Ring-closures

Ring Closure. The kinetics of chelate ring formation in the rraw-[PtCl2(glyXNH3)] anion have been studied in several series of mixed solvents containing water or an alcohol plus an aptotic organic component. The rate law was established [equation (3)], the term in [H20] or [ROH] being ascribed to the presence of two molecules 

Minnitti, S. Lanza, P. Uguagliati, and U. Belluco, Inorg. Chim, Acta, 1976, 19, L55. 

Toniolo and G. Cavinato, Inorg. Chim. Acta Letters, 1978, 26, L5. 

Omarova, A. V. Babkov, and A. I. Busev, Tezisy Doklady Vses. Chugaevskoe Soveshch. Khim. Kompleksn. Soedinenii, 12th, 1975, 2, 152 (Chem. Abs., 1976, 85, 149 623). 

A type of ring closure reaction involves the use of metal phosphine coordination complexes as, for example, (12.365) [2]. 

Interference from Ring-closure.—In 1966, Kustin, Pasternack, and Weinstock published a paper entitled Steric effects in fast metal complex substitution reactions , in which they reported a temperature-jump study involving the nickel(ii) and cobalt(ii) complexes with a- and jS-alanine. With a-alanine, the substitution at cobalt was significantly faster than at nickel, but with the jS-isomer, whereas the Ni + substitution rate was approximately the same as before, substitution at Co + was significantly slower. The rate constants shown in Table 4 were obtained for the 1 1 

The data for the formation of the five-membered ring (4) are normal the cobalt rate is about thirty times as large as the nickel rate, and both are consistent with the mechanism described above, in which release of a water molecule from the inner co-ordination sphere of the metal ion is ratedetermining. For the six-membered ring (5), the situation is rather different. 

Further studies have shown that the steric effect is present in the formation of the analogous complexes with -aminobutyrate (Table 5). 

Makinen, Pearlmutter, and Stuehr have studied the reaction of a- and -alanine and histidine with Cu +. As predicted, the chelate effect is 

Similar results have been obtained by Pearson and Anderson for the formation of mono(acetylacetonato)copper(ii) in water and methanol. Both the keto and enol tautomers of acac react with Cu + at rates which are much less than expected for normal substitution. The second-order rate constant for the reaction of the enol form is the same in water and methanol (2 x 10 lmol s ), as expected for a mechanism in which the rate-determining step is the sterically difficult closure of the six-membered ring. For the reaction between the Cu ion and the keto form of acac, the slow step is thought to be the metal-ion-catalysed proton transfer from the weakly-bound keto tautomer. This suggestion is supported by the increase in rate constant of two orders of magnitude on changing from water (121 mol s ) to methanol (13001 mol s ) and the results of deuterium isotope substitution studies. 

If this is not a fortuitous fit, then a mechanism of two parallel reactions, one involving two water molecules in the transition state and the other none, may be indicated. Though the rates of ring closure vary markedly with solvent composition, activation parameters are the same within experimental uncertainty in all the solvent mixtures (aqueous alcohols, aqueous acetone) studied.  

Ring closure is also observed in the reactions of cis or trans-[Pt(NH2CH2CH20H)(L)Cl2], where L = NHg, NH2CH2CH2OH, or py, with bases. The kinetics of these reactions have been studied, and a mechanism has been proposed. The cis influence on ring closure was foimd to decrease in the order py NH2CH2CH20H NH3 the trans influences of these three ligands were very similar.  

This section is devoted to cyclizations and cycloadditions of ion-radicals. It is common knowledge that cyclization is an intramolecular reaction in which one new bond is generated. Cycloaddition consists of the generation of two new bonds and can proceed either intra- or intermolecularly. For instance, the transformation of 1,5-hexadiene cation-radical into 1,4-cyclohexadienyl cation-radical (Guo et al. 1988) is a cyclization reaction, whereas Diels-Alder reaction is a cycloaddition reaction. In line with the consideration within this book, ring closure reactions are divided according to their cation- or anion-radical mechanisms. 

Among the methods of organic synthesis, Diels-Alder reaction holds an important position. The cycloaddition of 1,3-dienes with olefins is one of the most thoroughly studied reactions in organic chemistry. 

The ion-radical Diels-Alder reactions represent a new development (see, e.g., reviews by Hintz et al. 1996, Berger and Tanko 1997). These reactions initiated with ion-radicals proceed faster by several orders of rate magnitude than the corresponding conventional reactions. This section presents the most important cyclizations developed through cation- and anion-radical schemes and the scheme that includes both cation- and anion-radicals. 

The most frequently used synthesis of isatins is the Sandmeyer procedure, which involves the formation of an isonitrosoacetanilide (3) from an aniline (2), chloral hydrate, and hydroxylamine. The isonitroso- 

Although o-bromo, o-chloro, ° and o-iodo anilines give 7-haloisatins, o-fluoroaniline has been reported not to give an isatin. 2,4-Difluoroaniline also fails to give an isatin although cyclization 

Giovannini, P. Portmann, A. Johl, K. Schnyder, B. Knecht, and H. P. Zen-Ruffinen, Helv. Chim. Acta 40, 249 (1957). 

Generally meta-substituted anilines give rise to a mixture of 4- and 6-substituted isatins - - although 4-trifluoromethyl, 4-nitro/ 4-amino, 4-hydroxy, 4-carboxy, 6-methoxy, and 6-bromo isatins have been reported without the other isomer. 

The Sandmeyer method has been used with di- and trisubstituted anilines to prepare and substituted 

This is not the case in a thermodynamically controlled reaction. Thermodynamic condol means that all compounds in the reaction mixture are in equilibrium, they constantly are interconverted into one another. The relative ratio of the products depends on the relative thermodynamic stability of each compound. If the desired macrocycle is the most stable compound, fine, but how can the concentration of a macrocycle be increased when it is not the global most stable product It has to be forced to be a more stable compound. This can be done by adding an additional component which interacts with the desired macrocycle in such a way that the resulting complex is the most stable compound. 

The field of dynamic combinatorial chemistry takes advantage of the template effect, and numerous macrocycles have been stabilized by a proper tanplate. Also for the construction of macrocycles for concave reagents, the template effect is very valuable. 

The reaction of [PtEtaCbipy)] with methyl acrylate to give [Pt CH(Me)(C02Me) 2-(bipy)l involves an unusual reaction sequence. The first step is the displacement of the bipy by methyl acrylate. Subsequent / -elimination and insertion are finally followed by return of the bipy to the platinum.  

The ki term corresponds to direct ring closure in the alkanolamine complex (4), the kz term to ring closure in the conjugate base (5) of the complex. The differences 

Ring-opening. At a given pH, the rate law for the opening of the ethanolamine chelate ring in cis- and /ra 5-[Pt(LL)2] and in /ranj-[PtCl(LL)(NH3)], where LL = (singly) deprotonated ethanolamine, in the presence of chloride is 

This rate law, of the form normal for nucleophilic substitution at platinum(ii) [cf. equation (1) above], implies parallel spontaneous and chloride-promoted reaction pathways. The observed dependence of rates on pH was rationalized in terms of ligand protonation equilibria, Chelate ring-opening is an important feature in the displacement of bidentate ligands, discussed in the following section. 

Venediktov and A. V. Belyaev, Izvest. sibirsk. Otdel. Akad. Nauk, Ser. khim. Nauk, 1974, 46 Ghent. Abs., 1974, 80, 115 565g). 

There have also been some investigations of cis-trans isomerization reactions in the absence of catalysts. For the isomerization of cw-[Pt(NH3)2Cl2] the first-order 

These may occur through a mechanism that involves formation of a tight ion pair by fission of the C—Cl bond and its collapse to give a co-ordinated chloride. 

SCHEME 8.13 Products expected from aldol cyclizations of 1,4- to 1,7-diketones. 

Heterocyclic rings show the same size preferences. Halohydrins and base give epoxides under irreversible conditions. Hemiacetals, acetals, and lactones under reversible conditions favor five- or six-membered rings, where 

The closure of four-membered rings requires special methods. Three reactions are frequently used the acyloin condensation (Eq. 8.16), photochemical cycloaddition (Eq. 5.6), and thermal ketene cycloadditions. 

Alkenes and acetylenes will cycloadd photochemically to other alkene molecules, especially those conjugated to carbonyl groups, to give cyclobutanes or cyclobutenes [29]. The molecules are raised to an excited electronic state, sometimes via a radiation-absorbing sensitizer compound, add to form the ring, and descend to the electronic ground state. In doubly unsym-metric cases, the regio- and stereochemistry can be complex and dependent on conditions. Nevertheless, many are synthetically useful. Two examples are shown in Equations 8.19 [30] and 8.20 [31]. 

Ketenes add thermally to alkenes to give cyclobutanones. Dichloroketene is readily generated in situ from trictiloroacetyl chloride and copper-activated zinc metal. In Equation 8.21, 1-hexyne was treated with dichloroketene to give the four-memhered ring. The chlorine atoms were then removed reductively with zinc dust [32]. 

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Electi ocyclic reactions are examples of cases where ic-electiDn bonds transform to sigma ones [32,49,55]. A prototype is the cyclization of butadiene to cyclobutene (Fig. 8, lower panel). In this four electron system, phase inversion occurs if no new nodes are fomred along the reaction coordinate. Therefore, when the ring closure is disrotatory, the system is Hiickel type, and the reaction a phase-inverting one. If, however, the motion is conrotatory, a new node is formed along the reaction coordinate just as in the HCl + H system. The reaction is now Mdbius type, and phase preserving. This result, which is in line with the Woodward-Hoffmann rules and with Zimmerman s Mdbius-Huckel model [20], was obtained without consideration of nuclear symmetry. This conclusion was previously reached by Goddard [22,39]. 

SUBSTITUTED BUTADIENES. The consequences of p-type orbitals rotations, become apparent when substituents are added. Many structural isomers of butadiene can be foiined (Structures VIII-XI), and the electrocylic ring-closure reaction to form cyclobutene can be phase inverting or preserving if the motion is conrotatory or disrotatory, respectively. The four cyclobutene structures XII-XV of cyclobutene may be formed by cyclization. Table I shows the different possibilities for the cyclization of the four isomers VIII-XI. These structmes are shown in Figure 35. 

Cyclic structures Ring dosures are described by a bond to a previously defined atom which is specified by a unique ID number. The ID is a positive integer placed in square brackets behind the atom. An " " indicates a ring closure. 

Besides specifications on atoms, bonds, branches, and ring closure, SLN additionally provides information on attributes of atoms and bonds, such as charge or stereochemistry. These are also indicated in square [ ] or angle < > brackets behind the entity e.g., trans-butane CH3CH=[s=t]CHCH3). Furthermore, macro atoms allow the shorthand specification of groups of atoms such as amino adds, e.g., Ala, Protein2, etc. A detailed description of these specifications and also specifications for 2D substructure queries or combinatorial libraries can be found in the literature [26]. 

Thus, to name just a few examples, a nucleophilic aliphatic substitution such as the reaction of the bromide 3.5 with sodium iodide (Figure 3-21a) can lead to a range of stereochemical products, from a l l mbrture of 3.6 and 3.7 (racemization) to only 3.7 (inversion) depending on the groups a, b, and c that are bonded to the central carbon atom. The ring closure of the 1,3-butadiene, 3.8, to cyclobutene... 

The method is incorporated into the CORA (Classification of Organic Reactions for Analysis) system [Sf Here, wc want to illustrate the merits of this approach by an example of its application to a specific problem, the prediction of the regioselec-tivity of a ring closure reaction. This is detailed in the following tutorial. 

The ring closure bond between atoms 1 and 5 would be strongly coupled to the other internal coordinates inless dummy atoms are used to define the Z-matrix (right). 

A particular advantage of the low-mode search is that it can be applied to botli cyclic ajic acyclic molecules without any need for special ring closure treatments. As the low-mod> search proceeds a series of conformations is generated which themselves can act as starting points for normal mode analysis and deformation. In a sense, the approach is a system ati( one, bounded by the number of low-frequency modes that are selected. An extension of th( technique involves searching random mixtures of the low-frequency eigenvectors using Monte Carlo procedure. 

An interesting application is the preparation of 1 2 3 4-tetrahydrocarb azole (VI), which is formed when phenylhydrazine is added to a boiling aolutiai of cyclohexanone in acetic acid the plienylhydrazone (V) Intermediately produced undergoes ring closure directly ... 

Baldwin s Rules (Suggestions) for Ring Closure JOC 1977, 42,3846 JCSCC 197G, 734, 736, 738... 

For irreversible ring closure reaction, the kinetic product will predominate. 

Note 5. At room temperature the 3,3-sigmatropic rearrangement begins. The anmonia, still present during the work up, will cause ring closure of the allenic dithioester to a 2-ff-thiopyran derivative. 

Within the cubane synthesis the initially produced cyclobutadiene moiety (see p. 329) is only stable as an iron(O) complex (M. Avram, 1964 G.F. Emerson, 1965 M.P. Cava, 1967). When this complex is destroyed by oxidation with cerium(lV) in the presence of a dienophilic quinone derivative, the cycloaddition takes place immediately. Irradiation leads to a further cyclobutane ring closure. The cubane synthesis also exemplifies another general approach to cyclobutane derivatives. This starts with cyclopentanone or cyclohexane-dione derivatives which are brominated and treated with strong base. A Favorskii rearrangement then leads to ring contraction (J.C. Barborak, 1966). 

A very mild and efficient synthesis of N-substituted -lactams uses the Mitsunobu reaction (see section 2.6.2) for the ring closure of seryl dipeptides protected at the terminal N as 4,5-diphenyloxazol-2(3f/)-one ( Ox ) derivatives (see section 2,6.3)... 

A-4-Thiazoline-2-ones and ring substituted derivatives are usually prepared by the general ring-closure methods described in Chapter II. Some special methods where the thiazole ring is already formed have been used, however. An original synthesis of 4- 2-carboxyphenyl)-A-4-thiazoline-2-one (18) starting from 2-thiocyanato-2-halophenyl-l-3-indandione (19) has been proposed (Scheme 8) (20, 21). Reaction of bicyclic quaternary salts (20) may provide 3-substituted A-4-thiazoline-2-one derivatives (21) (Scheme 9) (22). Sykes et al. (23) report the formation of A-4-thiazoline-2-ones (24) by treatment ef 2-bromo (22) or 2-dimethylaminothiazole (23) quaternary salts with base (Scheme 10). 

Ring opening and further ring closure of 2-imino-oxythiolan-l,3 derivatives (32) by water and/or methanol lead to the corresponding A-4-thiazoline-2-one (26) (Scheme 14) (30-32). 

The thiazolyl-2-thioglycollic acid (119) undergoes intramolecular ring closure to give mesoionic compound 120 under treatment with acetic anhydride and triethylamine (Scheme 60) (192). The parent acid (119) can be recovered from 120 by hydration with hot 50% aqueous sulfuric add. Compound 120 affords monohydrate of bis(-cyclopentenothiazolyi-2-thio)acetone (121) (192). 

The reaction of amines with the 4-phenylazo derivative (228) results in their rearrangement into triazolines. Depending on the basicity of the amines and the size of the alkoxy group, three different triazolines (229. 230, and 231) are obtained (Scheme 117) (454. 459, 472). In all cases, the first step involves nucleophilic addition of the amine to the carbonyl group followed by ring opening and further ring closure. 

Hydroxy-THISs add to the C-C bond of diphenylcyclopropenethione (181. Inner salts without substituents in 5-posnion react similarly with diphenylcyclopropenone (Scheme 10) (4, 18). Pwolysis of the stable adducts (9) leads to rupture of the R-C-CY bond. Subsequent ring closure yields 10. When Y = O. 10 eliminates COS. producing 2-pyridone. When Y = S. 10 is isolated together with its isocyanate extrusion product, a thiopyran-2-thione (18). 

Thiazolium salts can be obtained either directly by slight modifications of ring-closure methods, already described for the parent bases, or by classical quaternization of the bases, the detailed mechanism of which have been reported in Chapter III the quaternization is best represented by a classical SNj mechanism, the solvent playing an important part (14) unless the reaction is run without any solvent. 

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