Ebook Organic chemistry principles in context Part 2

(BQ) Part 1 book Organic chemistry principles in context has contents: Fatty acid catabolism and the chemistry of the carbonyl group; investigating the properties of addition and condensation polymers; the industrial road toward increasing efficiency in the synthesis of hexamethylene diamine with stopovers at kinetic versus thermodynamic control of chemical reactions, nucleophilic substitution, and with a side trip to laboratory reducing agents,...and other contents.

Chapter Fatty Acid Catabolism and the Chemistry of the Carbonyl Group 7.1 The fatty acids in living organisms are saturated and unsaturated T HE “FATS OF LIFE” BY CAROLINE POND is full of interesting information about its subject matter including a story I remember reading years ago in a popular textbook of organic chemistry written by two professors at New York University, which is that the hoofs of reindeer contain a higher proportion of unsaturated fatty acids than the upper body areas of this animal There are many different kinds of fatty acids, some of which are shown in Figure 7.1 These molecules, with variable length long hydrocarbon chains terminated by carboxylic acid groups, can be broken down into two classes, saturated and unsaturated In fatty acids these terms take on special importance FIGURE 7.1 Structures and Melting Points of Various Saturated and Unsaturated Fatty Acids In biological systems unsaturated refers to those molecules that contain one or more carbon-carbon multiple bonds (section 4.10, Figure 4.12), which refers in the most part to sp2 carbon atom hybridized carbon-carbon double bonds in long chains made up mostly of sp3 hybridized carbon atoms (section 1.4, Figure 1.2) We have hardly noted triple bonds in our studies, that is, sp hybridized carbon, and triple bonds, although not unknown, are rarely found in natural fatty acids, so, for now, we can restrict our definition of unsaturated fatty acids to those containing carbon-carbon double bonds, which, as we shall see, are essential in the role fatty acids play in living systems Caroline Pond, in her book, points out that the shingle-backed lizard, which lives in the deserts of western Australia, when fed a diet of unsaturated fatty acids likes to spend its time in cooler places compared to being fed a diet of saturated fatty acids after which it likes to hang around in warmer places Other lizards apparently behave in a similar manner That’s pretty interesting As in the reindeer example mentioned above, differences in fatty acid composition are found routinely in different parts of warm blooded animals - more unsaturated in the appendages, more saturated in the inner body Pond discusses the fact that neat’s foot oil, which has been used as a lubricant since the middle ages, is derived from the fat in a cow’s hoofs and is a liquid at room temperature while suet from the inner parts of the body tends to be solid Pond also points out that marine plants have far more unsaturated fatty acids than terrestrial plants Moreover fish have a higher proportion of unsaturated to saturated fatty acids than land dwelling animals and fish living in colder waters have a greater proportion of unsaturated fatty acids than fish living in warmer waters Before we discover how the differences between saturated and unsaturated fats serve life’s functions, as seen in the examples just given, let’s first understand something about how fats are found in living organisms PROBLEM 7.1 Given the fact that derivatives of fatty acids are critical components of cell membranes in living entities, and that unsaturated fatty acids melt at lower temperatures than saturated fatty acids of the same number of carbon atoms, can you offer a biological reason for the ratios of saturated to unsaturated fatty acids found in the animals and plants noted in this section? PROBLEM 7.2 Do the proportions of fatty acids of different composition and degrees of unsaturation in Figure 7.3 (to be discussed below) support your answer to Problem 7.1? PROBLEM 7.3 Redraw the structures in Figure 7.1 showing all atoms and all lone electron pairs Assign hybridization and geometry to all carbon atoms that are not tetracoordinate Assign E or Z configuration to the double bonds (section 11.2) 7.2 Fatty Acids F ATTY ACIDS IN VIVO ARE NOT FOUND as free carboxylic acids as shown for the structures of several fatty acids exhibited in Figure 7.1 but rather as esters of glycerol, that is, triglycerides Now we will become familiar with carboxylic acids, alcohols and esters, important functional groups (section 3.9) widely found in organic molecules The general structure of a triglyceride is shown in Figure 7.2 in addition to the fatty acid composition of the triglycerides found in one vegetable oil, sesame oil The structures of these four fatty acids are shown in Figure 7.1 We’ve come across carboxylic acids ( sections 4.9, 5.4) and also seen a fatty acid before in Figure 5.2 They are an important functional group (section 3.9) As noted above, and as seen in Figure 7.1, fatty acids are structures with long hydrocarbon chains terminated by a carboxylic acid group The functional group in a triglyceride, an ester, is formed by the combination of a carboxylic acid and a molecule containing hydroxyl groups, that is, an alcohol Glycerol, shown in Figure 7.2, contains three hydroxyl groups and therefore can form three ester groups with three fatty acids, which can all be the same or differ in any way Esters could be thought of as anhydrides (meaning loss of water) of carboxylic acids and alcohols because the formation of an ester involves elimination of water, the HO- group of the carboxylic acid and an H+ from the alcohol hydroxyl group In this chapter we’ll study the properties of esters, as they are key to both the breakdown of fats, catabolism, and the build up of fats, anabolism (ancient Greek: ballō = I throw: kata = downward; ana = upward) FIGURE 7.2 Structures of a Triglyceride and Glycerol There are two prominent biological roles of fatty acids and the esters they form with glycerol, one structural and the other an energy source In their structural role, the fatty acids and their derivatives are important components of cell membranes, the feature of every cell that acts, among other roles, as the gateway for nutrients and exit out for expulsion of waste products of cellular metabolism The hydrophobic nature of fatty acids, which derives from their long hydrocarbon chains, acts to separate the aqueous interior of the cell from the aqueous environment that surrounds the cell It is the requirement that the membrane be a gateway, a passageway, which causes membranes to be composed of mixtures of saturated and unsaturated fatty acids As seen in Figure 7.1, unsaturated and saturated fatty acids of the same chain length, such as, oleic acid and stearic acid, melt differently, 13° C and 69° C, respectively Here we find the answer to why the cell membranes in the reindeer’s hoof contain a higher proportion of unsaturated triglycerides compared to the cell membranes in the warmer parts of the animal’s body, and to why the cold blooded lizards prefer a warmer climate when fed saturated fatty acids The melting point differences between saturated and unsaturated fats allow us to understand the proportions of the saturated to unsaturated fatty acids in the various animals and plants in Figure 7.3 Cell membranes composed of triglycerides of increasing proportion of unsaturated fatty acids remain fluid, can therefore act as gateways, at lower temperatures than membranes composed of higher proportions of saturated fatty acids Life exposed to lower temperatures turns to unsaturated fats to gain transport through cell membranes FIGURE 7.3 Table of the Proportions of the Various Fatty Acids from Different Animal And Plant Sources We’ll return to the reason for the lower melting points and therefore the higher fluidity of unsaturated compared to saturated fatty acids later in the book when we’ll study natural rubber (section 11.3) We’ll also discover a related phenomenon about the differing kinds of polyethylene which the chemical industry can produce For now let’s focus on how triglycerides are broken down to glycerol and fatty acids These fatty acids then undergo catabolism to acetyl coenzyme A ( Figure 5.3), which is an intermediate that is a source of energy and as well a biochemical building block All these processes involve applications of fundamental principles of organic chemistry PROBLEM 7.4 Use the structures of the fatty acids in Figure 7.1 to understand the “structural code” used in Figure 7.3 and draw the structures of the fatty acid components of the triglycerides of many of the plants and animals in the table In your drawing these structures questions arise as to the proportion of each fatty acid within each triglyceride molecule? Are you able to answer the question in this problem unequivocally? Do questions of stereochemistry also arise? PROBLEM 7.5 In the conversion of isopentenyl diphosphate to dimethyl allyl diphosphate in sections 5.5-5.6, we came across the concept of enantiotopic groups Does this stereochemical designation apply to glycerol? PROBLEM 7.6 Considering the shape around a cis versus a trans double bond and the fact that the favored conformation around the many CH2 groups in a fatty acid chain take an anti conformation (section 1.13), and considering that in a membrane the chains are packed close together, offer a reason (hypothesize) why cis fatty acids make membranes that are more fluid, that is, have lower melting points, than trans fatty acids PROBLEM 7.7 Considering the composition of the triglycerides in sesame oil, Figure 7.2, and that there are three hydroxyl groups in glycerol available to form esters, how many different triglyceride structures are possible? PROBLEM 7.8 Make a list of all the functional groups you have come across in the book so far or that you are aware of from elsewhere and draw their structures 7.3 Saponification I N CHAPTER 5, SECTION 5.1 we were introduced to Michel Chevreul, the beloved and long lived French chemist whose investigations of the water insoluble constituents of life led to the discovery of cholesterol and several fatty acids and also to the understanding that fatty acids occurred in nature as the esters of glycerol, a molecule he characterized but did not discover Glycerol was discovered by Carl Wilhelm Scheele in the 1780s by heating fatty substances with litharge, a basic compound of lead He called it oelsüss and described the substance as a sweet principle of oils and fats Scheele’s characterization of glycerol as a sweet principle reminded me that many years ago when I was a student, long before concerns about toxicity and environmental hazards came to the fore, there was tradition we heard about to taste new substances – place a trace on the tongue Why you think the Germans used the word carbonsäure for carboxylic acids? Carl Wilhelm Scheele It is difficult to mention Scheele’s name without saying something more about this very interesting 18th century Swedish-German chemist Scheele, who lived a relatively short life, from 1742 to 1786, maybe because of tasting too many chemicals, was not someone with enviable laboratory facilities In spite of his first laboratory being described as a “cold and draughty wooden shed,” Scheele discovered chlorine and oxygen and laid the foundation for photographic film in his discovery of the action of light on silver salts Later in his career he was given a position where he was allowed to research one day a week, by someone Partington called a “considerate master.” Nevertheless, when Scheele turned his attention to what we call now organic chemistry he discovered many organic acids including tartaric, prussic, malic, lactic, uric and citric acids and for our current interests, a neutral molecule, as mentioned above, glycerol I remember when I was a young research student, my mentor, Kurt Mislow, telling me that the drive to carry out research by some is so overpowering that they will it under any circumstances, not matter how difficult I wonder if he was thinking of Scheele What a chemist! When Professor James Moore of Rensselaer Polytechnic Institute read the paragraph about Scheele he sent me the following note: I know of this noted alchemist only because the Institute of Organic Chemistry at the U of Mainz is on Johann-Joachim-Becher Weg “The chemists are a strange class of mortals, impelled by an almost insane impulse to seek their pleasures amid smoke and vapour, soot and flame, poisons and poverty; yet among all these evils I seem to live so sweetly that may I die if I were to change places with the Persian king.” Johann Joachim Becher, Physica subterranea (1667) Quoted in R Oesper, The Human Side of Scientists (1973), 11 FIGURE 7.4 In Vitro Basic Hydrolysis (Saponification) of a Triglyceride The history and production of soap is intertwined with the chemistry of the ester functional group, which links glycerol and the fatty acids (Figure 7.2) The earliest recorded history of the making and use of soap goes back nearly five thousand years, although its modern widespread use in bathing is much more recent (the last two hundred years or so) However, the fundamental chemistry for making soap has not changed over all these years Fats or oils from plants or animals are subjected to a basic substance in water The earliest process certainly involved the accidental discovery that ashes from burning wood on mixing with animal fat and water from a cooking process produced a substance we call soap The basic substance used was alkali, a mixture of soda ash, that is, Na2CO3, and potash, K2CO3, which continued to be obtained from wood ash well into the 1700s However, as the need for soap increased, as people bathed more frequently, the consequence was destruction of large swaths of European forests to get the wood to make the ash Some potash could be obtained by burning sea weed and this was a source in England and Scotland with plenty of coastline but it was clear that some new source had to be found In the late 1700s Nicolas Leblanc, stimulated by a monetary prize from the French crown, a prize he was eventually denied because of the French Revolution, found a way to transform common salt, NaCl, to soda ash Sulfuric acid was used to convert sodium chloride to sodium sulphate, Na2SO4, which was then reacted with limestone, CaCO3, to produce the soap making chemical, soda ash (sodium carbonate) This history of soap brings us back to Carl Wilhelm Scheele, who along with all his other accomplishments noted above, was the one who discovered the essential reaction for the process in the conversion of common salt to sodium sulphate using sulfuric acid And, in an interesting tale of the long and winding paths allowing Europeans to bathe in large numbers, we find that sulfuric acid was first produced by Jabir ibn Hayyan, an Arab-Persian alchemist who lived in the eighth century In fact, the medieval Muslim world had advanced methods for making soap and a recipe found on the web from a manuscript of that time is: “ sesame oil, a sprinkle of potash, alkali and some lime - mix and boil pour into a mold and leave to set to produce a hard soap.” I guess you now know precisely the fatty acid salts in this eighth century soap 12.21 The Mechanism of No-Mechanism Reactions I N A PAPER PUBLISHED IN THE SCIENTIFIC journal, Tetrahedron, in 1962, William Doering whom we have met before regarding his discovery of Hückel’s book (section 6.8), and his postdoctoral student at Yale, W R Roth, wrote about the quandary associated with “no-mechanism” reactions: “ Nomechanism is the designation given, half in jest, half in desperation, to “thermoreorganization” reactions like the Diels-Alder and the Claisen and Cope rearrangements in which modern, mechanistic scrutiny discloses insensitivity to catalysis, little response to changes in medium and no involvement of common intermediates, such as carbanions, free radicals, carbonium ions and carbenes.” Doering and Roth succinctly summarized a major problem in the understanding of a large number of important chemical reactions little knowing that around the time of their writing, a theory was being developed to forever rid organic chemistry of the nomechanism designation for these and many related reactions This was the work of Woodward and a junior fellow at Harvard, Roald Hoffmann Their work in turn was related to that of a Japanese scientist from Kyoto University, Kenichi Fukui who with his colleagues had published a paper in 1952 entitled: “A Molecular Orbital Theory of Aromatic Hydrocarbons.” The effort of these scientists demonstrated that considerations of the energies and symmetry properties of molecular orbitals could yield understanding of the chemical reactions of organic molecules, results that led to the Nobel Prize for Hoffmann and Fukui in 1981 Woodward who certainly would have shared in the prize died in 1979 Kenichi Fukui Roald Hoffmann Applying molecular orbital ideas to the Diels-Alder reaction illustrates the essential features of this approach, which takes several forms including “correlation diagrams,” “aromatic and anti-aromatic transition states” and “frontier orbitals.” The latter is the approach we will focus on here An excellent treatment of the field with a discussion of all approaches to the use of molecular orbital theory applied to concerted percyclic reactions can be found in Chapter 11 of Part A of the book by Carey and Sundberg we have earlier refered to (section 12.15) Hückel’s insight to focus only on the p-electrons of aromatic molecules allowed understanding of the special stability of these cyclic molecules (section 6.8) Application of Hückel’s approach in focusing on the p-electrons of the double bonds in linear chains or rings that are not aromatic, such as seen in the reactants undergoing the Diels-Alder reaction (Figure 12.2), and other reactions to be discussed below, leads to understanding of the symmetry characteristic of the molecular orbitals occupied or occupiable by these p-electrons These orbital characteristics then determine if these reactions are possible and their detailed mechanisms nodes FIGURE 12.48 The molecular orbital symmetries of an extended π-array can be described by the symmetries of the wave functions of a particle in a box In 1970, Woodward and Hoffmann published “The Conservation of Orbital Symmetry,” a detailed discussion of their insights into what had been called “nomechanism reactions.” (The essential ideas were first published in the Journal of the American Chemical Society in the mid-1960s) Within the first pages of the book the following sentence can be found, “The envelopes of polyene orbitals coincide with the curve of the wave function of a particle in a one-dimensional box.” We’ve seen the simplest example of a polyene in sections 10.4 and 10.5 in the discussion of industry’s use of 1,3-butadiene Higher polyenes would then follow the pattern of this butadiene as in 1,3,5-hexatriene and so on The relationship between the allowed standing waves of a particle in a box and the molecular orbitals that can be occupied by the electrons of these two polyenes, through are found in Figure 12.48 As for atomic orbitals discussed in sections 1.4 and 1.5, each molecular orbital can hold two electrons of opposite spin, as shown in Figure 12.48 The p orbitals shown in the discussion of hybridization in Chapter (sections 1.4 and 1.5) and which are used throughout the book, and shown to form the double bonds in the two structures in Figure 12.48, contain what is called a node, which is in the plane of the sigma bonds that form the two structures The nodal plane is devoid of electron density and separates the two lobes of the p orbital, which differ in their symmetries This difference is often designated by a plus and a minus sign for each lobe of each p orbital or in Figure 12.48 by being shaded and unshaded, which works equally well Observing the p orbitals in the system, which is perpendicular to the sigma framework of both 1,3-butadiene and 1,3,5- hexatriene, one discovers shaded and unshaded p orbital lobes on adjacent carbon atoms The differing symmetries of these p orbital lobes translates to the absence of electron density between them and therefore to a node which is now perpendicular to the sigma (σ) framework of the molecule Arthur C Cope The number of nodes perpendicular to the σ framework for each molecular orbital, ψ1 through ψ4, correspond to the number of nodes in the standing waves for the particle in a box, with the energy of the molecular orbitals increasing in going from ψ1 to ψ4 As for atomic orbitals, we fill each molecular orbital in turn, with increasing energy, with two electrons The highest occupied molecular orbital, HOMO, therefore for 1,3-butadiene with four p electrons is ψ2 with the lowest unoccupied molecular orbital, LUMO, ψ3 The two more electrons in the p system of 1,3,5-hexatriene mean that HOMO is ψ3 while LUMO is ψ4 The symmetries of these molecular orbitals are determined by the number of nodes as shown in Figure 12.48 The larger are the number of nodes the higher the energy of the molecular orbital The highest occupied and lowest unoccupied molecular orbitals, HOMO and LUMO are what are called the frontier orbitals, those that Fukui had pointed attention to in his 1952 publication, and it is these orbitals that we will focus on for our analysis of the Diels-Alder (Figure 12.2) and other reactions discussed in this section Experience with the Diels-Alder reaction informs us that the isolated double bond is most reactive when conjugated with electron withdrawing groups as seen in the first example and other examples in Figure 12.2 In one way of thinking we therefore imagine the HOMO of the diene pouring electrons into the LUMO of the ene, although as we’ll see whichever way the electrons are imagined the symmetry characteristics of the molecular orbitals produce the same results Figure 12.49 shows the molecular orbital symmetry properties of HOMO and LUMO of ethylene and 1,3-butadiene and the interactions of these molecular orbitals in the Diels-Alder reaction The examples of the Diels-Alder reaction in Figure 12.2 demonstrate that the stereochemical relationships of the pendant groups on the double bonds of the ene and the diene (cis or trans (Z or E)) is maintained in the product of the reactions The stereochemical result requires that the ene, that is ethylene in the example in Figure 12.49, must approach the diene, that is 1,3-butadiene, so that the terminal carbon atoms of ethylene bond to the same face of the butadiene This is precisely the result required by the overlap of orbitals of the same symmetry as shown in Figure 12.49, which is independent, as shown, of using the HOMO or LUMO of either reactant The only requirement is that the frontier orbitals of the reactants are HOMO for one and LUMO for the other All Diels-Alder reactions can be understood by the orbital symmetry characteristics shown in Figure 12.49 A no-mechanism reaction is turned into a reaction that can be understood by consideration of orbital symmetries FIGURE 12 49 The highest and lowest occupied orbital symmetries of the reactants in the Diels-Alder reaction explain the characteristics of this reaction class FIGURE 12.50 The highest and lowest occupied orbital symmetries of ethylene allow understanding of the otherwise difficult to explain failure of two ethylene molecules to thermally form cyclobutane FIGURE 12.51 The geometries of the ring closing and ring opening reactions of extended πsystems, which occur and not occur, can be understood by the symmetries of the highest and lowest occupied molecular orbitals Orbital symmetries also yield understanding of why two molecules of an alkene such as ethylene refuse to undergo a pericyclic reaction to produce the four membered ring cyclobutane although simply moving electrons, as shown in Figure 12.50, would appear to allow this reaction path Analysis of the symmetries of the HOMO and LUMO orbitals of ethylene (Figure 12.50) yield understanding The simultaneous overlap of the orbitals would require a shaded orbital to overlap with an unshaded orbital producing a node No bond could form In molecular orbital terms this is an anti-bonding situation Another class of pericyclic reactions is termed electrocyclic reactions such as the cyclization of 1,3,5-hexatriene to cyclohexadiene as shown in Figure 12.51 for substituted 1,3,5-hexatrienes The substitution reveals the specific stereochemical consequences of the reaction, stereochemical consequences that could not be understood until orbital symmetries and frontier orbitals were considered In Figure 12.51 we see that each diastereomeric triene shown yields specifically only one cyclohexadiene diastereomer via formation of the sigma bond by rotation of the terminal atoms of the triene toward each other This is termed disrotatory motion since the pendant groups are moving in opposite directions The reason for this motion can be seen by inspection of the symmetry of the orbitals in the HOMO, which must form the new sigma bond Many reactions of this kind are known in which the symmetry of the HOMO orbital controls the necessary motion In 1,3-butadiene and its ring closed form, cyclobutene, the motion that transposes the ring opened and ring closed form is conrotatory Here the HOMO, ψ 2, of 1,3-butadiene (Figure 12.48) has the p-orbital lobes of opposite symmetry facing in the same direction requiring an opposite motion to that seen in 1,3,5-hexatriene Another class of pericyclic reactions, sigmatropic rearrangements that could not be understood, becomes comprehensible by considering the symmetries of frontier orbitals Let’s look at two examples among many in this class of reaction, including an important reaction critical to the biochemistry of vitamin D which we won’t cover here but you are encouraged to look up Rearrangements that appear possible in both propylene and 1,3-pentadiene are shown in Figure 12.52 In both processes a hydrogen atom is transferred from the terminal methyl group with shifting of the positions of the double bonds Consider that the rearrangements shown in Figure 12.52 involve a hydrogen atom in reaction (1) and a propylene radical (three electrons), and in reaction (2) a hydrogen atom and a 1,3-pentadiene radical (five electrons) The HOMO for the propylene radical therefore must be ψ2, while the HOMO for the 1,3-pentadiene radical must be ψ3 As seen in Figure 12.48 ψ2 has one node and ψ3, two nodes with these nodal planes shown in Figure 12.52 Whatever may be the symmetries of the carbon framework, the hydrogen atom to be transferred, with only the s-orbital occupied, must be of onesymmetry As shown therefore in Figure 12.52 a smooth (concerted) transfer of the hydrogen atom in the three carbon system (reaction (1)) is not possible while that in the five carbon system (reaction (2)) is consistent with the orbital symmetry Only the latter rearrangement is experimentally observed The discussion in this section is only the top of the iceberg of this beautiful correspondence between an aspect of quantum mechanics and a class of organic chemical reactions, which, as noted above, is well covered in Chapter 11 of Part A of the book by Carey and Sundberg (sections 12.9 and 12.15) FIGURE 12.52 Why some molecules allow hydrogen atoms to be intramolecularly transferred from sp3 carbon atoms to the terminus of double bonds, and only with specific geometries, can be understood by consideration of highest and lowest occupied molecular orbitals PROBLEM 12.97 Considering that a photochemical process can promote an electron from the HOMO to the LUMO, analyze the possibility that light could produce cyclobutane from two ethylene molecules PROBLEM 12.98 If the sigmatropic rearrangements presented in Figure 12.52 were instead presented as the transfer of a carbon atom with a positive charge instead of the hydrogen atom how would your analysis of the process be changed? PROBLEM 12.99 Look up the chemical changes associated with the in vivo production of vitamin D and its precursors and identify all pericyclic reactions and determine their orbital symmetry characteristics PROBLEM 12.100 Analyze the sigmatropic rearrangement of a hydrogen atom from carbon-7 to carbon-1 of 1,3,5-hepatriene (CH2=CHCH=CH-CH=CH-CH3) Would it be allowed under any conditions? PROBLEM 12.101 Consider the electrocyclic reaction of 1,3,5,7-octatetraene to an eight member-ring with three double bonds Would it occur via a conrotatory or disrotatory motion and justify your answer by considering frontier orbitals CHAPTER TWELVE SUMMARY of the Essential Material T HE FOCUS OF THIS CHAPTER IS MULTI-STEP SYNTHESIS or, in other words, the methods organic chemists use to make molecules that are not easily connected to the starting materials, which are generally commercially available Here we look at the work of two of the masters of this field, R B Woodward and E J Corey and the approaches they took in the syntheses of two molecules that offered considerable challenge to the ability of organic chemists to synthesize complex molecules Their success in these endeavors convinced the field of the power of the science of organic chemistry to accomplish multistep synthesis essentially without boundaries In Part I of this chapter we follow Woodward in his synthesis of cholesterol, a feat that opened the door in this field and we come to see that his success was based on the science reaching a high level of understanding of structure and mechanism Every step Woodward took was based on considerations of the theory that supported the science at that time He began with a reaction long interesting to him, the Diels-Alder reaction, which forms ring compounds from acyclic precursors and then how understanding of the nature of carbanions and equilibration processes and the stereochemistry of six-member rings allowed attaining fused rings that could later on his path lead to the construction of two of the rings of cholesterol Taking the synthesis further along required adding a third fused ring, which was accomplished using three reactions familiar to us from our study of in vivo syntheses, the Michael, the Claisen, and the aldol condensations In adding the fourth fused ring Woodward was faced with the problem that the reaction he wanted to use could take place to yield multiple products instead of the single molecule he sought This arose from various sources within the starting molecule of enolate formation, which Woodward dealt with by using the reactivity of the most favored enolate in a reaction with an amine to form an eneamine, which then acted as a protecting group In this manner we learn some things about the reactions of amines and carbonyl chemistry and the nature of eneamines and Schiff bases Woodward now could use the enolate he wanted in a Michael reaction with acrylonitrile, a conjugated alkene we can add to the Michael reactants we’ve seen before The nitrile group was then hydrolyzed to the carboxylic acid, a reaction we’ve seen before in our study of polymers The carboxylic acid is then activated by formation of a mixed anhydride, a method of increasing the reactivity of carboxylic acids we’ve also seen before, and this anhydride then reacts with the OH group produced by the enol formation of a ketone carbonyl in the third fused ring The synthetic route is now set up to form the fourth fused ring using one of the most famous reactions in organic chemistry, the Grignard reaction, in which carbon bound to magnesium is nucleophilic in a manner that causes reaction with various classes of carbonyl functional groups We take the opportunity to learn something of this reaction and see the scope of its use Using this Grignard chemistry Woodward was able to close the fourth ring by giving rise to a dicarbonyl compound that could undergo an Aldol condensation Woodward is now set up with nearly the carbon skeleton of cholesterol with however, one of the four rings as a six rather than a five membered ring To accomplish the necessary transformation of this ring Woodward had to remove a protecting group based on a vicinal diol forming a ketal with acetone Here we are reminded of the chemistry of hemiacetals and hemiketals and full acetals and ketals, which brings us back to our studies of sugar chemistry When the ketal is removed, Woodward is able to oxidize the resulting vicinal diol to a dialdehyde breaking open the six membered ring Another Aldol condensation then mostly yields the five member ring he wanted with one aldehyde group placed to continue the synthesis At this point in the synthesis Woodward no longer wanted to work with racemic materials and we discover the elegant way he used a natural product to distinguish the enantiomers based on the principle we first came across in Chapter Again our attention is turned to the Grignard reaction as the alkyl pendant group is placed on the five membered ring that had been formed by the Aldol condensation However, the product of the Grignard reaction produces an OH group that has to be removed This result leads us to have to look into a class of reactions not previously focused on, elimination, and we spend a bit of time looking into these double bond-forming reactions and then see how the absence of specificity to form constitutionally isomerically pure alkenes is of no problem to Woodward because of his planned approach Simple hydrolysis of an acetate ester then produces cholesterol, which is found by mixed melting point to be identical to natural material We are now prepared to study the work of the other master in this field of multistep synthesis, E J Corey The target now is another biologically important class of molecules, the prostaglandins Again, as in Woodward’s beginning toward cholesterol, the Diels-Alder reaction proves critically important But in this use of the reaction the diene structure is such as to produce fused rings that are bicyclic in a different way We look into this structure and discover an understanding based on the conformational properties of cyclohexane Again, the nitrile group has a role in being part of the structure of one of the Diels-Alder reactants but here this group is not hydrolyzed but, rather, its leaving group properties are utilized The resulting ketone allows an introduction to another reaction, the Baeyer-Villager reaction, which enables conversion of ketones to lactones The resulting bicyclic structure including the lactone sets up a structural situation in which formation of an iodonium ion allows a ring closing to take place that, remarkably forms a key prostaglandin intermediate in which several stereochemical centers simultaneously take the proper configurations This chemistry causes us to further our understanding of how ring closing reactions take place in organic chemistry and we see how thermodynamic and kinetic parameters play a role and, specifically, ring strain and entropy Corey is then faced with the pendant alkyl groups in the prostaglandin structure, each of which contains a double bond but one cis and the other trans and, specifically, placed in the alkyl chains We see why Corey turns to a reaction based on phosphorus invented by Wittig to solve the problem and understand how this approach accomplished the task at hand We look into the Wittig reaction and one of its variants and discover that the presence or absence of resonance stabilization of the ylid intermediate in this reaction is the source of the stereochemical control and how a cyclic intermediate, the oxaphosphetane, determines the stereochemical outcome for the double bond We also see how the strength of the phosphorus oxygen bond drives the reaction forward and why regiochemical control is the rule This point seemed than an excellent time to look at another important class of synthetically useful reactions in which a strong bond to oxygen is the driving force, but this time to boron And our taking this diversion to boron-based chemistry is encouraged by the fact that the Nobel committee saw the parallel to the phosphorus-based chemistry in awarding the prize to both originators of the chemistries and that both reaction classes involve double bonds In hydroboration however, the double bond is not made but rather water can be added to the double bond in a controlled manner and with the OH group added to the least substituted carbon – anti-Markovnikov Hydroboration is compared to oxymercuration and we study the mechanism of both and discover the source of their different results All this brings us to discover that Corey had been using a protecting group in disguise, one that was not easily recognized but turned out, by using a special reducing agent, to allow a lactone to be turned into a hemiacetal The equilibration of this hemiacetal exposes, then, the aldehyde group to undergo another Wittig reaction to form the second alkyl chain with its controlled regiospecificity and stereospecificity And, in the course of this chemistry, we see still another protecting group that works with hydroxyl groups, a necessity in the synthetic path to avoid the presence of active hydrogen Finally we appreciate the brilliance of Corey’s synthetic work in seeing how his path brings him to all three prostaglandin structures by simple maneuvers toward the end of the synthesis We’ve seen that both Woodward and Corey made critical use of a reaction that had early on fascinated Woodward, the Diels-Alder reaction In this reaction, one of the most well known and used in organic chemistry, we’ve seen how rings can be formed by the interaction between a diene and an alkene and the specific requirements for this reaction to be successful, and the precise stereochemical consequences of the reaction We end the formal part of the explanation of the synthetic work of these two masters with a section referring to no-mechanism reactions, which before the mid-1960s referred to the Diels-Alder reaction among others coming under the general heading of concerted pericyclic reactions Here we discover that the approach Hückel took in understanding the special characteristics of aromatic molecules (Chapter 6) by focusing only on the orbital characteristics of the p-electrons can be applied to understanding a broad class of reactions allowing organic chemists to discard the term “no-mechanism reactions.” The key to understanding arises from the combination of the symmetry of orbitals and the importance of frontier orbitals to chemical reactions The two part chapter discusses Corey’s formal proposal of the retrosynthetic idea in which synthetic plans are made not by considering the starting material but rather the end product and then working backward We apply this approach to several industrial products and see how the methods used fit Here we see the value of the relatively low pKa of hydrogen atoms bound to triply bound carbon atoms and how the carbanion produced by loss of this proton can be used synthetically in important ways both in industry and in Corey’s synthesis of Cecropia juvenile hormone We also come to understand the hybridization source of this surprising acidity And finally you were invited to try your hand at some synthetic tasks in the problems that follow the chapter THE END ... amino acid; and histidine, 26 3rd, which are all along the chain designated from the N-terminus of the protein The protein contains 449 amino acids linked end to end in its structure The folding... is interesting to see how the protein chain begins and ends The sequence of amino acids begins with alanine, followed by aspartic acid, and then by glutamine and so on until the last three amino... three amino acids in the sequence, lysine, serine and finally, glycine By convention, the beginning of the protein is designated as the end of the chain with a free amino group, NH2, or some derivative