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• Professor and Academic Chair, Department of Anaesthesiology and Intensive Care Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden

O 739 the acylation of enamines Enamines are made from secondary amines and aldehydes or ketones via the iminium salt: you met them in Chapter 14 and have seen them in action in Chapters 21 antibiotic resistant viruses order doxycycline 100mg visa, 26 virus scan doxycycline 200 mg cheap, and 27 bacteria 3 shapes buy doxycycline 200mg with mastercard. In Chapter 26 we saw that reliable C-alkylation occurs with reactive allyl halides and halocarbonyl compounds antibiotics for sinus infection during pregnancy generic doxycycline 100mg online, but that unwanted N-alkylation often competes with simple alkyl halides. He first prepared an acid chloride from cyclopentadiene, and the enamine from cyclopentanone and the secondary amine morpholine. Combining the enamine with the acid chloride led to a clean acylation at carbon in 82% yield and eventually to a successful synthesis of the natural product longifolene. O O O N O Cl Cl N O O 82% yield Aza-enolates also react cleanly at carbon with acid chlorides. When the ketone is unsymmetrical, the aza-enolate forms on the less substituted side, even when the distinction is between primary and secondary carbons. The best of our previous regioselective acylations have distinguished only methyl from more highly substituted carbon atoms. Acylation at carbon You will not be surprised to find that the immediate product tautomerizes to an acyl-enamine further stabilized by an internal hydrogen bond. The first step is the formation of the acylium ion, which cyclizes on to one of the two possible enols of the ketone. This process will + O remind you of Friedel­Crafts acylation but a better analogy is perhaps the aldol reaction where metals such as lithium hold the reagents together so that reaction can occur around a six-membered ring. F N MeN O ofloxacin N H Members of this class usually have an amine and a fluorine atom on the benzene ring as well as other embellishments as in ofloxacin, a recent example. The magnesium atom prevents O-acylation with acid chlorides, and decarboxylation (p. Acylation at nucleophilic carbon (other than enols and enolates) We should not leave the subject of acylation at carbon without considering a problem that affects all such reactions to some degree. It can be Z R Z R Z R base understood most easily if we imagine some functional group Z that is able to stabilize a H H H H Cl carbanion, and the acylation of that carO banion with an acid chloride-something O like this. All looks well until we consider what Z R Z R Z R base might happen to the product under the reaction conditions. It too can form an H anion, and a very stable one at that, O O O because, not only is it stabilized by Z, but stabilized enolate anion it is also an enolate. Since this anion is more stable (less basic) than the original anion, if there is an equilibrium between the two carbanions in the reaction mixture, the original carbanion will be sufficiently basic to act as the base that removes the proton from the product. Z Z H R H O O O stabilized enolate anion R Z R Z R So, instead of being acylated, the starting anion is protonated. This side-reaction could reduce the maximum possible yield in the acylation reaction to 50%: half the starting material forms the product by acylation, while the other half simply deprotonates the product. In most of this chapter, we used enolates as our nucleophiles and worked under equilibrating conditions with alkoxide bases. But the problem does arise in reactions such as the acylation of simple phosphorus ylids. By this device good yields of keto-sulfone can be formed even when both partners are aliphatic compounds with acidic protons. Too much saturated fatty acid seems to be bad for us, clogging arteries, while some unsaturated fatty acids seem to protect us against that fatal condition. There are hundreds of fatty acids in living things but most have one special characteristic-they have an even number of carbon atoms. In fact, at some stage in the biosynthesis of palmitic acid, there was a carbonyl group at each atom marked with a green blob here. It is because these long chains are much easier to assemble by the Claisen ester 744 28. Orsellinic acid, for example, is clearly formed directly by an aldolstyle cyclization of this tetracarbonyl precursor. The esterifying group is a thiol called coenzyme A, and we shall just represent this molecule as R (you can find its full structure on p. The first reaction is between a malonate half-hioester and an acetate thioester of coenzyme A. Look at the mechanism and you will see how similar it is to the Claisen ester condensation.

In this chapter we are going to chest infection order 200 mg doxycycline amex look at one of the most important ways of making C­C bonds: using organometallics treatment for dogs back legs buy 100mg doxycycline overnight delivery, such as organolithiums and Grignard reagents fast acting antibiotics for acne quality doxycycline 100mg, and carbonyl compounds antibiotic 3 day dose buy 100 mg doxycycline with visa. H+, H2O new C­C bond 75% yield the organometallic reagents act as nucleophiles towards the electrophilic carbonyl group, and this is the first thing we need to discuss: why are organometallics nucleophilic? We then move on to, firstly, how to make organometallics, then to the sort of electrophiles they will react with, and then finally to the sort of molecules we can make with them. Organometallic compounds contain a carbon­metal bond the polarity of a covalent bond between two different elements is determined by electronegativity. The more electronegative an element is, the more it attracts the electron density in the bond. Using organometallic reagents to make C­C bonds How important are organometallics for making C­C bonds? It is a compound that prevents several species of insects from maturing and can be used as a means of controlling insect pests. Only very small amounts of the naturally occurring compound can be isolated, but it can instead be made in the lab from simple starting materials. At this stage you need not worry about how, but we can tell you that, of the sixteen C­C bonds in the final product, seven were made by reactions of organometallics, many of them the sort of reactions we will describe in this chapter. As further proof, take this important enzyme inhibitor, closely related to arachidonic acid which you met in Chapter 7. It has been made by a succession of C­C bond-forming reactions using organometallics: eight of the twenty C­C bonds in the product were formed using organometallic reactions. In the extreme case of complete polarization, the covalent bond ceases to exist and is replaced by electrostatic attraction between ions of opposite charge. When we discussed (in Chapter 6) the electrophilic nature of carbonyl groups we saw that their reactivity is a direct consequence of the polarization of the carbon­oxygen bond towards the more electronegative oxygen, making the carbon a site for nucleophilic attack. In organolithium compounds and Grignard reagents the key bond bond is polarized in the opposite direction-towards carbon-making carbon a nucleophilic centre. This is true for most organometallics because, as you can see from this edited version of the periodic table, metals (such as Li, Mg, Na, K, Ca, and Al) all have lower electronegativity than carbon. Reactions involving the filled orbital will therefore take place at C rather than Li. This is a useful idea because it allows us to organometallic carbanion metal cation think about the way in which methyl+ reacts as though it were R Li R Li lithium reacts-as though it were an ionic compound Me­Li+-and you may sometimes see MeLi or MeMgCl + MgX R MgX reacts as though it were R represented in mechanisms as Me­. The true structure of organolithiums and Grignard reagents is rather more complicated! It turns out that they generally form complex aggregates with two, four, six, or more molecules bonded together, often with solvent molecules. In this book we shall not be concerned with these details, and it will suffice always to represent organometallic compounds as simple monomeric structures. Carbon atoms that carry a negative charge, for example Me­, are known as carbanions. Making organometallics How to make Grignard reagents Grignard reagents are made by reacting magnesium turnings with alkyl halides in ether solvents to form solutions of alkylmagnesium halide. Iodides, bromides, and chlorides can be used, as can both aryl and alkyl halides, though they cannot contain any functional groups that would react with the Grignard reagent once it is formed. The reaction is therefore known as an oxidative insertion or oxidative addition, and is a general process for many metals such as Mg, Li (which we meet shortly), Cu, and Zn. The mechanism of the reaction is not completely understood but a possible (but probably not very accurate) way of writing the mechanism is shown here: the one thing that is certain is that the first interaction is between the metal and the halogen atom. Using organometallic reagents to make C­C bonds the reaction takes place not in solution but on the surface of the metal, and how easy it is to make a Grignard reagent can depend on the state of the surface-how finely divided the metal is, for example. Initiation can be accomplished by adding a small amount of iodine or 1,2-diiodoethane, or by using ultrasound to dislodge the oxide layer. The ether solvent is essential for Grignard formation because (1) ethers (unlike, say, alcohols or dichloromethane) will not react with Grignards and, more importantly, (2) only in ethers are Grignard reagents soluble. Each inserting reaction requires two atoms of lithium and generates one equivalent of lithium halide salt. As with Grignard formation, there is really very little limit on the types of organolithium that can be made this way. The table lists some of the most important commercially available organolithiums and Grignard reagents. Commercially available organometallics methyllithium (MeLi) methylmagnesium chloride, bromide, and iodide (MeMgX) ethylmagnesium bromide (EtMgBr) n-butyllithium (n-BuLi or just BuLi) Li sec-butyllithium (sec-BuLi or s-BuLi) Li butylmagnesium chloride (BuMgCl) tert-butyllithium (tert-BuLi or t-BuLi) Li allylmagnesium chloride and bromide MgX phenyllithium (PhLi) phenylmagnesium chloride and bromide (PhMgCl or PhMgBr) Organometallics as bases Organometallics need to be kept absolutely free of moisture-even moisture in the air will destroy them.

After initial enrollment in the study in 1986 antimicrobial chemicals generic doxycycline 200 mg with mastercard, the women were surveyed again in 1997 and 2004 antibiotic resistance threats in the united states 2013 discount doxycycline 100 mg fast delivery, and this longitudinal data provides a rich source of information on lifestyle habits virus affecting kids buy discount doxycycline 200 mg online, disease incidence antibiotics for sinus infection while breastfeeding safe 100 mg doxycycline, and mortality in this large cohort. They also reported on the risk of mortality among users of other specific nutritional supplements. In 1986, at baseline, 63 percent of the women were supplement users, and by 2004 the prevalence of supplement use had increased to 85 percent. The editors of the journal highlighted the article by designating it as part of their "less is more" series showing that in some cases less health care results in better health. They also invited a commentary from the authors of the controversial meta-analysis on antioxidants and mortality. This triple-play created a considerable media buzz and resulted in enhanced coverage-somewhat like the burst of attention given to the meta-analysis on vitamin E and mortality in 2004. The authors of the 2011 article purported to compare mortality in dietary supplement users versus nonusers, but in fact they provided no data on mortality among true nonusers of dietary supplements. For example, there were 12,769 users of multivitamins and 17,428 users of calcium supplements in 1986. The authors compare mortality in multivitamin users to mortality in the 25,474 women who did not use multivitamins-even if the women were using other dietary supplements, such as calcium. Similarly, the authors compare mortality in users of calcium supplements to mortality in the 20,735 women who did not use calcium-even if the women were using other dietary supplements such as multivitamins. In no case are users of any specific supplement compared to the 14,443 women who actually used no dietary supplements. The confounding is exacerbated by the fact that many of the women were taking numerous dietary supplements. At baseline, 25 percent of the women used two or three supplements, eight percent used four or five supplements, and seven percent used six or more. The four categories of iron dosage were: less than 50 mg per day, 50 to 200 mg per day, 200 to 400 mg per day, and over 400 mg per day. Waiting for symptomatic nutrient deficiency before adopting prudent dietary improvement or supplementation is counter to good sense and contrary to good public health policy. None of Thus, the effect of any specific supplement on mortality is confounded by the possible effects (negative or positive) of other supplements. The authors say multivitamins slightly increased total mortality, while calcium slightly decreased total mortality-but each the Benefits of Nutritional Supplements 36 the other studies found a negative impact on mortality, and some found beneficial effects when taking account of consistent longterm use or the combination of a multivitamin with other supplements. For example, in the Multiethnic Cohort Study of over 180,000 people, there was no association between multivitamin use and total mortality. Also, the study did not include any analysis related to the length of time the women had been using particular supplements. Many older people have difficulty absorbing adequate amounts of dietary vitamin B-12, and thus the Institute None* None * Except beneficial effect with consistent longterm use 37 the Benefits of Nutritional Supplements of Medicine and the Dietary Guidelines for Americans both recommend that people over the age of 50 eat foods fortified with B-12 or take a supplement of B-12. Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality. Reexamination of a meta-analysis of the effect of antioxidant supplementation on mortality and health in randomized trials. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. Prepared by the Johns Hopkins University Evidence-based Practice Center for the Agency for Healthcare Research and Quality. Bottom Line There is an abundance of evidence indicating that people who eat good diets and obtain adequate or even generous intakes of essential nutrients have better health that people who do not. Some of these health effects relate to improved normal body functions, such as having more energy, more endurance, better cognitive function, and improved disease resistance. Other effects may relate to a reduced incidence of some chronic diseases, including heart disease and cancer. A few scientists have jumped on "total mortality" as a measure of the overall impact of specific nutrients or nutritional supplements. Such analyses should be interpreted with caution, especially when the purported effects are very small and not related to the known mechanisms of action of the nutrients involved.

Syndromes

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Rates of reactions in ring sizes of 14 and above are essentially little different from those in acyclic compounds bacteria zombie plants purchase doxycycline 100 mg otc. To get large rings to inflection point buy discount doxycycline 100 mg on-line form virus joints infection doxycycline 100mg for sale, it is often necessary to antimicrobial keratolytic cheap 100mg doxycycline carry out the cyclization reaction in very dilute solution to discourage competing intermolecular reactions. However, there are many ring-forming reactions that are under thermodynamic and not kinetic control. For example, you have already seen that glucose exists predominantly as a six-membered ring in solution. The important thing is that acetone reacts with mannitol to form three five-membered acetals (dioxolanes) while benzaldehyde forms only two sixmembered acetals. This is quite a common result: when there is a choice, acetone prefers to react across a 1,2-diol to give a five-membered ring, while aldehydes prefer to react across a 1,3-diol to form a six-membered ring. Drawing a conformational diagram of the product on the right helps to explain why. All of the substituents are equatorial, making this a particularly stable structure. Now imagine what would happen if acetone formed this type of six-membered ring acetal. There would always be an axial methyl group, and the six-membered rings would be less stable. Aminals are another class of saturated heterocycles that form very readily under thermodynamic control: aminals are nitrogen analogues of acetals. They are usually made by refluxing a 1,2-diamine with an aldehyde in toluene (no acid catalyst is needed because the nitrogens are very nucleophilic), and this makes a very useful way of forming a chiral derivative of an achiral aldehyde. The product has a new chiral centre, and it forms as a single diastereoisomer because the phenyl ring prefers to be on the exo face of the bicyclic system (see Chapter 33). Combatting S-the Thorpe­Ingold effect Compare the following relative rates for epoxide-forming cyclization reactions. The second looks as though it suffers more steric hindrance but it is tens of thousands of times faster! Cl O krel = 1 4 Cl krel = 4 x 10 O O O Adding substituents to other ring-forming reactions makes them go faster too: in the next two examples the products are oxetanes and pyrrolidines. Here are the relative equilibrium constants for the formation of an anhydride from a 1,4-dicarboxylic acid (the unsubstituted acid is called succinic acid, and the values are scaled so that Krel for the formation of succinic anhydride is 1). The explanation comes in two parts, one of which may be more important than the other, depending on the ring being formed. The first part is more applicable to the formation of small rings, such as the first example we gave you. If you measure the bond angles of chains of carbon atoms, you expect them to be close to the tetrahedral angle, 109. The crystal structure of the 1,3-dicarboxylic acid in the margin, for example, shows a C­C­C bond angle of 110°. They will repel the carbon atoms already there, and force them a little closer than they were, making the bond angle slightly less. X-ray crystallography tells us that adding two methyl groups to our 1,3-dicarboxylic acid decreases the bond angle by about 4°. The bond angle has to become about 60°, which involves about 50° of strain for the first diacid, but only 46° for the second. By distorting the starting material, the methyl groups have made it slightly easier to form a ring. More substituents mean that some conformations are no longer accessible to the starting material-the green arcs below show how the methyl groups hinder rotation of the N and Br substituents into that region of space. Saturated heterocycles and stereoelectronics Because the same arguments apply to So for the reaction as a whole (the difference in entropy between starting material and products), increased substitution favours ring closure even under thermodynamic control. O Cyclization reactions can be classified by a simple system involving: (1) the ring size being formed; (2) whether the bond that breaks as the ring forms is inside (endo) or outside (exo) the new ring; and (3) whether the electrophile is an sp (digonal), sp2 (trigonal), or sp3 (tetrahedral) atom. The ring being formed has three members; the breaking C­Br bond is outside the new ring (exo); н Oxyanions add readily to alkynes: see Chapter 31, p.

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References:

• https://www.medrxiv.org/content/10.1101/2020.03.29.20045880v1.full.pdf
• https://www.cellmedicine.com/wp-content/uploads/2017/11/Stem-Cell-Therapy-A-Rising-Tide-MS-Chapter-9-17D.pdf
• https://www.mjc.edu/instruction/agens/native_tree_and_shub_id_2nd_edit.pdf
• https://uat.dietitians.ca/DietitiansOfCanada/media/Documents/Resources/Nutrition-and-Mental-Health-complete-2012.pdf?ext=.pdf
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