitution of the pairs furan/benzo[b]furan and 23 thiophene/benzo[b]thiophene showed the bicyclic systems to be less reactive than the monocyclic heterocycles, the exact degree of difference varying from electrophile to electrophile. Finally, in the 1,2- and 1,3-azoles there is a fascinating interplay of the propensities of an electron-rich five-membered heterocycle with an imine, basic nitrogen. This latter reduces the reactivity of the heterocycle towards electrophilic attack at carbon, both by inductive and by mesomeric withdrawal, and also by conversion into salt in acidic media. For example, depending on acidity, the nitration of pyrazole can proceed by attack on the pyrazolium cation, or via the free base. A study of acid-catalysed exchange showed the order: pyrazole > isoxazole > isothiazole, paralleling pyrrole > furan > thiophene, but each is much less reactive than the corresponding heterocycle without the azomethine nitrogen, but equally, that each is still more reactive than benzene, the partial rate factors for exchange at their 4-positions being 6.3  109, 2.0  104 and 4.0  103 respectively. Thiophene is 3  105 times more rapidly nitrated than 4-methylthiazoles; the nitration of a 2-(thien-2-yl)thiazole illustrates the relative reactivities.

3.3 Nucleophilic substitution at carbon 3.3.1 Aromatic nucleophilic substitution - mechanism Nucleophilic substitution of aromatic compounds proceeds via an addition (of Y-) then elimination (of a negatively charged entity, most often Hal-) two-step sequence, of which the former is usually rate- determining. It is the stabilisation (delocalisation of charge) of the negatively charged intermediates (Meisenheimer complexes) which is the key to such processes, for example in reactions of ortho and para chloronitrobenzenes the nitro group is involved in the charge dispersal.

3.3.2 Six-membered heterocycles In the heterocyclic field, the displacement of good leaving groups, often halide, by a nucleophile is a very important general process, especially for six-membered electron-poor systems. In the chemistry of five- membered aromatic heterocycles, such processes only come into play in special situations such as where, as in benzene chemistry, the leaving group is activated by an ortho or para nitro group, or in the azoles, where the leaving group is attached to an imine unit. Positions α and γ to an imine nitrogen are activated for the initial addition of a nucleophile by two factors: (i) inductive and mesomeric withdrawal of electrons by the nitrogen and (ii) inductive withdrawal of electrons by the halogen. The -adduct intermediate is also specially stabilised when attack is at α- and γ- positions, since in these intermediates the negative charge resides largely on the nitrogen: α and γ positions are much more reactive in nucleophilic displacements than β positions. A quantitative comparison for displacements of chloride with sodium methoxide in methanol showed the 2- and 4-chloropyridines to react at roughly the same rate as 4-chloronitrobenzene, with the γ-isomer somewhat more reactive than the α-halide. It is notable that even 3-chloropyridine, where only inductive activation can operate, is appreciably more reactive than chlorobenzene.

24 Rates of reaction with MeO-, relative to chlorobenzene, at 50 °C

The presence of a formal positive charge on the nitrogen, as in N-oxides and N-alkylpyridinium salts, has a further very considerable enhancing effect on the rate of nucleophilic substitutions, N-oxidation having a smaller effect than quaternisation -in the latter there is a full formal positive charge on the molecule but N- oxides are overall electrically neutral. In reactions with methoxide, the 2 -, 3- and 4-chloropyridine N- oxides are 1.9 x 104, 1.1 x I05, and 1.1 x 103 times more reactive than the corresponding chloropyridines, and displacements of halide in the 2-, 3- and 4-chloro-l-methylpyridinium salts are 4.6 x 1012, 2.9 x 108, and 5.7 x 109 times more rapid. Another significant point to emerge from these rate studies concerns the relative rate enhancements, at the three ring positions: the effect of the charge is much greater at an α than at a γ position such that in the salts the order is 2>4> 3, as opposed to both neutral pyridines, where the order of reactivity is 4 > 2 > 3, and N-oxides, where the α-positions end up at about the same reactivity as the γ- position. The utility of nitrite as a leaving group in heterocyclic chemistry is emphasised by a comparison of its relative reactivity to nucleophilic displacement: 4-nitropyridine is about 1100 times more reactive than 4- bromopyridine. A comparison of the rates of displacement of 4-methylsulfonylpyridine with its N-methyl quaternary salt showed arise in rate by a factor of 7 x 108. Although methoxide is not generally a good leaving group, when attached to a pyridinium salt it is only about 4 times less easily displaced than iodide, bromide and chloride; fluoride in the same situation is displaced about 250 times faster than the other halides. Turning to bicyclic systems, and a study of reaction with ethoxide, a small increase in the rate of reaction relative to pyridines was found for chloroquinolines at comparable positions. In the bicyclic compounds, quaternisation again greatly increases the rate of nucleophilic substitution, having a larger effect (~107) at C-2 than at C-4 (~105). Relative rates for nucleophilic displacement with EtO- at 20°C

Diazines with halogen α and γ to nitrogen are much more reactive than similar pyridines, for example 2-chloropyrimidine is ~106 times more reactive than 2-chloropyridine.

3.4 Radical substitution at carbon Both electron-rich and electron-poor heterocyclic rings are susceptible to substitution of hydrogen by free radicals. Although electrically neutral, radicals exhibit varying degrees of nuclcophilic or electrophilic character and this has a very significant effect on their reactivity towards different heterocyclic types. These electronic properties are a consequence of the interaction between the SOMO (Singly Occupied Molecular Orbital) of the radical and either the HOMO, or the LUMO, of the substrate, depending on their relative energies; these interactions are usefully compared with charge transfer interactions.

25 Nucleophilic radicals carry cation-stabilising groups on the radical carbon, allowing electron density to be transferred from the radical to an electron-deficient heterocycle; they react therefore only with electron-poor

and ,٠CH2OH, alkyl٠ heterocycles and will not attack electron-rich systems: examples of such radicals are :Substitution by such a radical can be represented in the following general way .acyl٠

Electrophilic radicals, conversely, are those which would form stabilized anions on gaining an electron, and

٠CH(CO2Et)2. Substitution by such a ٠CF3 and therefore react readily with electron-rich systems: examples are radical can be represented in the following general way:

Aryl radicals can show both types of reactivity. A considerable effort (mainly older work) was devoted to substitutions by aryl radicals; they react with electron-rich and electron-poor systems at about the same rate but often with poor regioselectivity.

2.4.1 Reactions of heterocycles with nucleophilic radicals

The Minisci reaction The reaction of nucleophilic radicals, under acidic conditions, with heterocycles containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyridines, quinolines, diazines, imidazoles, benzothiazoles, and purines are amongst the systems which have been shown to react with a wide range of nucleophilic radicals, selectively at positions α and γ to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because N-protonation of the heterocycle both greatly increases its reactivity and promotes regioselectivity towards a nucleophilic radical, most of which hardly react at all with the neutral base. A particularly useful feature of the process is that it can be used to introduce acyl groups, directly, i.e. to effect the equivalent of a Friedel-Crafts substitution - impossible under normal conditions for such systems. Tertiary radicals are more stable, but also more nucleophilic and therefore more reactive than methyl radicals in Minisci reactions. The majority of Minisci substitutions have been carried out in aqueous, or at least partially aqueous, media, making isolation of organic products particularly convenient. Several methods have been employed to generate the required radical, many depending on the initial formation of oxy- or methyl radicals which then abstract hydrogen or iodine from suitable substrates; both these are illustrated by the typical examples shown below. The re-aromatisation of the intermediate radical- cation is usually brought about by its reaction with excess of the oxidant used to form the initial radical.

An instructive and useful process is the two-component coupling of an alkene with an electrophilic radical: the latter 26 will of course not react with the protonated heterocycle, but after addition to the alkene a nucleophilic radical is generated which will react.

When more than one reactive position is available in a hclcrocyclic substrate, as is often the case for pyridines for example, there are potential problems with regioselectivity or/and disubstitution (since the product of the first substitution is often as reactive as the starting material). Regioselectivity is dependent to a certain extent on the nature of the attacking radical and the solvent, but may be difficult to control satisfactorily.

A point to note is that for optimum yields, radical substitutions are often not taken to full conversion (of starting heterocycle), but as product and starting material are often easily separated this is usually not a problem. Ways of avoiding disubstitution include control of pH (when the product is less basic than the starting material), or the use of a two-phase medium to allow extraction (removal) of a more lipophilic product out of the aqueous acidic reaction phase. Very selective monosubstitution can also be achieved by the ingenious use of an N+-methoxy-quaternary salt, in place of the usual protonic salt. Here, rearomatisation is the result of loss of methanol, leaving as a product a much less reactive, neutral pyridine.

3.4.2 Reactions with electrophilic radicals Although much less well developed than the Minisci reaction, substitution with electrophilic radicals can be used in some cases to achieve selective reaction in electron-rich heterocycles.

LESSON 5

Pyridines: reactions and synthesis

Pyridine and its simple derivatives are stable and relatively unreactive liquids, with strong penetrating odours that are unpleasant to some people. They are much used as solvents and bases, especially pyridine itself, in reactions such as N- and O-tosylation and -acylation. Pyridine and the monomethylpyridines (picolines) are completely miscible with water. Pyridine was first isolated, like pyrrole, from bone pyrolysates: the name is constructed from the Greek for fire, ‘pyr’ and the suffix ‘idine’, which was at the time being used for all aromatic bases - phenetidine, toluidine, etc. Pyridine and its simple alkyl derivatives were for a long time produced by isolation from coal tar, in which they occur in quantity. In recent years this source has been displaced by synthetic processes: pyridine itself, for example, can be produced on a commercial scale in 60-70% yields by the gas-phase high- temperature interaction of crotonaldehyde, formaldehyde, steam, air and ammonia over a silica-alumina catalyst. Processes for the manufacture of alkylpyridines involve reaction of acetylenes and nitriles over a cobalt catalyst.

The pyridine ring plays a key role in several biological processes, most notably in the oxidation/reduction coenzyme nicotine adenine dinucleotide (NADP); the vitamin niacin (or the corresponding acid) is required for its biosynthesis. Pyridoxine (vitamin B6) plays a key role as the coenzyme in transaminases. Nicotine, a highly toxic alkaloid, is the major active component in tobacco, and the most addictive drug known.

Many synthetic pyridine derivatives are important as therapeutic agents, for example Isoniazide is a major antituberculosis agent, Sulphapyridine is one of the sulfonamide antibacterials, Prialdoxime is an antidote for poisoning by organophosphates, and Amlodipine is one of several antihypertensive 1,4-dihydropyridines. Some herbicides (Paraquat) and fungicides (Davicil) are also pyridine 28 derivatives. Nemertelline is a neurotoxin from a marine worm; epibatidine, isolated from a South American frog, shows promise as an analgetic agent.

5.1 Reactions with electrophilic reagents 5.1.1 Addition to nitrogen In reactions which involve bond formation using the lone pair of electrons on the ring nitrogen, such as protonation and quaternisation, pyridines behave just like tertiary aliphatic or aromatic amines. When a pyridine reacts as a base or a nucleophile it forms a pyridinium cation in which the aromatic sextet is retained and the nitrogen acquires a formal positive charge. 5.1.1.1 Protonation of nitrogen Pyridines form crystalline, frequently hygroscopic, salts with most protic acids. Pyridine itself, with pKa=5.2 in water, is a much weaker base than saturated aliphatic amines which have pKa values mostly between 9 and 11.

N N H Electron-releasing substituents generally increase the basic strength; 2-methyl-(pKa 5.97), 3-methyl (5.68) and 4-methylpyridine (6.02) illustrate this. The basicities of pyridines carrying groups which can interact mesomerically as well as inductively vary in more complex ways, for example 2- methoxypyridine (3.3) is a weaker, but 4-methoxypyridine (6.6) a stronger base than pyridine; the effect of inductive withdrawal of electrons by the electronegative oxygen is felt more strongly when it is closer to the nitrogen, i.e. at C-2. Large 2- and 6-substituents impede solvation of the protonated form: 2,6-di-t-butylpyridine is less basic than pyridine by one pKa unit and 2,6-di(tri-t-propylsilyl)pyridine will not dissolve even in 6N hydrochloric acid. 5.1.1.2 Nitration at nitrogen This occurs readily by reaction of pyridines with nitronium salts, such as nitronium tetrafluoroborate. Protic nitrating agents such as nitric acid of course lead exclusively to N-protonation. l-Nitro-2,6-dimethylpyridinium tetrafluoroborate is one of several N-nitropyridinium salts which can be used as non-acidic nitrating agents with good substrate and positional selectivity. The 2,6-disubstitution serves to sterically inhibit resonance overlap between nitro group and ring and consequently increase reactivity as a nitronium ion donor, however the balance between this advantageous effect and hindering approach of the aromatic substrate is illustrated by the lack of transfer nitration reactivity in 2,6-dihalo-analogues.

5.1.1.3 Amination of nitrogen The introduction of nitrogen at a different oxidation level can be achieved with hydroxylamine O-sulfate.

5.1.1.4 Oxidation of nitrogen In common with other tertiary amines, pyridines react smoothly with percarboxylic acids to give N-oxides, which have their own rich chemistry. 5.1.1.5 Acylation at nitrogen Carboxylic, and arylsulfonic acid halides react rapidly with pyridines generating 1-acyl- and 1- arylsulfonylpyridinium salts in solution, and in suitable cases some of these can even be isolated as crystalline solids. The solutions, generally in excess pyridine, are commonly used for the preparation of esters and sulfonates from alcohols and of amides and sulfonamides from amines. 4-Dimethylaminopyridine (DMAP) is widely used (in catalytic quantities) to activate anhydrides in a similar manner. The salt derived from DMAP and t-butyl chloroformate is stable even in aqueous solution at room temperature.

5.1.1.6 Alkylation at nitrogen Alkyl halides and sulfates react readily with pyridines giving quaternary pyridinium salts.

5.1.2 Substitution at carbon In most cases, electrophilic substitution of pyridines occurs very much less readily than for the correspondingly substituted benzene. The main reason is that the electrophilic reagent, or a proton in the reaction medium, adds preferentially to the pyridine nitrogen, generating a pyridinium cation, which is naturally very resistant to a further attack by an electrophile. When it does occur then, electrophilic substitution at carbon must involve either highly unfavoured attack on a pyridinium cation or relatively easier attack but on a very low equilibrium concentration of uncharged free pyridine base. Some of the typical electrophilic substitution reactions do not occur at all -Friedel-Crafts alkylation and acylation are examples - but it is worth recalling that these also fail with nitrobenzene. Milder reagents, such as Mannich reactants, diazonium ions and nitrous acid, which in any case require activated benzenes for success, naturally fail with pyridines. 5.1.2.1 Proton exchange H-D exchange via an electrophilic addition process, such as operates for benzene, does not take place with

30 pyridine. A special mechanism allows selective exchange at the two α-positions in DCl-D2O or even in water at 200 °C, the key species being an ylide formed by 2/6-deprotonation of the 1H-pyridinium cation. 5.1.2.2 Nitration Pyridine itself can be converted into 3-nitropyridine only inefficiently by direct nitration even with vigorous conditions, as shown below, however a couple of ring methyl groups facilitate electrophilic substitution sufficiently to allow nitration to compete with side-chain oxidation.

5.1.2.3 Sulfonation Pyridine is very resistant to sulfonation using concentrated sulfuric acid or oleum, only very low yields of the 3-sulfonic acid being produced after prolonged reaction periods at 320 °C. However, addition of mercuric sulfate in catalytic quantities allows smooth sulfonation at a somewhat lower temperature. The role of the catalyst is not established; one possibility is that C-mercuration is the first step.

5.1.2.4 Halogenation 3-Bromopyridine is produced in good yield by the action of bromine in oleum. 3-Chloropyridine can be produced by chlorination at 200 °C or at 100 °C in the presence of aluminium chloride.

2-Bromo- and 2-chloropyridines can be made extremely efficiently by reaction of pyridine with the halogen, at 0-5 °C in the presence of palladium(II) chloride.

5.2 Reactions with oxidizing agents The pyridine ring is generally resistant to oxidizing agents, vigorous conditions being required, thus pyridine itself is oxidized by neutral aqueous potassium permanganate at about the same rate as benzene (sealed tube, 100 °C), to give carbon dioxide. In acidic solution pyridine is more resistant, but in alkaline media more rapidly oxidised, than benzene.

In most situations, carbon substituents can be oxidised with survival of the ring, thus alkylpyridines can be converted into pyridine carboxylic acids with a variety of reagents. Some selectivity can be achieved: only α- and γ-groups are attacked by selenium dioxide; the oxidation can be halted at the aldehyde oxidation level. 5.3 Reactions with nucleophilic reagents Just as electrophilic substitution is the characteristic reaction of benzene and electron-rich heteroaromatic compounds (pyrrole, furan etc.), so substitution reactions with nucleophiles can be looked on as characteristic of pyridines. It is important to realise that nucleophilic substitution of hydrogen differs in an important way from 31 electrophilic substitution: whereas the last step in electrophilic substitution is loss of proton, an easy process, the last step in nucleophilic substitution of hydrogen has to be a hydride transfer, which is less straightforward and generally needs the presence of an oxidising agent as hydride acceptor. Nucleophilic substitution of an atom or group which is a good anionic leaving group however is an easy and straightforward process.

5.3.1 Nucleophilic substitution with ‘hydride’ transfer 5.3.1.1 Alkylation and arylation Reaction with alkyl- or aryllithiums proceeds in two discrete steps: addition to give a dihydropyridine N- lithio-salt which can then be converted into the substituted aromatic pyridine by oxidation (e.g. by air), disproportionation, or elimination of lithium hydride. The N-lithio-salts can be observed spectroscopically and in some cases isolated as solids. Attack is nearly always at an α-position; reaction with 3-substituted-pyridines usually takes place at both available α-positions, but predominantly at C-2. This regioselectivity may be associated with relief of strain when the 2-position rehybridises to sp3 during addition.

5.3.1.2 Amination Amination of pyridines and related heterocycles, generally at a position α to the nitrogen, is called the Chichibabin reaction, the pyridine reacting with sodamide with the evolution of hydrogen.

5.3.2 Nucleophilic substitution with displacement of good leaving groups Halogen, and also, though with fewer examples, nitro, alkoxysulfonyl, and methoxy substituents at α- or γ- positions, but not at β-positions, are relatively easily displaced by a wide range of nucleophiles via an addition-elimination mechanism facilitated by (a) electron withdrawal by the substituent and (b) the good leaving ability of the substituent. γ-Halopyridines are more reactive than the α-isomers; β-halopyridines are very much less reactive, being much closer to, but still somewhat more reactive than halobenzenes. Fluorides are more reactive than the other halides.

Replacement of halide by reaction with ammonia can be achieved at considerably lower temperatures under 6-8 kbar pressure.

5.6 Reactions with radical reagents; reactions of pyridyl radicals 5.6.1 Halogenation At temperatures where bromine (500 °C) and chlorine (270 °C) are appreciably dissociated into atoms, 2- and 2,6-dihalopyridines are obtained via radical substitution. 5.6.2 Carbon radicals This same preference for α-attack is demonstrated by phenyl radical attack, but the exact proportions of products depend on the method of generation of the radicals. Greater selectivity for phenylation at the 2- and 4-positions is found in pyridinium salts.

Of more preparative value are the reactions of nucleophilic radicals, such as HOCH2 and R2NCO which can be easily generated under mild conditions. These substitutions are carried out on the pyridine protonic salt, which provides both increased reactivity and selectivity for an α-position; the process is known as the Minisci reaction. It is accelerated by electron-withdrawing substituents on the ring. 5.6.3 Dimerisation Both sodium and nickel bring about ‘oxidative’ dimerisations, despite the apparently reducing conditions, the former giving 4,4'-bipyridine and the latter 2,2'-bipyridine. Each reaction is considered to involve the same anion-radical resulting from transfer of an electron from metal to heterocycle, and the species has been observed by ESR spectroscopy when generated by single electron transfer (SET) from lithium diisopropylamide. In the case of nickel, the 2,2'-mode of dimerisation may be favoured by chelation to the metal surface. Bipyridyls are important for the preparation of Paraquat-type weedkillers.

5.7 Reactions with reducing agents Pyridines are much more easily reduced than benzenes, for example catalytic reduction proceeds easily at atmospheric temperature and pressure, usually in weakly acidic solution but also in dilute alkali over nickel. Of the hydride reagents, sodium borohydride is without effect on pyridines, though it does reduce pyridinium salts, lithium aluminium hydride effects the addition of one hydride equivalent to pyridine, but lithium triethylborohydride reduces to piperidine efficiently.

Metal/acid combinations, which in other contexts do bring about reduction of iminium groups, are without effect on pyridines. Samarium(II) iodide in the presence of water smoothly reduces pyridine to piperidine.

5.12 Pyridine aldehydes, ketones, carboxylic acids and esters These compounds all closely resemble the corresponding benzene compounds in their reactivity because the carbonyl group cannot interact mesomerically with the ring nitrogen. The pyridine 2- (picolinic), 3- (nicotinic), and 4- (isonicotinic) acids exist almost entirely in their zwitterionic forms in aqueous solution; they are slightly stronger acids than benzoic acid.

Decarboxylation of picolinic acids is relatively easy and results in the transient formation of the same type of ylide which is responsible for specific proton α-exchange of pyridine in acid solution. This transient ylide can be trapped by aromatic or aliphatic aldehydes in a reaction known as the Hammick reaction. As implied by this mechanism, quaternary salts of picolinic acids also undergo easy decarboxylation. The process can also be carried out by heating a silyl ester of picolinic acid in the presence of a carbonyl electrophile.

5.15 Synthesis of pyridines 5.15.1 Ring synthesis Ammonia reacts with 1,5-dicarbonyl compounds to give 1,4-dihydropyridines which are easily dehydrogenated to pyridines. With unsaturated 1,5-dicarbonyl compounds, or their equivalents (e.g. pyrylium ions) ammonia reacts to give pyridines directly.

1,5-Diketones are accessible via a number routes, for example by Michael addition of enolate to enone (or precursor Mannich base), by ozonolysis of a cyclopentene precursor, or by reaction of silyl enol ethers with 3-methoxyallylic alcohols. They react with ammonia, with loss of two mol equivalents of water to produce a cyclic bis-enamine, i.e. a 1,4-dihydropyridine, which is generally unstable but can be easily and efficiently dehydrogenated to the aromatic heterocycle.

LESSON 6 Quinoline And Izoquinoline

Quinoline Izoquinoline Quinoline is a heterocyclic aromatic organic compound. Containing a benzene ring fused with pyridine ring. It is a hygroscopic liquid, with strong odor, slightly soluble in cold water, but dissolves in hot water. It is distillation of coal tar in 1834. Quinoline is a high – boiling liquid, Izoquinoline is a low – melting Solid. Quinoline and isoquinoline, the two possible structures in which a benzene ring is annelated to a pyridine ring, represent an opportunity to examine the effect of fusing one aromatic ring to another. Clearly, both the effect the benzene ring has on the reactivity of the pyridine ring, and vice versa, as well as comparisons with the chemistry of naphthalene must be considered. Thus the regioselectivity of electrophilic substitution, which in naphthalene favours an α-position, is mirrored in quinoline/isoquinoline chemistry by substitution at 5- and 8-positions. It should be noted that such substitutions usually involve attack on the species formed by electrophilic addition (often protonation) at the nitrogen, which has the effect of discouraging (preventing) attack on the heterocyclic ring.

Just as for naphthalene, the regiochemistry of attack is readily interpreted by looking at possible intermediates: those for attack at C-5/8 allow delocalisation of charge without disruption of the pyridinium ring aromatic resonance, while those for attack at C-6/7 would necessitate disrupting that resonance in order to allow delocalisation of charge.

So, just as quinoline and isoquinoline are reactive towards electrophiles in their benzene ring, so they are reactive to nucleophiles in the pyridine ring, especially (see above) at the positions α and γ to the nitrogen and, further, are more reactive in this sense than pyridines. This is consistent with the structures of the intermediates for, in these, a full and complete, aromatic benzene ring is retained. Since the resonance stabilisation of the bicyclic aromatic is considerably less than twice that of either benzene or pyridine, the loss in resonance stabilisation in proceeding from the bicyclic system to the intermediate is considerably less than in going from pyridine to an intermediate adduct. There is an obvious analogy: the rate of electrophilic substitution of naphthalene is greater than that of benzene for, in forming a -complex from the former, less resonance energy is sacrificed.

A significant difference in this typical behaviour applies to the isoquinoline 3-position - the special reactivity which the discussion above has developed for positions α to pyridine nitrogen, and which also applies to the isoquinoline 1-position, does not apply at C-3. In the context of nucleophilic displacements, for example, an intermediate for reaction of a 3-halo-isoquinoline cannot achieve delocalisation of negative charge onto the nitrogen unless the aromaticity of the benzene ring is disrupted. Therefore, such intermediates are considerably less stabilised and reactivity considerably tempered.

A great variety of methods is available for the ring synthesis of pyridines: the most obvious approach is to construct a 1,5- dicarbonyl compound, preferably also having further unsaturation and allow it to react with ammonia, addition of which at each carbonyl group, with losses of water, producing the pyridine. 1,4-Dihydropyridines, which can easily be dehydrogenated to the fully aromatic system, result from the interaction of aldehydes with two mol equivalents of 1,3- diketones (or 1,3-keto-esters, etc.) and ammonia; aldol and Michael reactions and addition of ammonia at the termini, produces the heterocycle. Reactions with electrophilic reagents Addition to nitrogen

Electrophilic substitution reactions at carbon atom

Nitration • Attack occurs at the benzo- rather than hetero-ring • Reactions are faster than those of pyridine but slower than those of naphthalene

In the case of quinoline, equal amounts of the 5- and 8-isomer are produced.

Sulfonation

Halogenation

• Halogenation is also possible but product distribution is highly dependent on conditions • It is possible to introduce halogens into the hetero-ring under the correct conditions • Friedel-Crafts alkylation/acylation is not usually possible

Nucleophilic Reactions

Amination - the Chichibabin reaction:

Quinoline can be hydroxylated with potassium hydroxide at high temperature with the evolution of hydrogen. 2-Quinolone is the isolated products.

Vigorous oxidation goes for the more electron-rich ring, the benzene ring, and destroys it leaving pyridine rings with carbonyl groups in the 2- and 3-positions.

quinolinic acid Derivatives of quinoline

8-Hydroxyquinoline is a monoprotic bidentate chelating agent. Related ligands are the Schiff bases derived from salicylaldehyde, such as salicylaldoxime and salen. The roots of the invasive plant Centaurea diffusa release 8-hydroxyquinoline, which has a negative effect on plants that have not co- evolved with it. The complexes as well as the heterocycle itself exhibit antiseptic, disinfectant, and pesticide properties. Its solution in alcohol are used as liquid bandages. It once was of interest as an anti-

38 cancer drug.

Drugs Containing a Quinoline/Isoquinoline

Bioactive Quinolines/Isoquinolines

quinine Quinine is an anti-malarial natural product isolated from the bark of the Cinchona tree. Quinine is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and anti-inflammatory properties.

Papaverine

Papaverine is an alkaloid isolated from the opium poppy and is a smooth muscle relaxant and a coronary vasodilator.

LESSON 7 Typical reactivity of the diazines: pyridazine, pyrimidine and pyrazine

The diazines - pyridazine, pyrimidine and pyrazine - contain two imine nitrogen atoms, so the lessons learnt with regard to pyridine are, in these heterocycles, exaggerated. Two heteroatoms withdraw electron density from the ring carbons even more than in pyridine, so the unsubstituted diazines are even more resistant to electrophilic substitution than is pyridine. A corollary of course, developed below, is that this same increased electron deficiency at carbon makes the diazines more easily attacked by nucleophiles than pyridines. The availability of nitrogen lone pair(s) is also reduced: each of the diazines is appreciably less basic than pyridine, reflecting the destabilising influence of the second nitrogen on the N-protocation. Nevertheless, diazines will form salts and will react with alkyl halides and with peracids to give N-alkyl quaternary salts and N-oxides, respectively. Generally speaking, such electrophilic additions take place at one nitrogen only, because the presence of the positive charge in the products renders the second nitrogen extremely unreactive towards a second electrophilic addition.

A very characteristic feature of the chemistry of diazines, which is associated with their strongly electron- poor nature, is that they add nucleophilic reagents easily. Without halide to be displaced, such adducts require an oxidation to complete an overall substitution. However, halo-diazines, where the halide is  or γ to a nitrogen, undergo very easy nucleophilic displacements, the intermediates being particularly well stabilised. All positions on each of the diazines, with the sole exception of the 5-position of a pyrimidine, are  and/or γ to an imine ring nitrogen and, in considering nucleophilic addition/substitution, it must be remembered that there is also an additional nitrogen withdrawing electron density. As a consequence, all the monohalodiazines are more reactive than either 2- or 4-halopyridines. The 2- and 4-halopyrimidines are particularly reactive because the anionic intermediates (shown below for attack on 2-chloropyrimidine) derive direct mesomeric stabilisation from both nitrogen atoms.

Despite this particularly strong propensity for nucleophilic addition, C-lithiation of diazines can be achieved by either metal-halogen exchange or, by deprotonation ortho to chloro or alkoxyl substituents, though very low temperatures must be utilized in order to avoid nucleophilic addition of the reagent.

In line with their susceptibility to nucleophilic addition, diazines also undergo Minisci radical substitution with ease. Considerable use has been made in diazine chemistry of palladium(O)-catalysed coupling processes, one of which is illustrated below.

Further examples of the enhancement of those facets of pyridine chemistry associated with the imine electron withdrawal, include a general stability towards oxidative degradation but, on the other hand, a tendency to undergo rather easy reduction of the ring. Although there is always debate about quantitative measures of aromaticity, it is agreed that the diazines are less resonance stabilised than pyridines - they are 'less aromatic'. Thus, Diels-Alder additions are known for all three systems, with the heterocycle acting as a diene; initial adducts lose a small molecule - hydrogen cyanide in the pyrimidine example shown - to afford a final stable product.

N-Oxides, just as in the pyridine series, show a remarkable duality of effect - they encourage both electrophilic substitutions and nucleophilic displacements. The sequence below shows pyridazine N-oxide undergoing first, electrophilic nitration, then, the product, nucleophilic displacement, with nitrite as leaving group.

N-Oxide chemistry in six-membered heterocycles provides considerable scope for synthetic manipulations. One of the very useful transformations is the introduction of halide  to a nitrogen on reaction with phosphorus or sulfur halides, the conversion being initiated by oxygen attack on the phosphorus (sulfur). The power of this transformation can be emphasised by noting that the unsubstituted heterocycle is converted, in the two steps, into a halide with its potential for subsequent displacement by nucleophiles.

The most studied diazine derivatives are the oxy- and amino-pyrimidines since uracil, thymine, and cytosine are found as bases in DNA and RNA. It is the enamide-like character of the double bonds in diazines with two oxygen substituents which allows electrophilic substitution - uracil, for example, can be brominated. One amino substituent permits electrophilic ring substitution and two amino, or one amino and one oxy, substituent, permit reaction with even weakly electrophilic reactants.

Diazinones, like pyridones, react with phosphorus halides with overall conversion into halides. Anions produced by N-deprotonation of diazinones are ambident, with a phenolate-like resonance contributor, but they generally react with electrophilic alkylating agents at nitrogen, rather than oxygen.

Diazine alkyl groups, with the exception of those at the 5-position of pyrimidine, can undergo condensation reactions which utilise the carbanion produced by removal of a proton. As in pyridine chemistry, formation of these anions is made possible by delocalisation of the charge onto one (or more) of the ring nitrogen atoms.

As can be seen from the illustrations below, each of the diazines can be constructed from an appropriate source of two nitrogens and a dicarbonyl compound. In the case of pyridazines, the nitrogen source is of course hydrazine and this in combination with 1,4-dicarbonyl compounds readily produces dihydropyridazines which are very easily dehydrogenated. Pyrimidines result from the interaction of a 1,3- dicarbonyl component and an amidine (as shown) or a urea (when 2-pyrimidones are formed) or a guanidine (when 2-aminopyrimidines are formed), without the requirement for an oxidation step.

To access a pyrazine in this way one needs a 1,2-diamine and a 1,2-dicarbonyl compound, and a subsequent oxidation, but if neither component is symmetrical, mixtures are formed. The dimerisation of 2- aminocarbonyl compounds also generates symmetrically substituted dihydropyrazines - perhaps the best known examples of such dimerisations involve the natural amino acids and their esters which dimerise to give dihydropyrazine-2,5-diones - 'diketopiperazines'.

LESSON 8 7.1 Typical reactivity of pyrroles, thiophenes, and furans In this lesson are gathered the most important generalizations which can be made, and the general lessons which can be learned about the reactivity, and relative reactivities, one with the other, of the prototypical five-membered aromatic heterocycles: pyrroles, thiophenes and furans.

The chemistry of pyrrole, thiophene and furan is dominated by a readiness to undergo electrophilic substitution, preferentially at an α-position but, with only slightly less alacrity, also at a β-position, should the α positions be blocked. For the beginning student of heterocyclic chemistry it is worth re-emphasizing the stark contrast between the five- and six-membered heterocycles - the former react much more readily with electrophiles than does benzene and the latter much less readily.

Positional selectivity in these five-membered systems, indeed their high reactivity to electrophilic attack, are well explained by a consideration of the Wheland intermediates (and by implication, the transition states which lead to them) for electrophilic substitution. Intermediate cations from both α- and β-attack are stabilized (shown for attack on pyrrole). The delocalization, involving donation of electron density from the hetero atom, is greater in the intermediate from α-attack, as illustrated by the number of low energy resonance contributors which can be drawn. Note that the C-C double bond in the intermediate for β-attack is not, and cannot become involved in delocalization of the charge. There is a simple parallelism between the reaction of a pyrrole with an electrophile and the comparable reaction of an aniline, and indeed pyrrole is in the same range of reactivity towards electrophiles as is aniline.

The five-membered heterocycles do not react with electrophiles at the hetero atom: perhaps this surprises the heterocyclic newcomer most obviously with respect to pyrrole, for here, it might have been anticipated, the nitrogen lone pair would be easily donated to an incoming electrophile, as it certainly 44 would be in reactions of its saturated counterpart, pyrrolidine. The difference is that in pyrrole, electrophilic addition at the nitrogen would lead to a substantial loss of resonance stabilization - the molecule would be converted into a cyclic butadiene, with an attached nitrogen carrying a positive charge localized on that nitrogen atom. The analogy with aniline falls down for, of course, anilines do react easily with simple electrophiles (e.g. protons) at nitrogen. The key difference is that, although some stabilization in terms of overlap between the aniline nitrogen lone pair and benzenoid π-system is lost, the majority of the stabilization energy, associated with the six-electron aromatic π-system, is retained when aniline nitrogen donates its lone pair of electrons to a proton (electrophile).

Of the trio - pyrrole, furan and thiophene - the first is by far the most susceptible to electrophilic attack: this susceptibility is linked to the greater electron-releasing ability of neutral trivalent nitrogen, and the concomitant greater stability of a positive charge on tetravalent nitrogen. This finds its simplest expression in the relative basicities of saturated amines, sulfides and ethers, respectively, which are seen to parallel nicely the relative order of reactivity of pyrrole, furan and thiophene towards electrophilic attack at carbon, but involving major assistance by donation from the hetero atom, i.e. the development of positive charge on the hetero atom.

In qualitative terms, the much greater reactivity of pyrrole is illustrated by its rapid reaction with weak electrophiles like benzenediazonium cation and nitrous acid, neither of which react with furan or thiophene. It is relevant to note that N,N-dimethylaniline reacts rapidly with these reactants, where anisole does not. Substituents ranged on five-membered rings have directing effects comparable to those which they exert on a benzene ring. Alkyl groups, for example, direct ortho and para, and nitro groups direct meta although, strictly, these two terms cannot be applied to the five-membered situation. The very strong tendency for α electrophilic substitution is however the dominating influence in most instances, and products resulting from attack following guidance from the substituent are generally minor products in mixtures where the dominant substitution is at an available α-position. The influence of substituents is felt least in furans.

An aspect of the chemistry of furans is the occurrence of a number of 2,5-additions initiated by electrophilic attack: a Wheland intermediate is formed normally but then adds a nucleophile, when a sufficiently reactive one is present, instead of then losing a proton. Conditions can, however, usually be chosen to allow the formation of a ‘normal’ α-substitution product if desired. The occurrence of such processes in the case of furan is generally considered to be associated with its lower aromatic resonance stabilization energy - there is less to regain by loss of a proton and the consequent return to an aromatic furan. 45

The lower aromaticity of furans also manifests itself in a much greater tendency to undergo cycloadditions, as a 4-π, diene component in Diels-Alder reactions. That is to say, furans are much more like dienes, and less like a six-electron aromatic system, than are pyrroles and thiophenes. However, the last two systems can be made to undergo cycloadditions by increasing the pressure or, in the case of pyrroles, by ‘reducing the aromaticity’ by the device of inserting an electron-withdrawing group onto the nitrogen. In direct contrast with electron-deficient heterocycles like pyridines and the diazines, the five-membered systems do not undergo nucleophilic substitutions, except in situations (especially in furan and thiophene chemistry) where halide is situated ortho or para to a nitro group. The ring synthesis of five-membered heterocycles has been investigated extensively and many and subtle methods have been devised. Each system can be prepared from 1,4-dicarbonyl compounds, for furans by acid catalysed cyclising dehydration, and for pyrroles and thiophenes by interaction with ammonia or primary amine, or a source of sulfur, respectively.

As illustrations of the variety of methods available, the three processes below show (i) the addition of isonitrile anions to α,β-unsaturated nitro compounds, with loss of nitrous acid to aromatize, (ii) the interaction of thioglycolates with 1,3-dicarbonyl compounds, for the synthesis of thiophene-2-esters, and (iii) the cycloaddition/cycloreversion preparation of furans from oxazoles.

46 47 7.2 Pyrroles: reactions and synthesis

Pyrrole and the simple alkyl pyrroles are colourless liquids, with relatively weak odours rather like that of aniline, which, also like the anilines, darken by autoxidation. Pyrrole itself is readily available commercially, and is manufactured by alumina-catalysed gas-phase interaction of furan and ammonia. Pyrrole was first isolated from coal tar in 1834 and then in 1857 from the pyrolysate of bone by a process which is similar to an early laboratory method for the preparation of pyrrole - the pyrolysis of the ammonium salt of the sugar acid, mucic acid. The word pyrrole is derived from the Greek for red, which refers to the bright red colour which pyrrole imparts to a pinewood shaving moistened with concentrated hydrochloric acid. The early impetus for the study of pyrroles came from degradative work relating to the structures of two pigments central to life processes, the blood respiratory pigment haem, and chlorophyll, the green photosynthetic pigment of plants. Such degradations led to the formation of mixtures of alkylpyrroles. Chlorophyll and haem are synthesised in the living cell from porphobilinogen, the only aromatic pyrrole to play a function - a vitally important function - in fundamental metabolism.

Ultimately, all life on earth depends on the incorporation of atmospheric carbon dioxide into carbohydrates. The energy for this highly endergonic process is sunlight, and the whole is called photosynthesis. The very first step in the complex sequence is the absorption of a photon by pigments, of which the most important in multicellular plants is chlorophyll-a. This photonic energy is then used chemically to achieve a crucial carbon-carbon bonding reaction to carbon dioxide, in which ultimately oxygen is liberated. Thus, formation of the by-product of this process, molecular oxygen, allowed the evolution of aerobic organisms of which man is one.

Haemoglobin is the agent which carries oxygen from lung to tissue in the arterial blood-stream in mammals; it is made up of the protein globin associated with a prosthetic group, the pigment haem (also spelt heme). The very close structural similarity of haem with chlorophyll is striking,

47 48 suggesting a common evolutionary origin. In oxygenated haemoglobin, the iron is six- coordinate iron(II) with an imidazolyl nitrogen of a protein histidine residue as ligand on one side of the plane of the macrocycle, and on the other, molecular oxygen. Haem without the ferrous iron is called protoporphyrin IX and the unsubstituted macrocycle is called porphyrin. Haem is also the active site of the cytochromes, which are enzymes concerned with electron transfer.

Another porphobilinogen-derived system is vitamin B12, the structure of which is significantly different, though related to chlorophyll and haem. The parent, unsubstituted macrocycle is called corrin.

Ketorolac, an analgesic and anti-inflammatory agent, is equal to morphine sulfate on a weight- to-weight basis for the alleviation of post-operative pain. Atorvastatin lowers chlolesterol levels.

6.2.1 Reactions with electrophilic reagents Whereas pyrroles are resistant to nucleophilic addition and substitution, they are very susceptible to attack by electrophilic reagents and react almost exclusively by substitution. Pyrrole itself, N- and C-monoalkyl and to a lesser extent C, C-dialkylpyrroles, are polymerised by strong acids so that many of the electrophilic reagents useful in benzene chemistry cannot be used. However, the presence of an electron-withdrawing substitutent such

48 49 as an ester, prevents polymerisation and allows the use of the strongly acidic, nitrating and sulfonating agents.

6.2.1.1 Protonation In solution, reversible proton addition occurs at all positions, being by far the fastest at the + nitrogen, and about twice as fast at C-2 as at C-3. In the gas phase, mild acids like C4H9 and + NH4 protonate pyrrole only on carbon and with a larger proton affinity at C-2 than at C-3. Thermodynamically the stablest cation, the 2H-pyrrolium ion, is that formed by protonation at C-2 and observed pKa values for pyrroles are for these 2-protonated species. The weak N- basicity of pyrroles is the consequence of the absence of mesomeric delocalization of charge in the 1H-pyrrolium cation.

The pKa values of a wide range of pyrroles have been determined: pyrrole itself is an extremely weak base with a pKa value of -3.8; this, as a 0.1 molar solution in normal acid, corresponds to only one protonated molecule to about 5000 unprotonated. However, basicity increases very rapidly with increasing alkyl substitution, so that 2,3,4,5-tetramethylpyrrole, with a pAa of +3.7, is almost completely protonated on carbon as a 0.1 molar solution in normal acid (cf. aniline, which has a pKa of +4.6). Thus alkyl groups have a striking stabilizing effect on cations isolable, crystalline salts can be obtained from pyrroles carrying t-butyl groups.

6.2.1.2 Nitration Nitrating mixtures suitable for benzenoid compounds cause complete decomposition of pyrrole, but reaction occurs smoothly with acetyl nitrate at low temperature, giving mainly 2- nitropyrrole. This nitrating agent is formed by mixing fuming nitric acid with acetic anhydride to form acetyl nitrate and acetic acid, thus removing the strong mineral acid. In the nitration of pyrrole with this reagent it has been shown that C-2 is 1.3  105 and C-3 is 3  104 times more reactive than benzene.

N-Substitution of pyrroles gives rise to increased proportions of β-substitution, even methyl causing the β:α ratio to change to 1:3, the much larger t-butyl actually reverses the relative positional reactivities, with a β:α ratio of 4:1, and the intrinsic α-reactivity can be effectively

49 50 completely blocked with a very large substituent such as a triisopropylsilyl (TIPS) group, especially useful since it can be subsequently easily removed.

6.2.1.3 Sulfonation For sulfonation, a mild reagent of low acidity must be used: the pyridine-sulfur trioxide compound smoothly converts pyrrole into the 2-sulfonate.

6.2.1.4 Halogenation Pyrrole halogenates so readily that unless controlled conditions are used, stable tetrahalopyrroles are the only isolable products. Attempts to monohalogenate simple alkylpyrroles fail, probably because of side-chain halogenation and the generation of extremely reactive pyrrylalkyl halides.

2-Bromo- and 2-chloropyrroles, unstable compounds, can be prepared by direct halogenation of pyrrole. Using 1,3-dibromo-5,5-dimethylhydantoin as brominating agent, both 2-bromo- and 2,5-dibromopyrroles can be obtained, the products stabilized by immediate conversion to their N-t-butoxycarbonyl derivatives. Conversely, bromination of N-Boc-pyrrole with N- bromosuccinimide gives the 2,5-dibromo derivative.

N-Triisopropylsilylpyrrole monobrominates and monoiodinatcs cleanly and nearly exclusively at C-3, and with two mol equivalents of N-bromosuccinimide dibrominates, at C-3 and C-4.

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6.2.1.5 Acylation Direct acetylation of pyrrole with acetic anhydride at 200°C leads to 2-acetylpyrrole as main product together with some 3-acetylpyrrole, but no N-acetylpyrrole. N-Acetylpyrrole can be obtained in high yield by heating pyrrole with N-acetylimidazole. Alkyl substitution facilitates C-acylation, so that 2,3,4-trimethyl-pyrrole yields the 5-acetyl derivative even on refluxing in acetic acid.

6.2.1.6 Alkylation Mono-C-alkylation of pyrroles cannot be achieved by direct reaction with simple alkyl halides either alone or with a Lewis acid catalyst, for example pyrrole does not react with methyl iodide below 100°C; above about 150°C a series of reactions occurs leading to a complex mixture made up mostly of polymeric material together with some poly-methylated pyrroles. The more reactive allyl bromide reacts with pyrrole at room temperature, but mixtures of mono- to tetrallylpyrroles together with oligomers and polymers are obtained.

6.2.1.7 Condensation with aldehydes and ketones Condensations of pyrroles with aldehydes and ketones occur easily by acid catalysis but the resulting pyrrolylcarbinols cannot usually be isolated, for under the reaction conditions proton-catalysed loss of water produces 2-alkylidenepyrrolium cations which are themselves highly reactive electrophiles. Thus, in the case of pyrrole itself, reaction with aliphatic aldehydes in acid inevitably leads to resins, probably linear polymers. Reductive trapping of these cationic intermediates produces alkylated pyrroles; all free positions react and as the example shows, acyl and alkoxycarbonyl substituents are unaffected. A mechanistically related process is the clean 4-chloromethylation of pyrroles carrying acyl groups at C-2.

Syntheses of dipyrromethanes have usually involved pyrroles with electron-withdrawing substituents and only one free α-position, the dipyrromethane resulting from attack by a second mol equivalent of the pyrrole on the 2-alkylidenepyrrolium intermediate.

51 52

However, conditions have been established for the production and isolation of bis(pyrrol-2-yl)methane itself from treatment of pyrrole with aqueous formalin in acetic acid; from reaction with formalin in the presence of potassium carbonate a bis-hydroxymethylation product is obtained. This reacts with pyrrole in dilute acid to give tripyrrane and from this, as the scheme shows, reaction with 2,5- bis(hydroxymethyl)pyrrole gives porphyrinogen which can be oxidised to porphyrin.

52 53 LESSON 9

NMR SPECTROSCOPY

1.1 INTRODUCTION TO 1H NMR SPECTROSCOPY

Nuclear magnetic resonance spectroscopy depends on the absorption of energy when the nucleus of an atom is excited from its lowest energy spin state to the next higher one. We should first point out that many elements are difficult to study by NMR, and some can't be studied at all. Fortunately though, the two elements that are the most common in organic molecules (carbon and hydrogen) have isotopes (1H and 13C) capable of giving NMR spectra that are rich in structural information. A proton nuclear magnetic resonance (1H NMR) spectrum tells us about the environments of the various hydrogens in a molecule; a carbon-13 nuclear magnetic resonance (13C NMR) spectrum does the same for the carbon atoms. Separately and together 1H and 13C NMR take us a long way toward determining a substance's molecular structure. We'll develop most of the general principles of NMR by discussing 1H NMR, then extend them to 13C NMR. The 13C NMR discussion is shorter, not because it is less important than 1H NMR, but because many of the same principles apply to both techniques. Like an electron, a proton has two spin states with quantum numbers of +½ and -½. There is no difference in energy between these two nuclear spin states; a proton is just as likely to have a spin of +½ as -½. Absorption of electromagnetic radiation can only occur when the two spin states have different energies. A way to make them different is to place the sample in a magnetic field. A spinning proton behaves like a tiny bar magnet and has a magnetic moment associated with it (Figure 1). In the presence of an external magnetic field H0, the spin state in which the magnetic moment of the nucleus is aligned with H0 is lower in energy than the one in which it opposes H0. As shown in Figure 2, the energy difference between the two states is directly proportional to the strength of the applied field. Net absorption of electromagnetic radiation requires that the lower state be more highly populated than the higher one, and quite strong magnetic fields are required to achieve the separation necessary to give a detectable signal.

FIGURE 1. (a) In the absence of an external magnetic field, the nuclear spins of the protons are randomly oriented. (b)

In the presence of an external magnetic field H0, the nuclear spins are oriented so that the resulting nuclear magnetic moments are aligned either parallel or antiparallel to H0. The lower energy orientation is the one parallel to H0, and more nuclei have this orientation.

A magnetic field of 4.7 T, which is about 100,000 times stronger than earth's magnetic field, for example,

53 54 separates the two spin states of 1H by only 8 × 10-5 kJ/mol (1.9 × 10-5 kcal/mol).

FIGURE 2. An external magnetic field causes the two nuclear spin states to have different energies. The difference in energy ΔE is proportional to the strength of the applied field.

From Planck's equation ΔE = hν, this energy gap corresponds to radiation having a frequency of 2 × 108 Hz (200 MHz), which lies in the radiofrequency (rf) region of the electromagnetic spectrum.

The response of an atom to the strength of the external magnetic field is different for different elements, and for different isotopes of the same element. The resonance frequencies of most nuclei are sufficiently different that an NMR experiment is sensitive only to a particular isotope of a single element. The frequency for 1H is 200 MHz at 4.7 T, but that of 13C is 50.4 MHz. Thus, when recording the NMR spectrum of an organic compound, we see signals only for 1H or 13C, but not both; 1H and 13C NMR spectra are recorded in separate experiments with different instrument settings. The essential features of an NMR spectrometer, shown in Figure 3, are not hard to understand. They consist of a magnet to align the nuclear spins, a radiofrequency (rf) transmitter as a source of energy to excite a nucleus from its lowest energy state to the next higher one, a receiver to detect the absorption of rf radiation, and a recorder to print out the spectrum. It turns out though that there are several possible variations on this general theme. We could, for example, keep the magnetic field constant and continuously vary the radiofrequency until it matched the energy difference between the nuclear spin states. Or, we could keep the rf constant and adjust the energy levels by varying the magnetic field strength. Both methods work, and the instruments based on them are called continuous wave (CW) spectrometers. Many of the terms we use in NMR spectroscopy have their origin in the way CW instruments operate, but CW instruments are rarely used anymore. CW-NMR spectrometers have been replaced by pulsed Fourier-transform nuclear magnetic resonance (FT-NMR) spectrometers. FT-NMR spectrometers are far more versatile than CW instruments and are more complicated. Most of the visible differences between them lie in computerized data acquisition and analysis components that are fundamental to FT-NMR spectroscopy. But there is an important difference in how a pulsed FT-NMR experiment is carried out as well. Rather than sweeping through a range of frequencies (or magnetic field strengths), the sample is placed in a magnetic field and irradiated with a short, intense burst of radiofrequency radiation (the pulse) that excites all of the protons in the molecule.

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FIGURE 3. Diagram of a nuclear magnetic resonance spectrometer.

The magnetic field associated with the new orientation of nuclear spins induces an electrical signal in the receiver that decreases with time as the nuclei return to their original orientation. The resulting free-induction decay (FID) is a composite of the decay patterns of all of the protons in the molecule. The FID pattern is stored in a computer and converted into a spectrum by a mathematical process known as a Fourier transform. The pulse-relaxation sequence takes only about a second, but usually gives signals too weak to distinguish from background noise. The signal-to-noise ratio is enhanced by repeating the sequence many times, then averaging the data. Noise is random and averaging causes it to vanish; signals always appear at the same place and accumulate. All of the operations - the interval between pulses, collecting, storing, and averaging the data and converting it to a spectrum by a Fourier transform - are under computer control, which makes the actual taking of an FT-NMR spectrum a fairly routine operation. Not only is pulsed FT-NMR the best method for obtaining proton spectra, it is the only practical method for many other nuclei, including 13C. It also makes possible a large number of sophisticated techniques that have revolutionized NMR spectroscopy.

1.2 NUCLEAR SHIELDING AND 1H CHEMICAL SHIFTS

Our discussion so far has concerned 1H nuclei in general without regard for the environments of individual protons in a molecule. Protons in a molecule are connected to other atoms - carbon, oxygen, nitrogen, and so on - by covalent bonds. The electrons in these bonds, indeed all the electrons in a molecule, affect the magnetic environment of the protons. Alone, a proton would feel the full strength of the external field, but a proton in an organic molecule responds to both the external field plus any local fields within the molecule. An external magnetic field affects the motion of the electrons in a molecule, inducing local fields characterized by lines of force that circulate in the opposite direction from the applied field (Figure 4).

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FIGURE 4. The induced magnetic field of the electrons in the carbon-hydrogen bond opposes the external magnetic

field. The resulting magnetic field experienced by the proton and the carbon is slightly less than H0.

Thus, the net field felt by a proton in a molecule will always be less than the applied field, and the proton is said to be shielded. All of the protons of a molecule are shielded from the applied field by the electrons, but some are less shielded than others. Sometimes the term deshielded is used to describe this decreased shielding of one proton relative to another. The more shielded a proton is, the greater must be the strength of the applied field in order to achieve resonance and produce a signal. A more shielded proton absorbs rf radiation at higher field strength (upfield) compared with one at lower field strength (downfield).

1 FIGURE 5. The 200-MHz H NMR spectrum of chloroform (HCCl3). Chemical shifts are measured along the x-axis in parts per million (ppm) from tetramethylsilane as the reference, which is assigned a value of zero.

Different protons give signals at different field strengths. The dependence of the resonance position of a nucleus that results from its molecular environment is called its chemical shift. This is where the real power of NMR lies. The chemical shifts of various protons in a molecule can be different and are characteristic of particular structural features. 1 Figure 5 shows the H NMR spectrum of chloroform (CHCl3) to illustrate how the terminology just developed applies to a real spectrum. Instead of measuring chemical shifts in absolute terms, we measure them with respect to a standard - tetramethylsilane (CH3)4Si, abbreviated TMS. The protons of TMS are more shielded than those of most organic compounds, so all of the signals in a sample ordinarily appear at lower field than those of the TMS reference. When measured using a 100-MHz instrument, the

56 57 signal for the proton in chloroform (CHCl3), for example, appears 728 Hz downfield from the TMS signal. But because frequency is proportional to magnetic field strength, the same signal would appear 1456 Hz downfield from TMS on a 200-MHz instrument. We simplify the reporting of chemical shifts by converting them to parts per million (ppm) downfield from TMS, which is assigned a value of 0. The TMS need not actually be present in the sample, nor even appear in the spectrum in order to serve as a reference. When chemical shifts are reported this way, they are identified by the symbol δ and are independent of the field strength.

Thus, the chemical shift for the proton in chloroform is:

1.3 EFFECTS OF MOLECULAR STRUCTURE ON 1H CHEMICAL SHIFTS

Nuclear magnetic resonance spectroscopy is such a powerful tool for structure determination because protons in different environments experience different degrees of shielding and have different chemical shifts. In compounds of the type CH3X, for example, the shielding of the methyl protons increases as X becomes less electronegative. In as much as the shielding is due to the electrons, it isn't surprising to find that the chemical shift depends on the degree to which X draws electrons away from the methyl group.

PROBLEM 2. Identify the most shielded and least shielded protons in

(a) 2-Bromobutane; (b) 1,1,2-Trichloropropane; (c) Tetrahydrofuran.

SAMPLE SOLUTION (a) Bromine is electronegative and will have its greatest electron-withdrawing effect on protons that are separated from it by the fewest bonds. Therefore, the proton at C-2 will be the least shielded, and those at C-4 the most shielded.

The observed chemical shifts are δ 4.1 for the proton at C-2 and δ 1.1 for the protons at C-4. The protons at C-1 and C-3 appear in the range δ 1.7-2.0.

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Table 1 collects chemical-shift information for protons of various types. The beginning and major portion of the table concerns protons bonded to carbon. Within each type, methyl (CH3) protons are more shielded than methylene

(CH2) protons, and methylene protons are more shielded than methine (CH) protons. These differences are small as the following two examples illustrate.

TABLE 1. Approximate Chemical Shifts of Representative Protons

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With the additional information that the chemical shift of methane is δ 0.2, we can attribute the decreased shielding of the protons of RCH3, R2CH2, and R3CH to the number of carbons attached to primary, secondary, and

59 60 tertiary carbons. Carbon is more electronegative than hydrogen, so replacing the hydrogens of CH4 by one, then two, then three carbons decreases the shielding of the remaining protons. Likewise, the generalization that sp2-hybridized carbon is more electronegative than sp3-hybridized carbon is consistent with the decreased shielding of allylic and benzylic protons.

Hydrogens that are directly attached to double bonds (vinylic protons) or to aromatic rings (aryl protons) are especially deshielded.

The main reason for the deshielded nature of vinylic and aryl protons is related to the induced magnetic fields associated with π electrons. We saw earlier that the local field resulting from electrons in a C-H  bond opposes the applied field and shields a molecule's protons. The hydrogens of ethylene and benzene, however, lie in a region of the molecule where the induced magnetic field of the π electrons reinforces the applied field, deshielding the protons (Figure 6). In the case of benzene, this is described as a ring current effect that originates in the circulating π electrons.

PROBLEM 3. Assign the chemical shifts δ 1.6, δ 2.2, and δ 4.8 to the appropriate protons of methylenecyclopentane

Acetylenic hydrogens are unusual in that they are more shielded than we would expect for protons bonded to sp-hybridized carbon. This is because the π electrons circulate around the triple bond, not along it (Figure 7a). Therefore, the induced magnetic field is parallel to the long axis of the triple bond and shields the acetylenic proton (Figure 7b). Acetylenic protons typically have chemical shifts near δ 2.5.

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FIGURE 6. The induced magnetic field of the w electrons of (a) an alkene and (b) an arene reinforces the applied field in the regions where vinyl and aryl protons are located.

The induced field of a carbonyl group (C=O) deshields protons in much the same way that a carbon-carbon double bond does, and the presence of oxygen makes it even more electron withdrawing. Thus, protons attached to C=O in aldehydes are the least shielded of any protons bonded to carbon. They have chemical shifts in the range δ 9-10.

FIGURE 7. (a) The π electrons of acetylene circulate in a region surrounding the long axis of the molecule. (b) The induced magnetic field associated with the π electrons opposes the applied field and shields the protons.

Protons on carbons adjacent to a carbonyl group are deshielded slightly more than allylic hydrogens.

PROBLEM 4. Assign the chemical shifts δ 1.1, δ 1.7, δ 2.0, and δ 2.3 to the appropriate protons of 2-pentanone.

The second portion of Table 1 deals with O-H and N-H protons. As the table indicates, the chemical shifts of these vary much more than for protons bonded to carbon. This is because O-H and N-H groups can be involved in intermolecular hydrogen bonding, the extent of which depends on molecular structure, temperature, concentration, and solvent. Generally, an increase in hydrogen bonding decreases the shielding. This is especially evident in carboxylic acids. With

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δ values in the 10-12 ppm range, O-H protons of carboxylic acids are the least shielded of all of the protons in Table 1. We should point out here, that hydrogen bonding in carboxylic acids is stronger than in most other classes of compounds that contain O-H groups.

1.4 INTERPRETING 1H NMR SPECTRA

Analyzing an NMR spectrum in terms of a unique molecular structure begins with the information contained in Table 1. By knowing the chemical shifts characteristic of various proton environments, the presence of a particular structural unit in an unknown compound may be inferred. An NMR spectrum also provides other useful information, including: 1. The number of signals, which tells us how many different kinds of protons there are. 2. The intensity of the signals as measured by the area under each peak, which tells us the relative ratios of the different kinds of protons. 3. The multiplicity, or splitting, of each signal, which tells us how many protons are vicinal to the one giving the signal. Protons that have different chemical shifts are said to be chemical-shift-nonequivalent (or chemically nonequivalent). A separate NMR signal is given for each chemical-shift-nonequivalent proton in a substance. Figure 8 1 shows the 200-MHz H NMR spectrum of methoxyacetonitrile (CH3OCH2CN), a molecule with protons in two different environments. The three protons in the CH3O group constitute one set, the two protons in the OCH2CN group the other. These two sets of protons give rise to the two peaks that we see in the NMR spectrum and can be assigned on the basis of their chemical shifts. The protons in the OCH2CN group are connected to a carbon that bears two electronegative substituents (O and C≡N) and are less shielded than those of the CH3O group, which are attached to a carbon that bears only one electronegative atom (O). The signal for the protons in the OCH2CN group appears at δ 4.1; the signal corresponding to the CH3O protons is at δ 3.3.

Another way to assign the peaks is by comparing their intensities. The three equivalent protons of the CH3O group give rise to a more intense peak than the two equivalent protons of the OCH2CN group. This is clear by simply comparing the heights of the peaks in the spectrum. It is better, though, to compare peak areas by a process called integration. This is done electronically at the time the NMR spectrum is recorded, and the integrated areas are displayed on the computer screen or printed out. Peak areas are proportional to the number of equivalent protons responsible for that signal.

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1 FIGURE 8. The 200-MHz H NMR spectrum of methoxyacetonitrile (CH3OCH2CN).

It is important to remember that integration of peak areas gives relative, not absolute, proton counts. Thus, a 3:2 ratio of areas can, as in the case of CH3OCH2CN, correspond to a 3:2 ratio of protons. But in some other compound a 3:2 ratio of areas might correspond to a 6:4 or 9:6 ratio of protons.

1 PROBLEM 6. The 200-MHz H NMR spectrum of 1,4-dimethylbenzene looks exactly like that of CH3OCH2CN except the chemical shifts of the two peaks are δ 2.2 and δ 7.0. Assign the peaks to the appropriate protons of 1,4- dimethylbenzene.

Protons are equivalent to one another and have the same chemical shift when they are in equivalent environments. Often it is an easy matter to decide, simply by inspection, when protons are equivalent or not. In more difficult cases, mentally replacing a proton in a molecule by a "test group" can help. We'll illustrate the procedure for a simple case - the protons of propane. To see if they have the same chemical shift, replace one of the methyl protons at C-1 by chlorine, then do the same thing for a proton at C-3. Both replacements give the same molecule, 1- chloropropane. Therefore the methyl protons at C-1 are equivalent to those at C-3.

If the two structures produced by mental replacement of two different hydrogens in a molecule by a test group are the same, the hydrogens are chemically equivalent. Thus, the six methyl protons of propane are all chemically equivalent to one another and have the same chemical shift. Replacement of either one of the methylene protons of propane generates 2-chloro-propane. Both methylene protons are equivalent. Neither of them is equivalent to any of the methyl protons. The 1H NMR spectrum of propane contains two signals: one for the six equivalent methyl protons, the other for the pair of equivalent methylene protons.

63 64

PROBLEM 7. How many signals would you expect to find in the 1H NMR spectrum of each of the following compounds? (a) 1-Bromobutane (e) 2,2-Dibromobutane (b) 1-Butanol (f) 2,2,3,3-Tetrabromobutane (c) Butane (g) 1,1,4-Tribromobutane (d) 1,4-Dibromobutane (h) 1,1,1-Tribromobutane

SAMPLE SOLUTION (a) To test for chemical-shift equivalence, replace the protons at C-1, C-2, C-3, and C-4 of 1-bromobutane by some test group such as chlorine. Four constitutional isomers result:

Thus, separate signals will be seen for the protons at C-1, C-2, C-3, and C-4. Barring any accidental overlap, we expect to find four signals in the NMR spectrum of 1-bromobutane.

Chemical-shift nonequivalence can occur when two environments are stereochemically different. The two vinyl protons of 2-bromopropene have different chemical shifts.

One of the vinyl protons is cis to bromine; the other trans. Replacing one of the vinyl protons by some test group, say, chlorine, gives the Z isomer of 2-bromo-l-chloro-propene; replacing the other gives the E stereoisomer. The E and Z forms of 2-bromo-1-chloropropene are diastereomers. Protons that yield diastereomers on being replaced by some test group are described as diastereotopic and can have different chemical shifts. Because their environments are similar, however, the chemical shift difference is usually small, and it sometimes happens that two diastereotopic protons accidentally have the same chemical shift. Recording the spectrum on a higher field NMR spectrometer is often helpful in resolving signals with similar chemical shifts.

PROBLEM 8. How many signals would you expect to find in the 1H NMR spectrum of each of the following compounds? (a) Vinyl bromide (b) 1,1-Dibromoethene (c) cis-l,2-Dibromoethene (e) Allyl bromide (d) trans-l,2-Dibromoethene (f) 2-Methyl-2-butene

SAMPLE SOLUTION (a) Each proton of vinyl bromide is unique and has a chemical shift different from the other two. The least shielded proton is attached to the carbon that bears the bromine. The pair of protons at C-2 are diastereotopic with respect to each other; one is cis to bromine and the other is trans to bromine. There are three proton signals in the NMR spectrum of vinyl bromide. Their observed chemical shifts are as indicated.

When enantiomers are generated by replacing first one proton and then another by a test group, the pair of protons are enantiotopic. The methylene protons at C-2 of 1-propanol, for example, are enantiotopic.

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Replacing one of these protons by chlorine as a test group gives (R)-2-chloro-1-propanol; replacing the other gives (S)-2-chloro-l-propanol. Enantiotopic protons have the same chemical shift, regardless of the field strength of the NMR spectrometer. At the beginning of this section we noted that an NMR spectrum provides structural information based on chemical shift, the number of peaks, their relative areas, and the multiplicity, or splitting, of the peaks. We have discussed the first three of these features of 1H NMR spectroscopy. Let's now turn our attention to peak splitting to see what kind of information it offers.

1.5 SPIN-SPIN SPLITTING IN 1H NMR SPECTROSCOPY

1 The H NMR spectrum of CH3OCH2CN (see Figure 8) discussed in the preceding section is relatively simple because both signals are singlets; that is, each one consists of a single peak. It is quite common though to see a signal for a particular proton appear not as a singlet, but as a collection of peaks. The signal may be split into two peaks (a doublet), three peaks (a triplet), four peaks (a quartet), or even more. Figure 9 shows the 1H NMR spectrum of 1,1- dichloroethane (CH3CHCl2), which is characterized by a doublet centered at δ 2.1 for the methyl protons and a quartet at δ 5.9 for the methine proton. The number of peaks into which the signal for a particular proton is split is called its multiplicity. For simple cases the rule that allows us to predict splitting in 1H NMR spectroscopy is

Multiplicity of signal for Ha = n + 1

where n is equal to the number of equivalent protons that are vicinal to Ha. Two protons are vicinal to each other when they are bonded to adjacent atoms.

Protons vicinal to Ha are separated from Ha by three bonds. The three methyl protons of 1,1-dichloroethane are vicinal to the methine proton and split its signal into a quartet. The single methine proton, in turn, splits the methyl protons' signal into a doublet.

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1 FIGURE 9. The 200-MHz H NMR spectrum of 1,1-dichloroethane (Cl2CHCH3), showing the methine proton as a quartet and the methyl protons as a doublet. The peak multiplicities are seen more clearly in the scale-expanded insets.

The physical basis for peak splitting in 1,1-dichloroethane can be explained with the aid of Figure 10, which examines how the chemical shift of the methyl protons is affected by the spin of the methine proton. There are two magnetic environments for the methyl protons: one in which the magnetic moment of the methine proton is parallel to the applied field, and the other in which it is antiparallel to it.

FIGURE 10. The magnetic moments of the two possible spin states of the methine proton affect the chemical shift of the

methyl protons in 1,1- dichloroethane. When the magnetic moment is parallel to the external field H0, it adds to the

external field and a smaller H0 is needed for resonance. When it is antiparallel to the external field, it subtracts from it and shields the methyl protons.

When the magnetic moment of the methine proton is parallel to the applied field, it reinforces it. This decreases the shielding of the methyl protons and causes their signal to appear at slightly lower field strength. Conversely, when

66 67 the magnetic moment of the methine proton is antiparallel to the applied field, it opposes it and increases the shielding of the methyl protons. Instead of a single peak for the methyl protons, there are two of approximately equal intensity: one at slightly higher field than the "true" chemical shift, the other at slightly lower field. Turning now to the methine proton, its signal is split by the methyl protons into a quartet. The same kind of analysis applies here and is outlined in Figure 11. The methine proton "sees" eight different combinations of nuclear spins for the methyl protons. In one combination, the magnetic moments of all three methyl protons reinforce the applied field. At the other extreme, the magnetic moments of all three methyl protons oppose the applied field. There are three combinations in which the magnetic moments of two methyl protons reinforce the applied field, whereas one opposes it. Finally, there are three combinations in which the magnetic moments of two methyl protons oppose the applied field and one reinforces it. These eight possible combinations give rise to four distinct peaks for the methine proton, with a ratio of intensities of 1:3:3:1. We describe the observed splitting of NMR signals as spin-spin splitting and the physical basis for it as spin-spin coupling. It has its origin in the communication of nuclear spin information via the electrons in the bonds that intervene between the nuclei. Its effect is greatest when the number of bonds is small. Vicinal protons are separated by three bonds, and coupling between vicinal protons, as in 1,1-dichloroethane, is called three-bond coupling or vicinal coupling. Four-bond couplings are weaker and not normally observable. A very important characteristic of spin-spin splitting is that protons that have the same chemical shift do not split each other's signal. Ethane, for example, shows only a single sharp peak in its NMR spectrum. Even though there is a vicinal relationship between the protons of one methyl group and those of the other, they do not split each other's signal because they are equivalent.

FIGURE 11. The methyl protons of 1,1-dichloroethane split the signal of the methine proton into a quartet.

PROBLEM 9. Describe the appearance of the 1H NMR spectrum of each of the following compounds. How many signals would you expect to find, and into how many peaks will each signal be split? (a) 1,2-Dichloroethane (c) 1,1,2-Trichloroethane (e) 1,1,1,2-Tetrachloropropane (b) 1,1,1-Trichloroethane (d) 1,2,2-Trichloropropane

SAMPLE SOLUTION (a) All the protons of 1,2-dichloroethane (ClCH2CH2Cl) are chemically equivalent and have the same chemical shift. Protons that have the same chemical shift do not split each other's signal, and so the NMR spectrum of 1,2-dichloroethane consists of a single sharp peak.• Coupling of nuclear spins requires that the nuclei split each other's signal equally. The separation between the two halves of the methyl doublet in 1,1-dichloroethane is equal to the separation between any two adjacent peaks of the methine quartet. The extent to which two nuclei are coupled is given by the coupling constant J and in simple cases is 3 equal to the separation between adjacent lines of the signal of a particular proton. The three-bond coupling constant Jab

67 68 in 1,1-dichloroethane has a value of 7 Hz. The size of the coupling constant is independent of the field strength; the separation between adjacent peaks in 1,1-dichloroethane is 7 Hz, irrespective of whether the spectrum is recorded at 200 MHz or 500 MHz.

1.6 SPLITTING PATTERNS: THE ETHYL GROUP

At first glance, splitting may seem to complicate the interpretation of NMR spectra. In fact, it makes structure determination easier because it provides additional information. It tells us how many protons are vicinal to a proton responsible for a particular signal. With practice, we learn to pick out characteristic patterns of peaks, associating them with particular structural types. One of the most common of these patterns is that of the ethyl group, represented in the

NMR spectrum of ethyl bromide in Figure 12. In compounds of the type CH3CH2X, especially where X is an electronegative atom or group, such as bromine in ethyl bromide, the ethyl group appears as a triplet-quartet pattern.

1 FIGURE 12 The 200-MHz H NMR spectrum of ethyl bromide (BrCH2CH3), showing the characteristic triplet-quartet pattern of an ethyl group. The small peak at δ 1.6 is an impurity. The signal for the methylene protons is split into a quartet by coupling with the methyl protons. The signal for the methyl protons is a triplet because of vicinal coupling to the two protons of the adjacent methylene group.

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We have discussed in the preceding section why methyl groups split the signals due to vicinal protons into a quartet. Splitting by a methylene group gives a triplet corresponding to the spin combinations shown in Figure 13 for ethyl bromide. The relative intensities of the peaks of this triplet are 1:2:1.

FIGURE 13. The methylene protons of ethyl bromide split the signal of the methyl protons into a triplet.

PROBLEM 10. Describe the appearance of 1H NMR spectrum of each of the following compounds. How many signals would you expect to find, and into how many peakswill each signal be split?

(a) ClCH2OCH2CH3 (d) p-Diethylbenzene (e) ClCH2CH2OCH2CH3

(b) CH3CH2OCH3 (c) CH3CH2OCH2CH3

SAMPLE SOLUTION (a) Along with the triplet-quartet pattern of the ethyl group, the NMR spectrum of this compound will contain a singlet for the two protons of the chloromethyl group.

Table 2 summarizes the splitting patterns and peak intensities expected for coupling to various numbers of protons.

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Table 2. Splitting Patterns of Common Multiplets (The intensities correspond to the coefficients of a binomial expansion (Pascal's triangle)

1.7 SPLITTING PATTERNS: THE ISOPROPYL GROUP

The NMR spectrum of isopropyl chloride (Figure 14) illustrates the appearance of an isopropyl group. The signal for the six equivalent methyl protons at δ 1.5 is split into a doublet by the proton of the H-C-Cl unit. In turn, the H-C-Cl proton signal at δ 4.2 is split into a septet by the six methyl protons. A doublet-septet pattern is characteristic of an isopropyl group.

FIGURE 14. The 200-MHz 1H NMR spectrum of isopropyl chloride, showing the doublet-septet pattern of an isopropyl group 1.8 SPLITTING PATTERNS: PAIRS OF DOUBLETS

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We often see splitting patterns in which the intensities of the individual peaks do not match those given in Table 2, but are distorted in that the signals for coupled protons "lean" toward each other. This leaning is a general phenomenon, but is most easily illustrated for the case of two nonequivalent vicinal protons as shown in Figure 15.

The appearance of the splitting pattern of protons 1 and 2 depends on their coupling constant J and the chemical shift difference Δν between them. When the ratio Δν/J is large, two symmetrical 1:1 doublets are observed. We refer to this as the "AX" case, using two letters that are remote in the alphabet to stand for signals well removed from each other on the spectrum. Keeping the coupling constant the same while reducing Δv leads to a steady decrease in the intensity of the outer two peaks with a simultaneous increase in the inner two as we progress from AX through AM to AB.

FIGURE 15. The appearance of the splitting pattern of two coupled protons depends on their coupling constant J and the chemical shift difference Δν between them. As the ratio Δν/J decreases, the doublets become increasingly distorted. When the two protons have the same chemical shift, no splitting is observed.

At the extreme (A2), the two protons have the same chemical shift, the outermost lines have disappeared, and no splitting is observed. Because of its appearance, it is easy to misinterpret an AB or AM pattern as a quartet, rather than the pair of skewed doublets it really is.

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FIGURE 16. The 200-MHz 1H NMR spectrum of 2,3,4-trichloroanisole, showing the splitting of the ring protons into a pair of doublets that "lean" toward each other.

A skewed doublet of doublets is clearly visible in the 1H NMR spectrum of 2,3,4-trichloroanisole (Figure 16). In addition to the singlet at δ 3.9 for the protons of the -OCH3 group, we see doublets at δ 6.8 and δ 7.3 for the two protons of the aromatic ring.

A similar pattern can occur with geminal protons (protons bonded to the same carbon). Geminal protons are separated by two bonds, and geminal coupling is referred to as two-bond coupling (2J) in the same way that vicinal coupling is referred to as three-bond coupling (3J). An example of geminal coupling is provided by the compound 1-chloro-1- cyanoethene, in which the two hydrogens appear as a pair of doublets. The splitting in each doublet is 2 Hz. Splitting due to geminal coupling is seen only in CH2 groups and only when the two protons have different chemical shifts. All three protons of a methyl (CH3) group are equivalent and cannot split one another's signal, and, of course, there are no protons geminal to a single methine (CH) proton.

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1.9 1H NMR SPECTRA OF ALCOHOLS

The -OH proton of a primary alcohol RCH2OH is vicinal to two protons, and its signal would be expected to be split into a triplet. Under certain conditions signal splitting of alcohol protons is observed, but usually it is not. Figure 17 presents the NMR spectrum of benzyl alcohol, showing the methylene and hydroxyl protons as singlets at δ 4.7 and 2.5, respectively. (The aromatic protons also appear as a singlet, but that is because they all accidentally have the same chemical shift and so cannot split each other.) The reason that splitting of the hydroxyl proton of an alcohol is not observed is that it is involved in rapid exchange reactions with other alcohol molecules. Transfer of a proton from an oxygen of one alcohol molecule to the oxygen of another is quite fast and effectively decouples it from other protons in the molecule. Factors that slow down this exchange of OH protons, such as diluting the solution, lowering the temperature, or increasing the crowding around the OH group, can cause splitting of hydroxyl resonances. The chemical shift of the hydroxyl proton is variable, with a range of δ 0.5-5, depending on the solvent, the temperature at which the spectrum is recorded, and the concentration of the solution. The alcohol proton shifts to lower field in more concentrated solutions.

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LESSON 10 Synthesis of aromatic heterocycles

The preparation of benzenoid compounds nearly always begins with an appropriately substituted, and often readily available, benzene derivative - only on very rare occasions is it necessary to start from compounds lacking the ring, and to form it during the synthesis. The preparation of heteroaromatic compounds presents a very different picture, for it involves ring synthesis more often than not. Of course when first considering a suitable route to a desired target, it is always important to give thought to the possibility of utilizing a commercially available compound which contains the heterocyclic nucleus and which could be modified by manipulation, introduction and/or elimination of substituents. This chapter shows how just a few general principles allow one to understand the methods, at first sight apparently diverse, which are used in the construction of the heterocyclic ring of an aromatic heterocyclic compound from precursors which do not have that ring. It discusses the principles, and analyses the types of reaction frequently used in constructing an aromatic heterocycle, and also the way in which appropriate functional groups are placed, in the reactants, in order to achieve the desired ring synthesis.

4.1 Reaction types most frequently used in heterocyclic ring synthesis By far the most frequently used process is the addition of a nucleophile to a carbonyl carbon (or the more reactive carbon of an O-protonated carbonyl). When the reaction leads to C-C bond formation, then the nucleophile is the β-carbon of an enol or enolate anion, or of an enamine, and the reaction is aldol in type:

When the process leads to C-heteroatom bond formation, then the nucleophile is an appropriate heteroatom, either anionic (-X-) or neutral (-XH):

In all cases, subsequent loss of water produces a double bond, either a C-C or a C- heteroatom double bond. Simple examples are the formation of an aldol condensation product, and the formation of an imine or enamine, respectively.

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These two basic processes, with minor variants, cover the majority of the steps involved in classical heteroaromatic ring synthesis. In a few instances, displacements of halide, or other leaving groups, from saturated carbon are also involved.

4.2 Typical reactant combinations Although there are some examples of nearly all possible retrosynthetic dissections and synthetic recombinations of five- and six-membered heterocycles, yet by far the majority of ring syntheses fall into two categories; in the first, for each ring size, only C-heteroatom bonding is needed i.e. the rest of the skeleton is present intact in one starting component; in the second, for each ring size, one C-C bond and one C-hetero atom linkage are required.

4.2.1 We can now look at more specific examples, and see how the principles above can lead to the aromatic heterocycles. In the first of the two broad categories, where only C-hetero atom bonds are needed, and for the synthesis of five-membered heterocycles, precursors with two carbonyl groups related 1,4 are required; 1,4- diketones, for example react with ammonia or primary amines to give 2,5-disubstituted pyrroles.

For six-membered rings, the corresponding 1,5-dicarbonyl precursor has to contain a C-C double bond in order to lead directly to the aromatic system (though it is relatively easy to dehydrogenate the dihydro- heterocycle which is comparably obtained if a saturated 1,5-dicarbonyl compound is employed).

4.2.2 In the second broad category, needing both C-C and C-hetero atom links to be made, one component must contain an enol/enolate/enamine, or the equivalent thereof, while the second obviously must have electrophilic centres to match. The following generalised combinations show how this works out for the two ring sizes.

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Note: (1) The R substituent shown in the last two of these schemes must be an acidifying group: ketone, ester, nitrile, or occasionally, nitro. (2) Some of the components shown in these examples have two electrophilic centres and some have a nucleophilic and an electrophilic centre; in other situations components with two nucleophilic centers are required. In general, components in which the two reacting centers are either 1,2- or 1,3-related are utilized most often in heterocyclic synthesis, but 1,4- (e.g. HX-C-C-YH) (X and Y are heteroatoms) and 1,5-related (e.g.

O=C-(C)3-C=O) bifunctional components, and also reactants which provide one-carbon units (phosgene,

C12C=O, or a safer equivalent) are also important. Amongst many examples of 1,2-difunctionalised compounds are 1,2-dicarbonyl compounds, enols (which first react in a nucleophilic sense at carbon and then provide an electrophilic centre (the carbonyl carbon), Hal-C-C=O, and systems with HX-YH units. Amongst often used 1,3-difunctionalised compounds are the doubly electrophilic 1,3-dicarbonyl compounds and α,β-unsaturated carbonyl compounds (C=C-C=O), doubly nucleophilic HX-C-YH (amidines and ureas are examples), and α- amino- or α-hydroxycarbonyl compounds (HX-C-C=O), which have an electrophilic and a nucleophilic centre. (3) The exact sequence of nucleophilic additions, deprotonations/protonations, and dehydrations is never known with certainty, but the sequences shown are the most reasonable ones; the exact order of steps almost certainly varies with conditions, particularly pH. (4) When a carbonyl component (an amide) is used then the resultant product carries an oxygen substituent at that carbon (pyridone in the example). Similarly, if a nitrile group is used instead of a carbonyl group, as an electrophilic centre, then the resulting heterocycle carries an amino group at that carbon, thus:

The two nucleophilic centres can both be heteroatoms, as in syntheses of pyrimidines and pyrazoles.

In syntheses of benzanellated systems, phenols can take the part of enols, and anilines react in the same way as enamines.

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4.3 Summary The chemical steps involved in heteroaromatic synthesis are mostly simple and straightforward, even though a first look at the structures of starting materials and product might make the overall effect seem almost alchemical. In devising a sequence of sensible steps it is important to avoid obvious pitfalls, like suggesting that electrophile react with electrophilic centre, or nucleophile with a source of electrons, but this aside it should be easy enough to devise a sensible scheme.

A complete step-by-step analysis of the reaction of 1,3-diphenylpropane-1,3-dione with acetophenone is presented below - note that many individual steps are involved but that each of them is very simple when considered separately.

The sequence shows an initiating step as nucleophilic attack by acetophenone enol on the protonated diketone, however an equally plausible sequence, shown below, starts with the nucleophilic addition of the enolic hydroxyl of the diketone to protonated acetophenone.

A final point to be made is that most of the steps in such sequences are reversible; the overall sequence proceeds to product nearly always because the product is the thermodynamically most stable molecule in the sequence, or because the product is removed from the equilibria by distillation or crystallization.

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LESSON 11 INTRODUCTION ,,Organic synthesis,, means, that the problem of this field is the construction the organic molecules. Why? From what? How? It is easy to answer the question from what? This is obvious, that from more simple molecules. Very often we understand ,,More simple,, as more available. Available natural resources for organic compounds are fossil organic raw materials: oil, gas, coal and living organisms. Composition of their processing determines the spectrum of the compounds, which may be synthesized on this base. For example polyethylene is a result of the big industry because its’ synthesis implemented from the inexpensive raw materials due to the polymerization of ethylene. Chemistry of aromatic compounds is the largest field of industrial and laboratory chemistry (polymers, drugs...), which is based on the fact, that the aromatic ring, which is the base of all aromatic compounds, contained in natural hydrocarbons and we get it in large quantities from petroleum and coal. Viscose and acetate filament, nitrocellulose, glucose and ethanol are the substances, which we obtain from polysaccharides, that are the widely common groups of organic substances. Very important the synthesis of the medications: vitamins, hormones, antibiotics, which is possibly due to the separation from the alive organisms and presence of primary natural raw materials. It is easy to define the structural elements in the molecules of polyethylene and phenol, that are accord to the initial obtainable compounds and to construct logical scheme. But it is not so easy to define the fragment in the target compound, which can show the nature of initial compound for synthesis. And that is why it is important to answer the question ,,How,,. And it becomes clear that the problem is not limited to availability of initial compound or of structural similarity. For example it is very winning to obtain the acetic acid form the available products methane and carbon dioxide: CH4+CO2=CH3COOH But this reaction doesn’t go because ∆G>0. But there is the other way to realize this process. The power of organic synthesis is that it is based on the knowledge of rules of the process of organic synthesis’ reactions. And this is the general tools for chemist-synthetic. In the chemical reaction the certain chemical bonds are break and the other are formed. This provides the possibility of organic synthesis. That is why one of the main problems of synthetic is the selection of the real reaction, which is suitable for the formation of the bond in the given place in molecule. In one reaction the limited chemical bonds are changed. That is why the construction of complex molecules goes step by step from the simple molecules. So the all process of synthesis we should divide into stages, sometimes into a big amount of stages each of which serves for

78 79 creation of certain bonds in the given fragment. It is rarely that these reactions are the same. Often the way of synthesis of the complex compound consists of the stages that are differ in the chemistry. And realization each of these stages is the separate problem. It is also possible to synthesise the same product by the different ways that require the different initial products and the different nature of the reaction. Therefore the more difficult problem for synthetic is to work out the optimal plan for synthesis. 1. THE AIMS OF ORGANIC SYNTHESIS 1.1. The aim is unambiguous and indisputable. Since ancient times the humanity has been obtaining the colors from the plant and animals. In XIII century BC has got the indigoid paint. To separate 1g of this paint it was necessary to 10000 of plants. It was a long process and that is why these paint was ten times more expensive than gold. In the ancient Rome getting this paint was secret and it was allowed to wear the clothes in this color only for kings. This secret was kept till the XX century, when the new science- organic synthesis was created. At that time was clear that the components of this paint were the chemical compounds indigo and 6,6-dibrome indigo. Bayer worked out not expensive method of synthesis in 1878, which was suitable for the industrial obtaining of indigo from the available initial products. At the same time was known a new paint alizarin. Alizarin was separated from the roots of tinktoria (Rubia tinktoria). This plant was used as a natural paint from the ancient times. First it was very expensive pant. But it became cheap when Greben and Liberman offered very simple method of synthesis of alizarin from anthracene, which is obtained from the coal tar. Such acquisitions made a great impression on the people. ,, The creed,, or ,,The thread of life,, in molecular biology is the DNA. The structure of this molecule was offered by Wotson and Crick in 1953. Since that time professor Koran has an aim to synthesize the DNA. This aim was realized after 20 years of hard work of a big collective, when was synthesized a fragment of DNA which encodes tyrosine transporting RNA. Vitamin C, ascorbic acid is very important vitamins. It was a time, when humanity had a problem like a deficient this vitamin in the food. At that time more sailors were died then from other wars and natural phenomena. Confirmation of structure of ascorbic acid, then laboratory and industrial synthesis of it from D-glucose made vitamin C a cheap product and disappeared the threat of scurvy disease. First the prostaglandins were separated and were described in XX century. These compounds are very important that are contained in mammalian tissues and have a big role in the function of such important systems like cardiovascular system, respiratory system, alimentary system. Prostaglandins (PG) are formed in organism in microscopic amounts. In the body of adult only 1mg of PG are formed in a day. It is very limited the chances of separation the PG from the natural sources. And also such kind of compounds are very unstable which make difficult the separation, identification and study of properties. That is why it was obvious to work out the

79 80 methods and ways of synthesis PG and many laboratories in the world started their experiments. During the short time the scientists have synthesized the natural PG and the synthetic analogs of it. ,,Does a tree costs human life?,, it was a article title in the magazine ,,Newsweek,, (5.09.1991). It was about the tissa. This plant contains very complex molecule - taxol. Taxol has passed the clinical trials and become the most perspective drug in the treatment of breast and uterus cancer. There are 45000 women are died from breast cancer and 12000 from uterus cancer in USA every year. They need 3 100-year trees for the treatment of one patient. From these three trees we obtain 25kg bark, and from this bark only a little amount (several mg) of taxol. Only for the clinical trials the Bristol-Mayers company needed 25kg taxol (it means 38000 trees). And this tree threatended destruction. And that is why the scientist started to search the ways for synthesis this product or to find the other natural sources for separation taxol. Now we know that tiss is not the only source from which we obtain taxol. There are going an intensive researches for the taxol synthesis. There are many successes in the field of organ transplantation. It was possibly due to the mastery of doctors. But it was impossible without the synthesis of immunomodulators. It is not difficult to note other examples that show the contribution of organic synthesis in the creation the modern civilization. 1.2. The aim is unambiguous but is not indisputable. During the history of the organic synthesis the scientists wanted to synthesize the different compounds which were separated from the living organisms even when they haven’t seen the connection between the real or potential usefulness. It is very important tradition, trend and during the last ten years it has become stronger. If it was needed many years for the realization of synthesis before, now the difference between the detecting a new natural compound and its’ synthesis is a several years or even months. There is no need to ask why we synthesize these compounds, what is the meaning of its’ obtaining. The aim is unambiguous but is not indisputable is very approximately. Even if there is no any information about the aim of synthesis and biological activity of the natural compound in the living organisms, the separation of that compound from the natural sources makes unambiguous the necessity of laboratory synthesis of that compound. The hall history of chemistry of natural compounds proves that. For example: There was separated sesquiterpene (ovalicine) from the Pesudoorotium ovalis in 1968. This metabolite has some properties of antibiotics but it wasn’t perspective like drug. Because there wasn’t any information about the biological role of it in the living organism. In spite of this the uniqueness and complexity of the structure of that molecule created a big wish to synthesis that molecule. Cory realized the synthesis of racemic mixture in 1985. One of the goals of Cory was to check the general principles of methodology or organic synthesis. The scheme of synthesis contained a big amount of sequence of stages and haven’t any practical application. Ten years later it was found that such kind of compounds like metabolite of mushroom play role in the angiogenesis and have tumoridical effect. On the base of these data there was checked the

80 81 activity of this preparation and was found that it is more active and less toxic. And that is why the all synthesis of this preparation was started. 1.3. The aim is indisputable but is not unambiguous. Synthesis of natural compounds is a very important but not only one problem. It is possibly to obtain the substances with useful properties not only by replication of nature. Very often the practically useful substances are obtained by the research process which is not connected with the synthesis of natural compound. And we meat a big problem what standards may be in the base of the certain aim of synthesis and how to predict the properties of an unknown substance. Many properties of the substance are predictable a priori only by analyzing the structure. For example it is not difficult to show a minimal digest of structural units that must be in the molecule of substance that give to substance some properties. Such kind of prediction may be done on the base of replication or on the base of very serious analyzing. More stable and common properties that are obtained during this kind of analyzing are considered the not ambiguity of properties. For example: Probably that the first field of organic chemistry which was developed fast was the chemistry of organic paints. In the base it was a chromophore-the groups of atoms that responsible for absorption of the light in the certain length. Diarilazo group is the spread chromophore synthetic paint which is contained in the molecule of azobenzole. It is studied very scrupulous the effect of other groups that are connected with the chromophore on the spectral characteristics, and therefore, on the color. For example azobenzole is orange, when the B-azobenzole with the general formula and with dialkylamina- and nitro-groups in para-position, are red. For all compounds of this range, that are differ on by alkyl radicals R1 and R2, we may say that the general color for theme is red and because they contain an amino-group, so they have a weak basic properties. And the color may be changed because of pH-changing. So if we have a problem to synthesize red azopaint which has weak basic properties it means that we should have a B-structure. But we can’t say anything about the character of alkyl groups. The researcher should consider some additional propositions. For example depending on the properties of A-range compounds (degree of basicity, solubility in water or organic solvents, the melting point…). It is not possibly to predict all these peculiar properties. The chemist only must synthesize a range of compounds, analyze the properties and choose the properties that meet the requirements. Empiric selection of perspective compound from many others is characteristic for invention new drugs and biological active compounds. The theory makes it possible only to assume but not assure that this or other compound which contains certain groups of structural fragments will have the necessary activity. More other properties of the future drug (toxicity, accumulation in organism, fast elimination from the organism, possible long-term and short-term side-effects, physics-chemical complex properties, stability under aseptic and storage, compatibility with other drugs…) may not be studied a priori. Therefore when we notice the perspective biological activity of compound which we separate from the natural sources or synthesize in the laboratory

81 82 we should synthesize many analogous and study relatively the all complex of properties that are important for the practical application of theme. The story of creation sulfonamides is the classical example. At first they started to use the derivatives of sulfonamides because the presence of groups of sulfonamides makes bigger ability to be bonded with woolen threads. It was thought that if the walls of bacteria are made from proteins, the sulfonamides may be bonded with the walls of bacteria and inhibit the growth. But it was wrong. The further studies have shown that sulfonamide-G ,,red prontozil,, has high activity against streptococcal infection in mice. We must note that there wasn’t any effective means against bacterial infections in 1932. And the most amazing property of this compound was that it was very active in vivo, when its’ activity dropped to zero in vitro. It became clear the G-compounds doesn’t act on staphylococcus. Azocompound hydrolyzes and forms D- sulfonamide in the organism of rat. D-sulfonamide is a very strong antibacterial compound. It was known already 5000 sulfonamides in 1947. They selected 100 compounds with the desirable complex properties during the broad screening. Some of theme have become drugs and are used as antibacterial preparations till now.

LESSON 12 Tactics of Synthesis

What we need to use certain reaction as a reliable synthesis method? The key problem for synthesis is C-C bond creation. That is why we should discuss the principles of C-C bond creation and the basic methods which are used for that aim. 1. Possibility of organic reaction process We have already mentioned unreality of acetic acid synthesis process:

CH4 + CO2 → CH3COOH Why this way is not real? And elementary composition, and the structure of these three compounds are foresee this way as a direct and the shorter way. But if we mix methane with CO2

82 83 there will not be any interaction. We may note at least two reasons which make this reaction not real. The first reason is thermodynamic factor. Acetic acid is richer in its energy content than a mixture of methane and carbon dioxide. But the reversible reaction is not possible unwittingly. The second reason is kinetic factor. Even if given reaction is thermodynamically possible (during the reaction the free energy is decreased), it is important the presence of appropriate channel, which is desirable to realize given interaction. I.e. real reaction mechanism presence, which is important to realize given reaction. Such channel does not exist for given reaction. But it is known bypassing ways which let us to win the barriers, which are seem insurmountable. This is bypassing stage for this reaction:

CH4 + Br2 → CH3Br + HBr (1) CH3MgBr + CO2 → CH3COOMgBr (2) CH3Br + Mg → CH3MgBr(3) CH3COOMgBr + HBr → CH3COOH + MgBr2 (4)

Such synthesis is very multy-stage and long process but it is real. All these four stages are real and easily realized. What is the secret of problem solution? If summarize all stages we obtain two reactions: CH4 + CO2 → CH3COOH (5) Mg + Br2 → MgBr2 (6) Now we can easily answer the question. The energy effects of second reaction cover the energy costs which are necessary for the first reaction. But the energy transmission itself does not provide the chemical conversion. It is useless to burn magnesium in the bromine and hope, that the CO2 and methane interaction energy will create. The key idea is that when we divide the overall reactions into the separate stages, we move the energy to release by parts and not at once. Besides these two reasons there is the third reason, which may be a serious barrier for the advisable organic conversions, when it is possible several reactions from the same initial products. The variety of these conversions possible ways is one of the important problems. We should note, that it is not possible to find such conditions under which all these four reactions will go in one flask. The chemist deals with many moving molecules. And it is not obvious, that these molecules will interact with certain other molecules (which is necessary to provide the interaction selectivity). Let discuss such kind of selectivity on the example of the key stage of acetic acid synthesis-on the example of MgBr2 and CO2 interaction. Methylmagnesium bromide is a compound with a highly polarized C-Mg bond , where the positive and negative charges are significantly delocalized. The reaction mechanism is very difficult and doesn’t studied at all. But we can show it on the simplified scheme (2.1.).

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The mentioned mechanism is energetically profitable, because of: 1) there are created the strong C-C covalent and O-Mg ionic bonds, 2) its direction corresponds to natural tendency: magnesium loses electrons and oxygen obtains electrons.

2. THERMODYNAMICACCEPTABILITY OF REACTION

THERMODYNAMIC AND KINETIC CONTROL

The fossil raw materials as a basic initial product for organic synthesis is created during the long biochemical processes. During this period the processes reached the equilibrium or extremely closed to it. It means, that the compounds, which are separated from the natural sources, are closed to the low free energy condition, extremely in the anaerob conditions. As a rule, organic synthesis, has a goal to receive compounds with more free energy, which is preserved as free bonds and as bigger chaotic state, than initial products. To create such kind of unbalanced systems, it is necessary to do some work, for what we should bring energy from outside. It may be thermal, electric, light energy. More often it is used chemical energy in organic synthesis. From the viewpoint of thermodynamics the organic synthesis assimilates to difficult and dangerous traveling in mountains with the big amount of ups, landing and bypassing the barriers, which aim is to achieve a higher level of certain point. To get the P final product from the initial A compound schematically may be showed in pic. 2.2.

The energy image of multy-stage synthesis of final P product from initial A product (B, C are

84 85 intermediates, Rgt 1 - Rgt 4 are the reagents). To realize thermodynamically permissible X → Y conversion, the X system which is involved in the reaction (it may be only one compound, or many components, all participants of the process) must overcome some potential barrier. Origins of the barrier due to the need to pass through the transition state, which is richer with energy, then the initial or final products. Due to the clashes very small number of molecules have energy, which is necessary to overcome the barrier. That is why the organic reactions go not instantly, but by measured speed, the size of which depends on the height of the barrier-activation energy. If the barrier is small, the reaction speed is higher, if the barrier is big, the reaction speed is lower (is closed to zero).

Figure 2

Potential barriers of reaction

In general the energy barrier between initial and final products may not be unlimited big. We always have theoretically measured extreme way, which determines the upper limit of barrier: to turn the initial products into the atoms to create necessary final products. The good examples to show the role thermodynamically and kinetic in stability. As known in the middle of the 19th century it was started a big dispute about of benzene structure. This compound had no certain general structure for a long time. Dewar offered A hypothetical structure 2 for benzene in 1867. It was shown very quickly, that this structure was wrong and it was accepted the Kekule B structure. But in 100 years it was proved, that the Dewar structure wasn’t phantasy. And van Tamelen managed to get benzene. As was waited, the A compound was thermodynamically more unstable, than B compound. In real the transmission A to B realized due to the energy release – 14-17J/mole. However the A compound is stable even under room temperature. And its transmission to B under these conditions goes very slow ( half-life of period is two days at 200C). All this shows

85 86 the presence of high energy barriers, which close the A compound in the potential hole and prevent its transmission into benzene. The synthesis of such kind of compound is possible just because it excludes all possible alternatives, which would bring to creation of B compound.

Another example could be adamantane 4. This hydrocarbon, which skeleton like the diamonds crystal structure repeatitive cycle, was considered as an exotic compound till second part of XX century, because its multy-staged synthesis was very hardworking process. It was subsequently shown, that among of many possible isomers, the isomer with the compound C10H16 has the lowest potential energy. Such kind of exclusive thermodynamic stability prompted its synthesis from the other isomers with the C10H16 composition. In fact it was discovered by von Schleyer that the readily available hydrocarbon 5 can be isomerized to adamantane 4, albeit under rather drastic acidic conditions. This method was further developed for large scale preparations of adamantane. The fact that adamantane was found in petroleum, an abundant pool of thermodynamically equilibrated compounds, is partially accounted for by the observed ease of its formation from the less stable hydrocarbons. It is important to emphasize, that the synthesis of given compound depends not only on energy factor, but also on external factors, in which given conversions go (the character of solvent, temperature, pressure and character of catalyst, irradiation and darkness), have a big role. We are able to provide the reaction direction, which is necessary for the solution of given synthetic problem, by selection the right parameters. Here is the example that shows the possible directions of conversions of one organic compound and what methods are necessary to control the reaction processes. (1) and (2) reactions go by the same stoichiometric mechanism: (2) C7H8 + Br2 = C7H7Br + HBr

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But the different final products are obtained-benzil bromide and p-bromotoluene. Depending on the target matter it is possible to carry out the reaction selectively, when the competitive process is practically suppressed. To understand how to reach that, it is important to analyze the mechanisms of the reactions. The mechanism of toluene bromination brings the creation of benzyl-toluene. It is shown in the scheme 2.4. The real reagent is the atom of bromine, which is obtained during the bromine molecule and photon interaction. In the bromine atom 50% of photon energy is present. That is why it is considered as a particle with the high activity, which is able to cut atoms and radicals from the other molecules. And despite the fact, that there is eight atoms of hydrogen in the toluene molecule, only three atoms of hydrogen (the methyl group hydrogen) interact with bromine atom. The reason of selectivity is in the result of that interaction-benzyl radical, which is the most stable from other radicals, which may be obtained from toluene. Interaction of toluene with bromine in the presence of FeCl3 goes by quite another mechanism. In this case due to the interaction between the bromine molecule and FeCl3 the complex + - Br [FeBr4] is obtained (scheme 2.5.). The methyl group hydrogen are very inert towards the charged particles and the visa versa: the polarized π-electron system of aromatic ring is easily interact with active cations, especially with Br+. Here is the simplified mechanism:

One pair of electrons of aromatic system is moved to the forward cation and obtain C-Br bond. As a result the electronic density redistribution and creates the positive charge to the carbon of methyl group as it is showed in the structure of σ-complex. Elimination of proton reduces the aromaticity. Fridel-Krafts reaction is carried by such mechanism. MeCOCl-AlCl3 complexacts as a reagent, which is source of acetiliumcation, MeCO+. The acetyl cation reacts with toluene to form a a-complex analogous to the intermediate 13 formed during the preparation of bromotoluene. Now let us compare two other reactions, both of which involve the addition of hydrogen (equations 4 and 5). Complete reduction of toluene under the action of hydrogen to form methylcyclohexane 10 proceeds easily in the presence of VIII group metals. The process occurs on the adsorbtion layer in the presence of catalyst with the well-developed surface by difficult mechanism.

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The fifth reaction is famous as Birch reduction. This reaction is mediated by Group 1 metals (usually sodium) in a liquid ammonia solution in the presence of a certain amount of alcohol. The net result is also the addition of hydrogen, but in this case only two hydrogen atoms are added. The reason for this peculiarity becomes apparent upon examination of the mechanism of this process. When a metal like sodium is dissolved in liquid ammonia, it dissociates into a sodium cation and a solvated electron (Scheme 2.6). The first step in the Birch reduction is the attack of the solvated electron on the aromatic system of toluene to produce the radical-anion 14. The radical-anion abstracts a proton from an alcohol and is transformed into the radical 15. This radical in turn adds a second electron and is converted to a carbanion 16. A final transfer of a proton from the medium to this anion gives the final product, the diene 11.

Among possible alternative isomers, the preferential formation of diene 11, with the indicated location of the double bonds, is determined by the structure of the initially formed, most stable intermediate, radical-anion 14. Thus, the reduction of a single bond of toluene, as is represented in equation 5, requires the presence of an electron source (sodium), a solvent capable of electron solvation (liquid ammonia), and a proton donor (alcohol). Toluene can also be oxidized, for example with permanganate to produce benzoic acid 12 (equation 6). The mechanism is somewhat analogous to radical bromination as it takes advantage of the susceptibility of the methyl hydrogens to attack by radicals. In this case a sequential replacement of all three hydrogens occurs, which results in the conversion of the methyl group into a carboxyl group. An interesting aspect of this conversion is that its course is determined primarily by the nature of the reagent and is minimally sensitive to the variations of the external

89 90 conditions. Thus this conversion can be successful in a toluene medium or an aqueous solution, at room temperature or upon heating, etc. The predominant product, while it may be formed at different rates and in different yields, invariably turns out to be benzoic acid. The reactions of toluene illustrate a very important peculiarity of many organic reactions: they proceed with the involvement of high-energy intermediates. The structure and reactivity of these species are actually the main factors that determine both the viability of the reactions and the + + pathways they would take. In the above examples, species like Br’, Br , CH3CO , σ-complex 13, radical-anion 14, and carbanion 15 participated as intermediates. These intermediates, however, should never be confused with transition states even though they may often be similar in energy and structure. The differences can be best illustrated by means of the energy profile diagram presented in Fig. 4. An intermediate, like C, corresponds to a fully defined chemical species which, at least in principle, can be isolated. It differs from ‘normal’ compounds like A or E only in a quantitative sense, owing to its higher energy content and the relatively low barriers that separate it from the more stable compounds. Both of these factors determine the high reactivity of typical intermediates. Their energy excess serves to promote reactions with otherwise unreactive compounds. Low barriers permit the reaction to occur rapidly.

Figure 4 Potential energy projile for a reaction pathway involving the formation of an intermediate. A - starting system; B, D - transition states; C - intermediate; E –Jinalproducts

A transition state (TS) is a completely different entity. It refers to a momentary state of a reacting system at a maximum of free energy. By definition, it cannot exist as a static structure. The energy profile diagram illustrates this in its own language: the absence of potential barriers at TS points B or D. Only a fleeting formation of the transition state is achieved; then the system must immediately slide down to a lower energy level like A, C, or E, where existing energy barriers maintain a static system. Fig. 4 illustrates yet another important feature about reactions of this type. The barrier to be crossed on the route between the starting compounds and the intermediate is higher than the barrier between the intermediate and the final products. This means that the formation of the

90 91 intermediate is the slowest process and will determine the overall rate of the reaction (since the conversion of C to products is extremely fast). The energy barrier for the transformation of the intermediate into products is low because the system has already accumulated a significant reserve of energy and has ascended almost to the summit of this barrier. Two conclusions can be drawn from what has just been said. Typically, reaction intermediates are present only in low concentrations because they react faster than they are formed. Therefore, the isolation and structure elucidation of the intermediates can be a troublesome task. Secondly, if the structure of an intermediate has been completely ascertained and it can be independently prepared, then its use as the reagent can lead not only to the sharp acceleration of the reaction but also to an increase in its selectivity. This point is worthy of additional comments. In order to form an intermediate from starting compounds it is frequently necessary to overcome a high energy barrier. Therefore, in order to achieve an acceptable rate of formation (and this is the rate-limiting step of the overall process!), it may be necessary to resort to various methods of forcing the reaction. These may include the use of high temperatures, irradiation, highly active reagents, or catalysts. If these ‘forcing conditions’ are applied directly to the system consisting of the initial compound and a reagent, then in addition to promoting the formation of the desired intermediates, these conditions can also facilitate various side reactions of both the reactants and the final products. These complications can be largely alleviated if there is a way to carry out the overall reaction as a sequence of independent steps, the first step being the preparation of the intermediate from the reagent (in the absence of the substrate) and the second step to react the substrate with the pre-formed intermediate. Here tremendous promise is offered by the chance to prefabricate the required intermediate under the conditions required for its generation, with subsequent reaction of the intermediate with a given substrate under conditions optimal for that step. In fact, quite a number of revised and efficient versions of well-known classical methods have been developed recently owing to the utilization of this fairly general approach. We shall refer rather often to this point in the following sections, but here it is worthwhile to look at just one example related to the reactions of toluene mentioned earlier. The Friedel-Crafts acetylation of toluene (equation 3, Scheme 2.3) takes place smoothly at room temperature, but aromatic systems containing electronwithdrawing groups, such as dichlorobenzene or nitrobenzene, react very sluggishly under these conditions. The use of more forcing conditions might be undesirable owing to the occurrence of side reactions. As was already shown, the catalyst in this reaction serves to polarize the MeCO-Cl bond to + - form an intermediate tentatively ascribed the structure of the acetylium salt [MeCO] [A1Cl4] . It turns out that the acetylium ion can actually be prepared as a stable salt, for example as + - + - [MeCO] [SbC16] . Since the reactive species is already present in this salt, [MeCO] [SbC16] serves as a mild and very active acetylating agent, even for unreactive aromatic compounds. More over, the reactions of this salt do not necessitate the presence of any acid catalyst. Hence,

91 92 reagents of this type can also be utilized for unstable substrates. We have seen, then, by the judicious selection of a reaction that is suitable for a given substrate and by the selection of proper reagents under welldefined conditions, that it is possible to regulate the reactivity of organic compounds and to direct their transformations as desired. The enormously rich potential of organic reactions in achieving most diversified transformations of organic compounds was well recognized long ago. At the same time it was also clear that not all of these reactions could be used as truly effective tools in organic synthesis. In fact, the main pathways for interconverting organic molecules had already been elucidated in the early 1930s. The synthetic potential of already discovered reactions was sufficiently diversified and the synthesis of almost any compound could have been considered as a possible enterprise, at least theoretically. Yet at that time the achievements in the area of total synthesis were rather modest. There was still a long way to go before the theoretically possible could be transformed into the practically viable. In fact this situation is typical for almost any other area of science and technology. Thus, for example, the elucidation of the basic principles of aeronautics and successful design of the airplanes made possible the first intercontinental flights in the early 1930s. These spectacular achievements manifested an appearance of a new and most promising way of transportation. Yet it took several decades of research and development in order to make aviation reliable, efficient, and relatively cheap. Only owing to these efforts could a modern global system of air transportation have been created. Basic underlying principles stayed the same but their implementation had changed dramatically! In much the same way, the transformation of the vast potential of organic chemistry of the 1930s and 1940s into the near omnipotence of modern organic synthesis was achieved not owing to the discovery of new fundamentalprinciples of organic chemistry but rather to a truly revolutionary developments of its tools and methodology. This evolution required tremendous efforts aimed primarily at the elaboration of well-known reactions into reliable and practical synthetic working tools. It was mandatory to raise the status of standard organic transformations up to the rank of synthetic method. We will now examine in greater detail what is required to conside an organic reaction to be a synthetic method.

92 93

LESSON 13

ORGANIC REACTION VS. SYNTHETIC METHOD

There is no strict definition of the term ‘synthetic method’ but it is not difficult to describe the meaning of this notion. An ideal synthetic method can be likened to an operator in mathematics, to a ‘black box’ in cybernetics, or to any device which can be applied to an object to achieve predictable changes. In a similar way, the synthetic method must serve as a standard device to induce an unambiguous change over the structure of the treated compounds. This ‘black box’ for synthesis might contain a standard sequence of operations, including one or more chemical reactions with the required reagents, necessary solvents and catalysts, procedures of reaction monitoring and product isolation, etc. As might be expected, the value of a given synthetic method is directly related to the nature of the transformation that can be accomplished with its help. This transformation must be focused and suitable for converting abundant starting materials into the less available compounds. For

93 94 example, aromatic hydrocarbons are readily available starting materials, the products of coal and petroleum processing. Many of their important functional derivatives, however, need to be artificially created. Major pathways to achieve transformation of aromatic hydrocarbons into more valuable derivatives are based on electrophilic substitution such as Lewis acid catalysed bromination or acylation (see above for the examples). Therefore these reactions were thoroughly studied and thus eventually elaborated into reliable and highly efficient methods general in their scope of application. The key transformation in a given method may imply the utilization of unstable intermediate compounds or reactants. However, if the net result of a sequence of two or three reactions can be tracked back to readily available materials, this sequence can also become the basis of a good synthetic method. For example, the reaction of organomagnesium compounds, the Grignard reagents, with carbon dioxide provides a smooth and fairly general entry into carboxylic acids. These reagents, however, are not very stable upon storage and only a limited number of them are commercially available. Fortunately, they are easily synthesized from readily available organic halides and magnesium and can be used immediately in their reaction with carbon dioxide. The sequence of three reactions shown below serves as an excellent method for the synthesis of a carboxylic acid from the corresponding organic halide with one-carbon chain elongation :

This method is universally applicable and therefore it is quite appropriate to represent it in the terminology of a ‘black box’ as follows, without any reference to the details:

R-Hal → [Grignard Method] → R-COOH

This example may also serve as a good illustration of the importance of a reaction’s generality as a major criterion for the evaluation of its merits as a synthetic method. Generality of the method implies that the reaction is feasible not only for a limited number of the compounds but can be efficiently applied to the vast majority of compounds containing a definite structural element, the functional group. In other words, generality suggests that the results of a reaction affecting a given functional group are minimally sensitive to the variations in the remainder of the molecule. It is the generality of a reaction that enables one to predict, with confidence, the results of the application of this method to a previously unexplored system, a situation frequently encountered in total syntheses. It is this very generality that allows one to describe a sequence schematically with the use of the symbol ‘R’, which tacitly implies that the final outcome does not depend on the nature of the group hidden behind this symbol. The discovery of a new reaction may occur merely owing to a lucky chance or rigorous reasoning and typically it refers to a few isolated examples. However, it is always followed by a

94 95 series of systematic investigations aimed at elucidation of the scope and limitations of the applicability of this reaction to a wide array of compounds. Without these studies it is hardly possible to make any assessments about the true value of the newly discovered reaction as a synthetic method. Let us consider, for example, the origin and evolution of the well-known Diels-Alder reaction. The net outcome of this process is the cycloaddition of conjugated dienes with alkenes, leading to the formation of cyclohexene derivatives (Scheme 2.7). Isolated examples of this cycloaddition, for example the dimerization of isoprene, were known for a long time but passed virtually unnoticed for lack of data on the course and scope of the reaction.

, A true discovery of this reaction was made in 1928, owing to the pioneering and insightful studies of Diels and Alder.2a From the very beginning of their investigations, Diels and Alder recognized the tremendous synthetic potential of the newly discovered cycloaddition and targeted their efforts at the elaboration of this reaction into a method applicable for the synthesis of polycyclic compounds. In a few years, an enormous amount of data was compiled which allowed them to elucidate the main peculiarities of the reaction course and delineate the limitations of its application. Owing to these efforts, the initial observations of an interesting, but limited value, transformation led, ultimately, to the elaboration of one of the most powerful methods in organic synthesis. This work was properly crowned in 1950 with a Nobel Prize and was perhaps even more fittingly recognized when it became generally known in the chemical community as the ‘Diels-Alder reaction’. Here is another example, different, but related to the same idea. The synthesis of carboxylic acids, mentioned earlier, is one of several powerful and general methods of synthesis based on the use of Grignard reagents (organomagnesium compounds). It was Grignard who discovered in 1900 that diethyl ether serves as both solvent and catalyst for the formation of these reagents from various organic halides and magnesium metal. At that time, the Grignard reaction represented one of the very few reliable methods for the creation of novel C-C bonds. The scope of its applicability, however, suffered from some limitations, most importantly the inability to prepare Grignard reagents from vinyl halides, C = C-Hal. This was especially unfortunate since

95 96 vinylic Grignard reagents could have been of significant synthetic value. The solution to this problem, which turned out to be amazingly simple, was found by Normant2b in the 1950s. It was discovered that the preparation of vinylic Grignard reagents could be accomplished merely by using tetrahydrofuran as the solvent instead of diethyl ether. With this discovery it was possible to utilize vinylic Grignard compounds fully as valuable intermediates and significantly broaden the scope of the Grignard reaction into a nearly universal synthetic method. While the generality of a reaction is primarily determined by its chemical mechanism (by the nature of the transformations involved), it may happen that the limitations of its preparative scope arise not owing to the chemistry but to purely ‘technical’ causes. For example, the solubility of reacting components may impose severe limits on the scope of an otherwise very general reaction. Complications of this nature are quite common when water-insoluble organic compounds must react with inorganic reagents (water, salts, etc.). For example, the oxidation with permanganate mentioned earlier, as well as other related oxidations, constitute efficient and fairly general methods. Potassium permanganate and other inorganic oxidants, however, are insoluble in the majority of organic solvents and their typical organic substrates are only marginally soluble in water. Because of this, the classical oxidation with permanganate required a heterogeneous system, conditions far from optimal. In the 1960s, however, a spectacular solution to this and related problems of incompatibility was discovered, the essence of which will now be considered. Let us consider why potassium permanganate is insoluble in benzene but soluble in water. In + - an aqueous solution the ions derived from the dissolution of KMn04, the K and Mn04 ions, exist not as free species but rather as complex aggregates formed by multiple tiers of the polar molecules of the solvent, water, surrounding the central ion. The energy gained in the formation of such a ‘coat’ more than compensates for the energy required to disrupt the crystal lattice of the solid salt with its transfer into the solution. A non-polar organic solvent such as benzene is unable to solvate charged species effectively and thus cannot dissolve inorganic salts. This dilemma was overcome with the aid of a third component, a compound soluble in benzene but at the same time serving to fulfill the role of a ‘coat’ for the ions. In particular, the compounds capable of doing this job are the macrocyclic polyethers of type 17 (Scheme 2.8), the so-called crown ethers discovered in the 1960s by Pedersen. The interior of a crown ether contains a cavity into which an unsolvated ion of potassium can fit. Six atoms of oxygen coordinate strongly with the central potassium ion and thus effectively replace the hydration shell. As a result, complexes such as 18 are quite soluble in a number of organic solvents. Therefore, adding a small quantity of crown ether 17 to a two-phase system of crimson- colored aqueous KMn04 and colorless benzene immediately turns the benzene crimson due to the transfer of KMn04 into the organic phase. It is not surprising that the oxidation of an organic compound in this system proceeds incomparably more efficiently than in the absence of crown ether. Owing to this simple trick, oxidation reactions of organic compounds with inorganic salts,

96 97 previously not very useful because of the phase barrier, were transformed into a set of valuable synthetic tools.

A multitude of other organic reactions imply the utilization of inorganic reagents insoluble in regular organic solvents. These reactions became viable owing to the use of new and unusual catalysts, such as 17, which are usually referred to as phase transfer catalysts.2d The ramifications of phase transfer phenomena are numerous and some of the most important will be discussed later in Section 4.2. For the moment we see that the solution of a purely technical problem resulted in a tremendous enrichment of the synthetic arsenal by broadening the applicability of old and well-known reactions. The general applicability of a reaction, however, while being a necessary requirement, is far from being sufficient to attest to a given reaction as being a good synthetic method. Classical organic chemistry is abundant with numerous reactions that were very promising and rather general in their time, but upon closer scrutiny turned out to be unsuitable as synthetic methods. In this respect, the Wurtz reaction seems to represent an especially instructive example. This reaction, coupling alkyl iodides, R1-I and R2-I, under the action of sodium metal, was discovered in the very dawn of organic chemistry (1855). It was probably the first example of an organic transformation leading to the formation of novel C-C bonds and its synthetic value seemed to be indisputable. In fact, textbooks in organic chemistry present the Wurtz reaction as a standard method for hydrocarbon preparation. In practice, though, this reaction was rarely used for that purpose (for the exceptions, see the synthesis of cyclic derivatives in Section 2.7.1). The basic reason for its 'unpopularity' lies in the fact that, in its classical version, the Wurtz reaction is efficient in the coupling of identical alkyl groups (R1 = R2), but if it were tried for nonidentical groups, a mixture of all possible products would usually arise. Furthermore, the utilization of sodium metal as a coupling reagent precluded the use of this reaction with functionally substituted derivatives (owing to their reactivity with sodium metal). These complications were eventually resolved with the later modifications of the Wurtz reaction (see below), and as a result the Wurtz reaction was properly reinstituted as a practical synthetic method. Thus the obligatory characteristic of a synthetically meaningful reaction is an unambiguity of its reaction course. It is not enough that a given transformation yields the desired product. It is mandatory that the desired product predominates in a mixture of products or, even better, is formed as an exclusive product in a reaction.

97 98

In fact, cleanliness is a rather severe criterion that must be met if a reaction is to be considered a useful synthetic method, This very important point deserves some additional examples from the history of organic chemistry. Recognized more than century ago as one of the basic properties of alkenes is their ability to undergo a number of addition reactions to the double bond with such reagents as water, bromine, inorganic and organic acids, alcohols, etc. (Scheme 2.9, opposite). However, in spite of the fact that these reactions were thoroughly studied and are general in their scope, only few of them (like the addition of bromine) have been accepted into the synthetic arsenal of contemporary organic chemistry due to one simple reason: they lack cleanliness. Even a simple hydration reaction, for example the addition of water to ethylene in the presence of sulfuric acid, leads not only to the formation of the expected product, ethyl alcohol, but also diethyl ether, ethyl sulfate, and some other minor products (Scheme 2.10).

98 99

This problem is even worse for alkenes more complex than ethylene. Equally simple reactions (in a formal sense!) such as the addition of hydrogen bromide or hypobromous acid are also far from being unambiguous and as a rule give rise to a mixture of isomers containing both the predominant Markovnikov (M) as well as anti-Markovnikov (aM) adducts. To convert these reactions into useful synthetic methods it was necessary either to change dramatically the reaction conditions or to elaborate an entirely new protocol, based on different elementary steps and leading to the same overall result. The second approach turns out to be extremely fruitful. For example, it is possible to add water or alcohol across a double bond with the help of a slightly more complicated but reliable protocol via a sequence of two clean

99 100 reactions: solvomercuration and reduction. To achieve a clean addition of the elements of hypobromous acid (Br+ and OH-) it is advantageous to use reagents such as N-bromosuccinimide 19 as the source of Br+ in an aqueous medium. So we see, the reactions given in the textbooks to illustrate the characteristic reactivity patterns of functional groups and the synthetic methods elaborated to realize their potential in practice can be vastly different. Cleanliness is an overall characteristic that embraces various aspects of a chemical transformation. One of the most basic among them is the selectivity of the reaction (to be discussed in detail in Section 2.5). Other features include the absence of side reactions and the possibility to carry out the required transformation under mild conditions to reduce the chances of affecting other active centers in the polyfunctional substrates. The necessity of meeting these conditions is the reason why the elaboration of a well-known reaction into a reliable synthetic method is a demanding and time- consuming process. Devoid of the excitement of pioneering work, it is nonetheless a highly crucial step in developing a workable synthetic protocol. Therefore it is only fair that the contributors to the development of a new synthetic method be no less credited than the discoverers of the original reaction. Earlier in this section we mentioned the Wurtz reaction as a potentially powerful but not very practical (in its original form) pathway for the creation of C-C bonds. Here it is appropriate to trace the evolution of this century-old reaction into a truly powerful synthetic method. The first attempts to overcome the drawbacks of the Wurtz coupling were based on the separation of the overall reaction into a two-step protocol, leading to the ultimate formation of the product R1-R2 (Scheme 2. I 1). However, organosodium compounds such as R1Na are rather unstable and are liable to react with the starting halide, R1-Hal, to produce immediately the undesired product R1- R1. This problem was solved, at least partially, by the use of Grignard reagents (organomagnesium analogs), which are more stable than sodium derivatives and, under carefully chosen conditions of generation, less prone to the undesirable coupling reactions. While the difficulties associated with the generation of the organometallic component (step 1) were avoided by this route, the entire problem was still not solved. It was observed that, along with the desired coupling with R2-Hal in step 2, the Grignard reagents might undergo transmetallation, to some extent, and thus form a mixture of products. A truly workable synthetic method came only after the development of a new generation of organometallic reagents, namely cuprate derivatives. We will encounter these reagents several times further on and here we will note only that their tendency to undergo transmetallation is greatly reduced. For the first time it was possible to carry out a highly specific coupling as a general reaction, leading exclusively to the formation of the desired product R1-R2 (Scheme 2.11). Moreover, it was found that the cuprate reagents are able to alkylate not only alkyl halides, but also alkyl sulfonates and acetates. Of great value as well is the inertness of cuprate reagents toward many functional groups. Cuprate-

100 101 mediated coupling reactions have become the method of choice for the creation of C-C bonds between variously functionalized moieties. The target organic compound can contain a different combination of functional groups. Consequently, an organic chemist should have a variety of synthetic methods, each with a different and clearly defined pattern of selectivity and area of application. Therefore, the development of a new modification of a known synthetic method, even if it does not differ in its final result from other known methods, invariably draws interest as a potentially useful addition to the existing set of available tools. Finally, it is necessary to emphasize the significance of yet another requirement of a good synthetic method - understanding the mechanism of its basic reaction. This understanding, which includes the nature of the elementary steps of the overall transformation, creates a sound theoretical basis to predict the outcome of the reaction when applied to novel substrates. A reaction with a well-established mechanism allows the investigator confidently to seek the optimal conditions necessary to accommodate both special structural features and reactivity, as well as the physical properties of a given compound. Knowledge of the mechanism is of special importance for synthetic efforts based upon the utilization of reactive intermediates as reagents, if one is to secure maximum selectivity and efficiency of the entire process.

101 102

The significance of theoretical studies as a mandatory prerequisite for the rational use of synthetic methods can be demonstrated by the story of the pericyclic reactions. The Diels-Alder reaction, a [4 +2] cycloaddition belonging to this class, was elaborated into a reliable synthetic method shortly after its discovery because its main properties were well-accounted for in the terms of a unified (albeit rather oversimplified) mechanism. On the other hand, the [2 + 2] cycloaddition of various alkenes, a reaction also known for many decades, stayed for a long time as a highly promising but little understood set of transformations. This process is described formally in Scheme 2.12.

102 103

A plethora of experimental data referring to these cycloadditions with various substrates under various conditions gave contradictory information and was difficult to interpret from the point of view of a single mechanism. For example, sometimes these cycloadditions were induced thermally, but sometimes only photochemical induction gave efficient results. Information regarding the stereochemistry of the reactions was insufficient and confusing. Needless to say, these uncertainties created an almost insurmountable obstacle in the way of utilizing [2 + 2] cycloadditions in a total synthesis. Problems pertaining to the interpretation of these and other pericyclic reactions were so puzzling that they were frequently referred to in textbooks published in the 1950s as 'no-mechanism' reactions, i.e. processes for which it was not possible to give a truly consistent mechanistic interpretation. The situation changed dramatically in the 1960s, however, when Woodward and Hoffmann found a generalized and rational interpretation of the course of various pericyclic reactions. The basics of the Woodward-Hoffmann theory can be found in any modern textbook on organic chemistry. For our purposes, it is essential to emphasize that according to their classification there are two distinct and clearly defined classes of pericyclic reactions: thermal reactions occurring between the reactant in the ground state, and photochemically induced reactions which proceed in the excited state. The Woodward-Hoffmann theory makes it possible to predict accurately both the conditions necessary for carrying out a particular pericyclic reaction and its stereochemical outcome. In particular, it became clear that the photochemical dimerizations (alkenes to cyclobutane derivatives, a [2 + 2] pericyclic reaction) and the thermally induced dimerizations are reactions of different classes, and proceed by entirely different mechanisms. Subsequent studies based on these mechanistic concepts elucidated the structural demands of the substrates, the optimal reaction conditions, and the selectivity pattern of these reactions. As a result of these pursuits, a previously rather obscure process was transformed into a popular and powerful synthetic method. In fact pericyclic reactions, which enable us to create ring systems in ‘one stroke’ with unusual ease and selectivity, have replaced, in many cases, the tedious and unreliable multiple step sequences. Their broad application over the past 20 years has contributed, to a significant extent, to the achievements of organic syntheses in the creation of complex polycyclic systems. In concluding this section we wish to emphasize one more time that not a single one of the most elaborated modern synthetic methods can be considered to be universal. Every method has its area of application and its limits defined both by the individual peculiarities of the reactivity pattern of the substrate and its possible liability to undergo some undesirable transformations under the conventional conditions of the method. Therefore, while considering the applicability

103 104 of this or that method, the entire ‘entourage’ of the system must be taken into account and hence it is still necessary to pursue the seemingly endless task of modifying even the most excellent synthetic method. In the following parts of this chapter we will examine the basics of the main synthetic methods. We begin with the most important among them, those leading to the creation of the carbon skeleton of an organic molecule.

LESSON 14 FUNCTIONAL GROUP INTERCONVERSIONS. THEIR ROLE IN ACHIEVEING SYNTHETIC GOALS

THE OXIDATION STATE OF THE CARBON CENTER IN FUNCTIONAL GROUPS. TRANSFORMATIONS WITHIN AND BETWEEN THE OXIDATION LEVELS. SYNTHETIC

104 105

EQUIVALENCY OF FUNCTIONAL GROUPS

Until now, we have examined only constructive reactions that result in the formation of new C-C bonds and have excluded those reactions that involve the transformation of functional groups. Functional group conversions, however, constitute an extremely important element of every target-oriented organic synthesis as a tool to make the necessary modifications of intermediate products and to establish the required functionality in the target molecule. Conversions of this type can be encountered at almost any stage of a multistep synthesis. In fact, it is the availability of a collection of reliable methods to bring about these transformations that makes the relatively limited number of pathways to create C-C bonds so effective in the synthesis of a nearly limitless variety of organic compounds of entirely different classes. The major portion of most texts on organic chemistry focuses upon reactions that result in the interconversion of functional groups. This huge body of factual material’9a will not be reviewed here in detail as it is impossible within the volume of this book and unnecessary for our purposes. Our goal is to highlight the importance of these interconversions in a total synthesis. The immense diversity of transformations can be actually reduced to a few types that we hope are sufficient to provide the reader with an understanding of the principles necessary to select the conversions for a chosen synthetic plan. We will start with some general comments about the term ‘functional group’. The carbon skeleton is the basic element of structure for any organic compound. It is for this reason that organic chemistry texts usually begin with a discussion of the saturated hydrocarbons, i.e. the alkanes and cycloalkanes. The replacement of the hydrogens in these hydrocarbons and/or the subsequent introduction of unsaturation gives rise to ‘functionalized’ derivatives like alkenes, alkynes, ketones, alcohols, esters, etc. In fact, even the hydrogen atoms in a hydrocarbon can be considered as a functional group since they can be substituted (via chlorination, nitration, oxidation, etc.) to yield a hydrocarbon derivative. In a sense, the notion of ‘functional group’ is a mere convention. However, it is generally understood that this notion refers to some specific moiety present in the structure. The nature of this moiety and its location determines the propensity of the molecule to interact with reagents and the selectivity pattern of the reactions with various agents. Various approaches may be used to classify functional groups and pathways for their interconversion. We will begin with an analysis of the oxidation states of carbon in various functional groups.

The Oxidation Level of the Carbon Center and the Classification of

105 106

Functional Groups and their Interconversions

By definition, oxidation reactions are associated with a loss of electrons from an atom or molecule. Changes in the oxidation states of reacting partners are easy to identify for purely ionic reactions. However, conversions of covalent organic compounds rarely can be described in the terms of ‘oxidation’ or ‘reduction’, unambiguously, without some additional provisos. Certainly, in the case of the conversion of a primary alcohol into a carboxylic acid (or the reverse process) it is clear that there is a net oxidation (reduction). There is no ambiguity in defining the hydrogenation of an alkene as a reduction or the epoxidation of an alkene as an oxidation. However, the application of these terms to other alkene additions, such as hydration or bromination, or to the respective eliminations yielding alkenes, is far from obvious. Nevertheless, these reactions can be reliably (albeit formally!) classified in the terms of oxidation or reduction if one applies a certain set of formal criteria and ascribes a zero- oxidation level to the carbon atom of alkanes. Consider the C-H bond in alkanes. Carbon is a more electronegative element than hydrogen. Consequently, the electron pair that forms this bond is shifted towards the carbon atom. In the extreme, an ionic representation of this bond can be given as pictured in 122 (Scheme 2.45). Within these conventions the carbon atom in an alkane can be approximated as a carbanion (oxidation level 0 by definition). Using this definition it becomes possible to apply oxidationreduction terminology to the processes as if they occurred to ion pair 122. Thus, oxidation of 122 with the loss of one electron leads to the radical 123. With the loss of two electrons, the oxidation leads to carbocation 124. Similarly, the conversion of an alkane to an alcohol and the alcohol into an aldehyde and the aldehyde eventually to a carboxylic acid can unambiguously be classified as an oxidation sequence with the loss of two, four, and six electrons. The oxidation levels 1, 2, and 3 are ascribed respectively to these functional derivatives. The conversion of an alkane to an alkene or alkyne can be interpreted in an analogous fashion.

106 107

This approach provides a basis for classifying important functional groups formally derived from alkanes, as shown in Scheme 2.46. One could extend this classification to even more complex polyfunctional compounds, but the principle should be already clear. This classification of functional groups provided the opportunity to identify clearly two

107 108 major types of their transformations: A. Isohypsic reactions. Conversions occurring without a change in the oxidation level of the carbon atoms.

B. Non-isohypsic reactions. Conversions occurring with a change in the oxidation level of the carbon atoms. These conversions may proceed as oxidations, leading to an increase in the oxidation level, or as reductions, resulting in the decrease of the oxidation level.

1. Oxidation level 1 (an alkane – 2e)

108 109

The changes in the oxidation level for a given reaction can be easily assessed by simply following the change in the oxidation status of the inorganic reagent used. Thus, for example, the formation of alcohols by alkene hydration, and the reverse elimination, are clearly isohypsic in that they involve water with no changes in its oxidation level. In contrast, all hydoxylation reactions of alkenes leading to the formation of glycols

109 110 correspond to the formal addition of the elements of hydrogen peroxide (H202) and unquestionably should be treated as a non-isohypsic transformation (oxidation). Like wise, reactions such as the addition of hydrogen (reduction) or bromine (oxidation) to double and triple bonds (and the reverse processes of dehydrogenation or debromination) are non- isohypsic as well. Following this logic, we should classify the formation of organolithium compounds or Grignard reagents via the interaction of metals (reducing agents) with alkyl halides as non- isohypsic reactions, which transfer substrates from oxidation level 1 into oxidation level 0 status. Thus we arrive at the apparently paradoxical such as organometallics have the same zero-oxidation status as the parent hydrocarbons. This conclusion is easy to grasp if one recalls that transformation of an organomagnesium compound into the respective hydrocarbon proceeds easily as a result of hydrolysis, an isohypsic reaction:

From the point of view of a total synthesis, generalizations can be made about the characteristics of functional group transformations of different types: 1. Almost any isohypsic transformation is feasible within the limits of a given oxidation level, as isohypsic transformations do not affect oxidation status and imply most usual substitution, addition or elimination reactions. 2. Non-isohypsic transformations are feasible only for certain types of derivatives, namely those especially apt to undergo oxidation or reduction. Thus, for example, the direct conversion of an ether into an acetal or ketal is difficult to achieve whereas the oxidation of an alcohol to an aldehyde or ketone (or the reverse process) is a trivial transformation. Similarly, the transition from an oxidation level of 2 to level 1 is problematic in the case when one tries to convert dihalides into monohalides while the transformation of alkynes intoalkenes may be safely considered a viable route to carry out this transition. Consider the following analogy. While one can walk freely into and out of various rooms located on the same floor (‘oxidation level’), there is no way to get directly from any room on one floor to a room on another floor without the help of special passage (stairway or elevator) that specifically serves as the tool for communication between the floors. Such an analogy, all its schematics notwithstanding, represents an accurate description of the possibilities and limitations for the transformations of functional groups. It enables us to focus our attention in the following sections on only a very

110 111 limited number of the most important transformations which, as we believe, can best serve to illustrate the scope and limitations of functional group interconversions in a synthesis.

Isohypsic Transformations. Synthetic Equivalency of Functional Groups of the Same Oxidation Level

As we have seen above, alcohols and alkenes are produced routinely in the numerous reactions utilized in the formation of carbon-carbon bonds. These two functionalities are extremely useful for both the same-level oxidation interconversions and reduction-oxidation transitions (as ‘stairways’ connecting different ‘floors’). Therefore, it is not surprising to see an enormous number of methods developed to capitalize on the diverse options of alkene and alcohol transformations. These methods occupy a key place among the reactions known for isohypsic conversions of level 1 functionalities. Among the numerous isohypsic transformations of alcohols is a set of reactions leading to the formation of esters, alkyl halides, or sulfonates, especially valuable for synthetical purposes. These derivatives are widely used as electrophilic reagents, the synthetic equivalents of the carbocation R+ in C-C bond-forming reactions with carbon nucleophiles.

Isohypsic reactions of alkenes, like electrophilic additions of H20 or HX, represent a conventional pathway for the preparation of alcohols and alkyl halides from alkenes. The scope of their application was originally limited as unsymmetrical alkenes (e.g. 125) gave product mixtures composed of both Markovnikov (M) adducts and anti-Markovnikov (aM) adducts. As was already mentioned above (see Scheme 2.10), an efficient and general method for the conversion of alkenes into alcohols or ethers 126 (Scheme 2.47), with a nearly complete M selectivity, was elaborated using mercury salts as electrophiles in conjunction with the reduction of the formed adducts. It is also possible to convert the same alkenes into anti-Markovnikov alcohols 127, using a different set of reactions, namely hydroboration of the double bond followed by oxidation of the intermediate alkylborane with hydrogen peroxide. A convenient method for the selective transformation of 125 into aM adduct 128 then implies the utilization of homolytic addition of HBr or, alternatively, a hydroboration- bromination sequence.

111 112

As was amply demonstrated in the preceding sections of this chapter, numerous C-C bond- forming reactions are applicable for the preparation of products with a terminal double bond. Thus the sequence (i) introduction of the terminal alkene moiety, (ii) isohypsic double bond transformation leading to the derivatives like 127 or 128, and (iii) the C-C bond-forming step, may be considered as a reliable operation for carbon chain elongation. The reverse reactions, such as the elimination of HX or H20 leading to the formation of alkenes, are also feasible and a set of methods is available to carry out these transformations. Here again the main limitations are due to the nonselectivity of the reaction in unsymmetrical systems. In many cases, however, this problem can be alleviated by the utilization of appropriately tuned conditions. At oxidation level 2 we will first examine the alkynes, which are readily formed either as a result of reactions utilized for creating C-C bonds or with the help of functional groups transformations.

112 113

Important in laboratory and industrial syntheses is the addition of alcohols, carboxylic acids, and hydrogen halides to alkynes, leading to the corresponding vinyl derivatives (Scheme 2.49). These compounds may also be regarded as the derivatives of enols and in many cases they can be more conveniently obtained from carbonyl compounds (Scheme 2.50).

Non-isohypsic Transformations as Pathways Connecting Different Oxidation Levels

The oxidation of alcohols to carbonyl compounds or carboxylic acids (and the corresponding reverse reductive transformations) are among the most significant routes for transitions between oxidation levels. A tremendous amount of effort has been spent to develop infallible methods that accomplish these conversions. These efforts have not been in vain and it is now possible to carry out virtually any of these conversions selectively even when complicating factors such as the lability of substrates or products, the presence of other reactive groups, and stereochemical or other issuess are involved (Scheme 2.60). The oxidation of alcohols seems to be an especially popular exercise for all those who are interested in the development of new methods. More than 140 procedures for the oxidation of alcohols are mentioned in Larock's monograph, Ige including several dozen marked specifically for the oxidation of primary or secondary, allylic or homoallylic alcohols.

113 114

Non-isohypsic transformations are especially important in the syntheses of various ni trogen-containing derivatives. A common route for obtaining amines is the reduction of nitrogen-containing derivatives of carboxylic acids (nitriles or amides), aldehydes and ketones (imines):

It is also possible to synthesize amines in a sequence of reactions where the non-isohypsic conversion (reduction) occurs at the nitrogen atom and the oxidation state of the carbon attached to it is not affected:

114 115

LESSON 15

FUNCTIONAL GROUP INTERCONVERSIONS AS STRATEGIC TOOLS IN A TOTAL SYNTHESIS

In certain cases it is possible to plan the synthesis of a compound from already available precursors which contain the required carbon skeleton and only a change in the nature and location of the functional groups is required to arrive at the target structure. A great deal of classical organic synthesis developed along this line. A good example of this is the first synthesis of cyclooctatetraene 137 by Wilstatter in 1911.21a As a starting compound for this synthesis, the natural alkaloid pseudopellterin 138 (isolated from the roots of pomegranate trees) was chosen for its eight-membered carbocyclic framework (Scheme 2.65). The challenge to Wilstatter was to use the available functionality in the ring to introduce four double bonds. He accomplished this by a sequence of conversions: a reduction of the carbonyl group; dehydration; and an iterative series of simple reactions, such as exhaustive methylation, Hofmann elimination, bromine addition, etc., which eventually led to the target molecule, 137. All ten steps of this remarkable synthesis were actually functional group transformations.

Another area largely based on functional group transformations is the synthetic chemistry of carbohydrates. There are usually two synthetic goals in this field. The first is the synthesis of natural monosaccharides and their analogs. The second is the assemblage of oligosaccharides and polysaccharides from the monosaccharides. Natural monosaccharides vary considerably in

115 116 their structure but the main differences between them lie in the location and nature of the functional groups and the configuration of the chiral carbons. The majority of monosaccharides have similar, if not identical, carbon skeletons consisting of C5 or C6 non branched carbon chains. Many natural monosaccharides such as D-glucose or L-arabinose are readily available. For their conversion into other monosaccharides it is usually sufficient to change the character of just a few functional groups. It might be necessary, for example, to transform a hydroxyl group into an amino group or a primary alcohol into a carboxyl group, or change the configuration of one or more chiral carbons. There is no need to create a carbon skeleton from scratch or to repeat steps Mother Nature has already done for us in the course of biosyntheses. For illustration purposes, let us examine the industrial synthesis of ascorbic acid 139 from D- glucose 140 (Scheme 2.66). The catalytic hydrogenation of 140 produces the hexa-atomic alcohol D-sorbitol 141. The latter is subjected to microbial oxidation which selectively introduces a keto group at position 2 (formerly the C-5 position in 140). The resulting isomer of glucose, L-sorbose 142, is converted into the protected derivative 143, which contains only one unprotected alcohol function at C-1 (corresponding to C-6 in the staring glucose structure). This group is readily oxidized to give a carboxyl function. The removal of the protecting groups from the resulting acid 144 leads to the openchain form of ascorbic acid 139a, which is converted spontaneously into the enol form of lactone 139.

116 117

As illustrated, the major steps in the conversion of 140 to 139 correspond to non-isohypsic transformations of functional groups: the reduction of an aldehyde to a primary alcohol, the oxidation of a secondary alcohol to a ketone, and the oxidation of a primary alcohol to a carboxylic acid. The introduction and removal of the isopropylidene protecting groups and the use of the bacterium Acetobacter suboxydans (a non-typical oxidizing agent) ensures selectivity in the reactions of the polyfunctional intermediate compounds. Oligo- and polysaccharides are constructed from monosaccharide units connected via glycosidic linkages. The key step in the synthesis of these systems is the creation of the glycosidic bond between the individual monosaccharide units. The formal scheme for the creation of such a bond is shown for the disaccharide lactose 145 (known as milk sugar) from the monosaccharide precursors D-galactose 146 and D-glucose 140 (Scheme 2.67). Here again there is no need to worry about the creation of a new C-C bond. Our only concern is with the formation of the O-glycosidic bond between the two sugar moieties. From the point of view of general organic chemistry, this is an elementary functional group transformation. It is very far from being trivial, however, when a glycosidic bond is considered. The stereoselective formation for this type of bond is difficult and remains a central concern in carbohydrate chemistry. Hundreds of publications, including several monographs, deal exclusively with this subject.

The synthesis of two other important biopolymers, proteins and nucleic acids, also involves a sequence of functional group transformations. Simple (amidic or phosphodiester) bonds are formed between readily available monomeric units (amino acids or nucleotides). Almost all synthetic efforts in this area are centered around the elaboration of an optimal method to achieve an efficient formation of this bond. Given the complexity of the final structure, this task is never too simple. It should now be clear that functional group transformations play more than an auxiliary role in synthesis. The importance of these reactions, especially with respect to the chemistry of natural compounds, makes it imperative to have a multitude of diverse and, at times, rather sophisticated methods to effect these often apparently trivial transformations.

PART IV HOW TO CONTROL THE SELECTIVITY OF ORGANIC REACTIONS

117 118

2.10 FORMAL CLASSIFICATION OF SELECTIVITY PROBLEMS The question of the selectivity of a reaction is so critical to organic synthesis that a detailed discussion is most certainly warranted. We will start by examining some general aspects of this problem. Reliability, for a given synthetic method, implies that it can be employed to achieve the given synthetic transformation efficiently and cleanly with no undesirable conversions occurring under the chosen conditions. Even if this condition is met, however, the problems associated with selectivity are far from being fully solved. Frequently a substrate may contain not just one but several functional groups that are capable of interacting with the same reagent(s). The synthetic task at hand often demands the involvement of only one of them. Furthermore, even the reaction of a single functional group carried out with the help of an otherwise ‘clean’ reaction may result in the formation of a mixture of products. The problems related to selectivity are diverse. Therefore, we will only examine a few typical cases to illustrate some of the main facets of this problem. General reasons that cause the nonselectivity of an organic reaction course can be classified in terms of the formal kinetics of the overall process. Type 1. Consecutive reactions. The common feature of these examples (Scheme 2.68) is that the product formed in the first step is capable of reacting further under essentially the same reaction conditions. If the requirement for selectivity is to stop the process after the first step, a variety of approaches can be attempted. For example, in case (a) both consecutive steps belong to the same type of chemical process. Therefore to ensure the selective hydrogenation of the alkyne to the alkene, it is necessary to utilize a catalyst that permits the reduction of the triple bond but not the double bond. This requirement is met in Lindlar’s catalyst, a palladium metal catalyst adsorbed on a carbonate that is partially deactivated with lead (Pd-CaC03-PbO).

In contrast, the chemistry of the oxidation of a primary alcohol to an aldehyde differs sharply from the oxidation of an aldehyde to a carboxylic acid (case (b)). Advantage, in this case, must be taken of the difference in the mechanisms of these steps. Among the reagents which can effectively oxidize alcohols and remain rather inert toward aldehydes are pyridinium

118 119 chlorochromate (a chromium trioxide-hydrogen chloride complex of pyridine) or dimethyl sulfoxide-Lewis acid. Ensuring the selective monoalkylation of ketones [case (c)] is of special importance in synthetic practice and numerous approaches are elaborated for this purpose. This problem deserves special comment and will be considered later (Section 2.13). Type 2. Parallel reactions. In these examples (Scheme 2.69), a mixture of closely related products may arise owing to the availability of several competing pathways for a given reaction. The challenge here is to direct the reaction exclusively (or at least predominantly) along one specific pathway. In case (a) the initial step, attack of Br+ leading to the formation of a cationoid intermediate, may occur both at C-1 and C-2. The preference of this attack determines the ratio of positional isomers (147 + 148):(149 + 150). The second step of the reaction is the interaction of the intermediate with the nucleophile HO-.

The orientation of the approach of the nucleophile determines the ratio of cis and trans isomers in the resulting mixture, (147 + 149):(148 + 150). In actuality, electrophilic addition of Br +- is directed almost exclusively at C-2 and hence products 147 and 148 are formed preferentially. While the ratio of these isomers is very sensitive to the reaction conditions, it is rather difficult to achieve a high stereoselectivity in the reaction and hence this method cannot be recommended for the preparation of the pure stereoisomers 147 or 148. In a somewhat related example, case (e), the stereochemistry of the product is determined by the direction of approach of the hydride reagent to the carbonyl group, which can occur either 'from above' or 'from below' the plane of the ring. The steric course of hydride reductions can easily be controlled by a careful choice of the reagent. Related examples will be considered in Section 2.12. Type 3. Consecutive-parallel reactions. In these examples (Scheme 2.70) we have to deal with the problems of the first two types combined. The starting compounds are polyfunctional. An initial reaction can occur at any of the available functions and therefore the reaction is likely to produce isomeric products. Then, as is the case with consecutive reactions, the intact functional groups still present in these products can be subject to additional transformations. It is obvious that the task of ensuring selectivity in these situations is by far more troublesome

119 120 than in the preceding cases. The challenge here is to carry out a reaction selectively at one of the available functional groups and at the same time employ an efficient 'block' to prevent the second reaction from occurring [e.g., the selective mono- or biacetylation of glycerol can be achieved in exactly this manner, reaction (91. This rather formal approach may be flawed, as it suggests that the reactivity of the functional group retained in the first product remains unchanged. In general this is not very likely the case. For example, in the course of the alkylation of toluene by the Friedel-Crafts process, reaction (g), the addition of the first alkyl group increases the nucleophilicity of the aromatic nucleus and as a result the second alkylation occurs more rapidly than the first one. Likewise, the third alkylation may occur even faster. The mutual interaction of functional groups is a very common phenomenon and its effect can be quite significant if the interacting functionalities are in close proximity in the molecule or separated by a system of conjugated double bonds. Such an influence can either accelerate or decelerate a given reaction. Taking advantage of these mutual interactions can secure the overall selectivity of the process. For example, if toluene undergoes a Friedel-Crafts acylation instead of an alkylation, the exclusive formation of a monoacylated product (predominantly the para isomer) would be observed as the presence of one acyl group deactivates the aromatic molecule toward further electrophilic substitution. The carbonyl group in the acylation product can be easily reduced and, thus, the overall monoalkylation of the starting toluene can be achieved in two highly selective steps [reaction (h), Scheme 2.70]. The examples shown above clearly illustrate the multifaceted problems related to the control of selectivity. It must also be added that, in principle, every organic compound is polyfunctional. Even methane, the simplest of organic molecules, can produce four different products upon chlorination, from CH3Cl to CC14. Not surprisingly, the question of selectivity receives top priority in the planning of an organic synthesis. Even our cursory examination demonstrates how diverse the obstacles may be on the route to complete selectivity. Equally varied are the approaches to overcome these obstacles. Type 1 selectivity problems are addressed in the above discussions relating to the fundamental requirements for a reaction to be considered useful as a synthetic method. We will concentrate our attention in the following sections mainly upon approaches utilized to solve type 2 and, to a lesser extent, type 3 selectivity problems. The discussion will cover some of the most common pathways based upon varying the nature of reagents and/or substrates, as well as on the changing the reaction mechanism. These are the major, but by no means the exclusive, options available for solving the problem of selectivity. It must not be overlooked that in certain cases a dramatic enhancement in selectivity can be also achieved by the thoughtful use of purely physical approaches, such as removing the main product from an equilibrating mixture, or careful control over the kinetics of the process by the proper choice of reaction parameters. Before going further, a few words about the terminology are necessary. Chemoselectivity refers to the selective reaction at one center in a substrate containing several non-identical functional groups. The term regio (or site) selectivity is applicable to reactions which may lead to the formation of positional isomers. The term stereoselectivity is applied to reactions that form

120 121 stereoisomers. In cases where total selectivity is achievable, the term speczjicity is used to describe chemo-, regio-, and stereospecificity (as opposed to selectivity). The final aspect of selectivity is related to forming optically active mirror image isomers (enantiomers). The problem of enantioselectivity is extremely important in organic synthesis, but will not be addressed in this text since this is an independent topic in its own right22b (see, however, discussion of some aspects of this problem in Chapter 4).

121 122

TESTS

1. Which of the following statements are true for benzene? 1) Benzene does not undergo electrophilic addition reactions. 2) All carbon-carbon bonds in benzene do not have the same length. 3) Carbon-carbon bond in benzene is somewhat shorter then typical double bond. 4) Six sp2 hybridized carbon atoms form a regular hexagon with the  electrons shared equally between neighboring nuclei. a) 12 b) 13 c) 34 d) 14

2. How many dibromo substituted derivatives are possible for benzene? a) 4 b) 3 c) 2 d) 1

3. Which of the following compounds is aromatic? a) Cyclopropene c) Cyclodecapentaene b) Cyclobutadiene d) Cyclopentadiene

4. Number of π electrons in coronene is equal to: a) 24 b) 18 c) 12 d) 22

5. Which of the statements are true for furan? 1) It is a five-membered system with two oxygen atoms in the ring; 2) The hetero atom has one lone pair as part of the aromatic sextet; 3) Furan has five equivalent canonical forms; 4) The dipole moment of furan is smaller than that of tetrahydrofuran.

a) 24 b) 23 c) 14 d) 34

6. Which of the statements are NOT true for pyrimidine? 1) It is a five-membered system with two nitrogen atoms in the ring; 2) There are corresponding two lone pairs of electrons not at all involved in the aromatic -electron sextet; 3) The number of canonical contributors to pyrimidine is more than in case of pyridine; 4) Unshared electron pair of both nitrogen atoms are located in a sp3 hybrid orbital.

a) 12 b) 14 c) 24 d) 13

7. Which of the following statements are true for pyridines?

122 123

1) 2-Methoxypyridine is a much stronger base than pyridine itself. 2) Pyridines carrying strongly electron-withdrawing substituents are so deactivated that electrophilic substitutions do not take place. 3) Pyridine is a much weaker base than saturated aliphatic amines. 4) 2,6-di-t-butylpyridine is more basic than pyridine.

a) 12 b) 34 c) 13 d) 23

8. The regioselectivity of pyridine reaction with alkyl- or aryllithiums predominantly at C-2 position may be associated with: a) mesomeric and inductive effects of in pyridine ring connected with 2-position; b) relief of strain when the 2-position rehybridises to sp3 during addition; c) electron repulsion between the two immediately adjacent lone pairs of nitrogen and carbon atoms; d) electronegative nitrogen, which makes 2-position carbon atom to become negatively charged.

9. Which of the following statements are true? 1) Friedel-Crafts acylation in pyridines is very difficult in contrast to benzene. 2) Exposure of a pyridine to electrophilic species immediately converts the heterocycle into a pyridinium cation with the electrophile attached to the nitrogen. 3) The positively charged pyridinium cation is many orders of magnitude more easily attacked at carbon by the electrophile than the original neutral heterocycle. 4) Nucleophilic substitution at carbon in quinoline must necessarily proceed through a doubly charged intermediate.

a) 12 b) 13 c) 34 d) 23

10. Meisenheimer complexes are formed during the: a) electrophilic addition b) nucleophilic addition c) nucleophilic substitution d) electrophilic substitution

11. The only isolable stable products of pyrrole halogenating is: a) monohalopyrrole, b) dihalopyrrole, c) trihalopyrrole, d) tetrahalopyrrole.

12. 3-Nitropyrrole reacts with electrophilic reagent and form mainly a) 2-substituted nitropyrrole, b) 2,5-disubstituted nitropyrrole, c) 5-substituted nitropyrrole, d) 4,5-disubstituted nitropyrrole.

13. 1,4-diketones react with ammonia to give:. a) 2,5-disubstituted pyridines,

123 124

b) 2,5-disubstituted pyrroles, c) 1,4-disubstituted pyrroles, d) 1,4-disubstituted pyridines.

14. What will be the final product of acetaldehyde and m-aminobenzenecarboxylic aldehyde interaction? a) isoquinoline, b) pyridazole, c) indole, d) quinoline.

15. Choose the answer, in which the compounds are placed in order of increasing of proton chemical shifts in the 1H NMR spectrum. a) C2H5, CH3Cl, CH3Br, CH3I b) CH3F, CH3OCH3, (CH3)3N, C2H5 c) CH3I, (CH3)3N, CH3F, (CH3)2O d) (CH3)4C, (CH3)3N, (CH3)2O, CH3F

16. How many signals would you expect to find in the 1H NMR spectrum of given molecule and into how many peaks will each signal be split? O

CH3CH2OCCHCH3

CH3 a) Five signals (two doublet, one triplet, one quartet and one septet), b) Three signals (one singlet, one doublet, and one quartet), c) Five signals (three triplets, one doublet, and one singlet), d) Four signals (one doublet, one triplet, one quartet and one septet).

17. CH4 + CO2 =CH3COOH Carriing out of the reaction directly is impossible. One of the ways can be represented by the following scheme:

CH4 → A → B → CH3COOH What is hibridization of A and B molecules: a) A – sp, B – sp2 and sp3 b) A – sp, B – sp2 c) A – sp3, B – sp2 and sp3 d) A – sp, B – sp3

18. Which of the following statements is wrong for the isohypsic reactions? a) there is no change of oxidation level of carbon of functional group in isohypsic reactions b) reactions of hydration of alkenes are isohypsic reactions c) reaction of esterifications are non-isohypsic d) dehydration of alcohols are isohypsic reactions

19. During addition of water to butene-1 in the presence of Hg(OAc)2 and further reduction by

NaBH4 following is produced.

124 125 a) 2- hydroxybutane b) 1- hydroxybutane c) 1- methoxybutane d) butadiene

20. A-»C reaction is:

. 1. exothermic 2. endothermic 3. advantageous termodinamically 4. not advantageous termodinamically a) 2.3. b) 1.3. c) 1.4. d) 2.4.

125