Regiochemistry

When the double bond is substituted with alkyl groups or other electron donating groups, the effect of the substituents on the regiochemistry leads to the trend known as Markovnikov addition. Markovnikov addition predicts the dominant product to arise from nucleophilic addition to the more substituted carbon. Note that nucleophilic addition to the more substituted carbon forms the more sterically crowded and thus less stable product (Eq. 10.7). Therefore, Markovnikov addition predicts the kinetic product, not the thermodynamic product. 

Major product Markovnikov addition Kinetic product 

Minor product Anti-Markovnikov addition Thermodynamic product 

Electron donating groups such as alkoxy and dialkylamino also stabilize carbenium ions, and so are expected to increase hydration rates. Furthermore, the protonation occurs 

An analogous stepwise mechanism was also proposed by Wohrle [36] for the cation-radical-initiated cycloaddition of electron-rich allenes with pentamethyl-cyclopentadiene in the presence of tris (p-tolyl) aminium hexafluoroantimonate (TTA SbF6 ) (Equation 1.15). 

When an unsymmetrical diene reacts with an unsymmetrical dienophile, two regioisomer adducts can be formed depending on the orientation of the substituents in the adduct [37] (Equations 1.16 and 1.17). 

The description of the regiochemistry of the cycloaddition products of dienes that have two or more dissimilar substituents may require incorporation of their name in the new notation (Equations 1.18 [38] and 1.19 [39]). 

The regioselectivity of the Diels-Alder reaction depends on the number and nature of substituents on diene and dienophile and on the reaction conditions (catalyst, temperature, pressure, solvent, etc.). Generally, 1- and 2-substituted 

Indazole itself and indazoles containing alkyl or aryl substituents in positions 3, 4, 5, and 6 form ligands where boron is bonded to the more hindered N-l which represent a special class of homoscorpionate ligands containing a protective pocket. 

Allylm i/orosilanes couple with aryl iodides at 80-100 °C in the presence of Pd(PPh )4 and TBAF, whereas the reaction with aryl triflates is carried out using Pd(OAc)2, 1,4-bis(diphenylphosphino)butane (dppb), and TASF. In both cases, C —C bond formation always occurs at the y-carbon of allylsilanes. Thus, starting with 3-methyl-2-butenyltrifluorosilane, coupled products having a quaternary carbon at the benzylic or the allylic position are readily prepared [Eq.(31)] [31]. 

The coupling reaction of (/ ,Z)-4-(difluorophenylsilyl)-2-hexene (69% ee) [33] with 2-naphthyl triflate in the presence of Pd(PPh3)4 as the catalyst and TASF in DMF afforded (5, )-2-(2-naphthyl)-3-hexene of 63% ee [Eq.(32)]. Thus, the stereochemistry was proved to be anti with y-regioselectivity (see Section 10.7.1). These results are consistent with the SE reaction of allyltrimethylsilanes. When TASF was replaced by CsF, the stereochemical outcome was again anti, but the CsF-mediated reaction in THF gave syn-coupled product. 

That is, the stereochemical course was switched from anti to syn. Thus, the solvent and salt effects were striking. To summarize these results, in a polar solvent such as DMF, the stereochemistry is always anti the syn stereochemistry results in a less-polar solvent such as THF in the presence of an alkaline-metal fluoride [34]. 

As discussed above, the cross-coupling reaction of organosilicon compounds proceeds stereospecifically, depending on the reaction conditions. Thus, the transformation C —Si - C —C is demonstrated to be accompanied by chirality transfer. Now, the question arises of how to prepare organosilicon compounds whose chiral allylic carbon is substituted by a silyl group. The most accessible solution is asymmetric hydrosilylation of olefins [35]. We studied asymmetric hydrosilylation of 1-substituted 1,3-butadienes using 

For asymmetric hydrosilylation of cyclic 1,3-dienes, PPF-OAc ligand was appropriate for achieving relatively high ee, and thus we could obtain 2- 

There are two hydroxyl groups in the molecule, and both of these could be protonated. However, only one molecule of water is eliminated. This reflects the El mechanism of the reaction. Only the tertiary alcohol can readily lose water to give a stable tertiary carbocation, and hence, only this undergoes elimination. Although an alternative elimination from this carbocation to give the 1-alkene is theoretically possible, the trisubstituted 2-alkene is more stable and hence is the predominant product  

In the ElcB reaction, the regiochemistry is entirely dependent on the ease of formation of the carbanion. Which hydrogen is the most acidic, and which one, when removed, gives the most stable carbanion We should briefly review carbanion stability. Because alkyl groups are electron donors, primary carbanions are the most stable, and tertiary ones the least  

We can now readily deduce the regiochemistry of elimination for 10.8 the reaction goes through an ElcB mechanism because the intermediate enolate anion is easily formed. 

FIGURE 10.21 Regiochemistry of E2 elimination from 2-substituted pentanes. 

TABLE 10.1 Features of Zaitsev and Hofmann Elimination in E2 Reactions 

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Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization... 

For intramolecular D-A rxns, geometric constraints can now reverse the normal regiochemistry of the addition as compared to the intermolecular rxn. 

Extensive studies on the Wacker process have been carried out in industrial laboratories. Also, many papers on mechanistic and kinetic studies have been published[17-22]. Several interesting observations have been made in the oxidation of ethylene. Most important, it has been established that no incorporation of deuterium takes place by the reaction carried out in D2O, indicating that the hydride shift takes place and vinyl alcohol is not an intermediate[l,17]. The reaction is explained by oxypailadation of ethylene, / -elimination to give the vinyl alcohol 6, which complexes to H-PdCl, reinsertion of the coordinated vinyl alcohol with opposite regiochemistry to give 7, and aldehyde formation by the elimination of Pd—H. 

Butenoic acid and 4-pentenoic acid (42) react with alkenyl halides or tri-flates to afford 7-alkenyl-7-lactones and the ( -alkenyl-5-valerolactone 44 via the TT-allylpalladium intermediate 43 formed by the elimination of Pd—H and its readdition in opposite regiochemistry using a phosphine-free Pd cata-lyst[43]. 

In the presence of peroxides hydrogen bromide adds to the double bond of styrene with a regioselechvity opposite to Markovmkov s rule The reachon is a free radical addi tion and the regiochemistry is governed by preferenhal formation of the more stable radical... 

There is an important difference in the regiochemistry of ring opening reactions of epoxides depending on the reaction conditions Unsymmetncally substituted epoxides tend to react with anionic nucleophiles at the less hindered carbon of the ring Under conditions of acid catalysis however the more highly substituted carbon is attacked... 

Shape selective catalysts, such as ZeoHtes of the H-ZSM-5 type, are capable of directing alkyl groups preferentially to the para position (18). The ratio of the catalyst to the substrate also plays a role ia controlling the regiochemistry of the alkylations. For example, selective alkylation of anilines at the para position is achieved usiag alkylatiag ageats and AlCl ia equimolar ratio (19). 

Excellent yields of the former product are also obtained with quinoline N-oxide. Improved yields of Reissert compounds are found under phase-transfer conditions (29). The regiochemistry of the method changes dramatically with /V-alkyl quin olinium salts, eg, /V-methy1quino1inium iodide [3947-76-0] (12), which form 4-cyanoquinoline [23395-72-4] (13) (30), through the intermediary in this example of A[-methyl-4-cyano-l,4-dihydroquinoline... 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

H0(CH2)20H, oxalic acid, CH3CN, 25°, 95% yield.Note that ketals prepared with oxalic acid from enones retain the olefin regiochemistry. ... 

Reactions of alkynes with electrophiles are generally similar to those of alkenes. Because the HOMO of alkynes (acetylenes) is also of n type, it is not surprising that there IS a good deal of similarity between alkenes and alkynes in their reactivity toward electrophilic reagents. The fundamental questions about additions to alkynes include the following. How reactive are alkynes in comparison with alkenes What is the stereochemistry of additions to alkynes And what is the regiochemistry of additions to alkynes The important role of halonium ions and mercurinium ions in addition reactions of alkenes raises the question of whether similar species can be involved with alkynes, where the ring would have to include a double bond ... 

The nature of the transition state in elimination reactions is of great importance, since it controls the regiochemistry of p elimination in compounds in which the double bond can be introduced in one of several positions. These effects are discussed in the next section. 

In the El cb mechanism, the direction of elimination is governed by the kinetic acidity of the individual p protons, which, in turn, is determined by the polar and resonance effects of nearby substituents and by the degree of steric hindrance to approach of base to the proton. Alkyl substituents will tend to retard proton abstraction both electronically and sterically. Preferential proton abstraction from less substituted positions leads to the formation of the less substituted alkene. This regiochemistry is opposite to that of the El reaction. 

The silyl and stannyl substituents are crucial to these reactions in two ways. In the electrophilic addition step, they act as electron-releasing groups promoting addition and also control the regiochemistry. A silyl or starmyl substituent strongly stabilizes carboca-tion character at the /3-catbon atom and thus directs the electrophile to the a-carbon. The reaction is then completed by the limination step, in which the carbon-sihcon or carbon-tin bond is broken. 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Calculations at several levels of theory (AMI, 6-31G, and MP2/6-31G ) find lower activation energies for the transition state leading to the observed product. The transition-state calculations presumably reflect the same structural features as the frontier orbital approach. The greatest transition-state stabilization should arise from the most favorable orbital interactions. As discussed earlier for Diels-Alder reactions, the-HSAB theory can also be applied to interpretation of the regiochemistry of 1,3-dipolar cycloaddi-... 

Additions of the halogen fluorides to unsaturated steroids [62, 95, 96, 97, 98, 99] and carbohydrates [62, 75] are well known Typical reagent combinations include l,3-dibromo-5,5-dimethylhydantoin (DBH) or the Af-halosuccinimides with hydrogen fluoride Reversal of the expected regiochemistry can be observed with certain steroidal olefins [JOO, 101] (equation 7)... 

Interhalogen compounds such as iodine monochloride have been added to fluoroalkyl-substituted alkenes. The observed unidirectional regiochemistry can be explained by the polarity ot the double bond [14] (equation 7)... 

Normally, phenylhydrazine reacts with the enol form of 1,1,1-trifluorometh-ylpentane-2,4-dione to give 5-methyl-l-phenyl-3-tnfluoromethylpyrazole as the major product. However, the use of pyrrolidine as a transient carbonyl-blocking group can completely reverse the regiochemistry of the addition and leads to 3-methyl-l-phenyl-5-trifluoromethylpyrazole [102] (equation 88)... 

Phenylmercury halides give the corresponding phenylmercury derivative, CgH5HgC(CF3)3 (61%) [156], and perfluorocyclobutene gives the corresponding cyclobutyl derivative [156], Mechanistically, the reaction could be interpreted as formation of the fluorocarbanion via nucleophilic addition of fluoride ion to the fluoroolefin followed by capture of the intermediate fluorocarbanion by the mercury salt [156]. The regiochemistry of the reaction is consistent with this mechanism [156] (equation 119). 

The regiochemistry is determined by the regiochemistry of the fluoride ion addition reaction, that is, via the most stable perfluorocarbanion intermediate Von Werner used a similar reaction to prepare silver compounds from perfluoro-2-methyl-2-butene and perfluoro 2 methyl-2-pentene [271] Silver(I) fluoride adds to bis(ttitluoromethyl)ketene in DMF without fluoride ion catalysis [270] The analogous trifluorovinylsulfurpentafluoride reacts similarly to give the isolable pentafluorosulfur derivative [272] (equation 187)... 

The additions of phenyl azide and phenylnitrile oxide to pentafluorophenyl-acetylene are also regiospecific [75, 7S] (equation 12). Interestingly, in the latter reaction, phenylacetylene gives regiochemistry that is opposite to that observed for pentafluorophenylacetylene [75]... 

Lastly, perfluoropropyne undergoes cycloaddition with diphenyldia-zomethane to give a single product, although the regiochemistry is undetermined... 

Because the fluorine substituents both inductively and hyperconjugatively withdraw electron density from the C(2)-C(3) tt bond, the LUMO is located there, and Diels-Alder reactions take place exclusively with this bond [25] 1,1 -Difluoro allene and fluoroallene reaet readily with a large selection of cyclic and acyclic dienes, and acyclic dienes, [2+2] cycloadditions compete with the Diels-Alder processes As shown in the example in equation 79, a significantly different regiochemistry is observed for the [2+4] cycloaddition compared with the [2+2]... 

Bis(tnfluoromethyl)-4,5-dihydrooxazin-6-ones [28] and their O-acetylated dcnvatives [96] are formed on treatment of acyl imines with acetyl chloride-hiethylamine at room temperature. The reaction was interpreted as a cycloaddition reaction involving a ketene [28] However, the periselectivity and regiochemistry of this reactwn-are not in agreement with results obtained from the reaction of... 

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