Reactions intermolecular

All reactions described in this section are explained by (i) the oxidative addition of a halide to generate the arylpalladium halide 14 (ii) insertion of an alkene to form 15, which is regarded as carbopalladation of alkenes and (iii) formation of the new alkene 16 by elimination of /I-hydrogen (dehydropalladation). The reaction was reported independently by Mizoroki [3] and by Heck [4], and is called the Mizoroki Heck or Heck reaction [5]. 

It is worth noting at this point that, for stable DBA (dibenzylideneacetone) Pd(0) complexes, three types, namely Pd(dba)2, Pd2(dba)3, and Pd2(dba)3-CHCh are 

A dramatic increase of the TON is observed in the Heck reaction under high pressure. A value of 770 000 was achieved in the coupling reaction of iodobenzene with 2,3-dihydropyrrole under 8kbar at 100 °C. High pressure seems to stabilize the catalyst [12]. 

Chlorides are inert to Pd(0) under normal reaction conditions [13]. Chloroarenes react by the use of more electron-donating bidentate ligands, such as dippp, under somewhat severe conditions [14], Chlorides react easily with Ni(0) complexes. Also, f-Bu3P is a good ligand for the Heck reaction of chloroarenes [14a]. 

Further reaction of the bromide 33 with acrylonitrile in the presence of PI13P affords the disubstituted product 34 [21]. Selection of amines used in the reaction is critical. Fumaroyl dichloride (35) undergoes oxidative addition, decarbonylation and insertion of acrylate to produce octatrienedioate (36) [22]. 

The possibility of the occurrence of unusual condensation reactions with alkylphenols might be anticipated from the increased activation of the ring. Amongst the first, dimerisation of the alkenylphenol shown may be mentioned. 4-iso-Propenylphenol intrifluoracetic acid at ambient temperature furnished after 5mins.,1-(4-hydroxyphenyl)-1,3,3-trimethylindan-6-olin acceptable yiekJ(ref.64). 

6-Xylenol afforded a dimeric product upon bacterial action resulting in 

10-dihydroxy-3,5,8,10-tetramethyltricyclo[6.2.2.0 ndodeca-5,11-diene-4,9-dione (ref.65), a known natural product. Sodium periodate oxidation of 2,6-xylenol also gave the same product in racemic form. Carvacrol under similar conditions (chap. 5, ref. 18) gives a related product, which has been formulated with the structure shown. 

By contrast, 4-methylphenol in benzene or dichloromethane containing a little triifluoracetic acid reacts at the 2-position to the hydroxyl group with 2-methoxycarbonylbenzo-1,4-quinone over 4 hours at ambient temperature to 

2-iso-Propylphenol and 2-(4-hydroxy-3-isopropylbenzoyl)benzoic acid in ice-cold ethereal solution treated dropwise with concentrated sulphuric acid during 5 mins, and reacted for a further 15 mins, afforded 3,3-bis(4-hydroxy-3-isopropyl-phenyl)phthalide in 76% yield presumably by way of the 3-monophthalide (ref.68). 

Following the introduction of the intramolecular azido-Schmidt reaction, it was reported that potent Lewis acids such as TiCL were found to facilitate certain intermolecular 

Photoelectron, UV and NMR spectroscopy, as well as MNDO calculations all predict a reduced HOMO-LUMO gap for alkenes with captodative substitution, and an enhanced reactivity of the p carbon [43]. This explains their radicophilic behavior and their high reactivity in cycloaddition processes, the diradicaloid transition states of which are stabilized when the mechanism is asynchronous cf. Sec. 3.3.7). 

Chiral dioxolanone 71 and oxazolidinone 72 alkenes, which can be readily prepared from lactic acid or alanine, respectively, undergo diastereoselective radical 

Despite the fact that enamides (E)-28 and (Z)-28 react more slowly than 22, the rearranged products 29 were isolated as single diastereomers, which were 

Two possible adducts (69 or 70) can be formed in this process depending on the nature of the electrophile used. This observation suggests that the allyHc 

These species undergo transmetallation producing the allylmagnesium halide 73 and regenerating alkylcopper 71. The same reactivity pattern has been shown for conjugated enynes 74 when they were treated with secondary and tertiary alkyl 

The application of copper-catalyzed intermolecular carbomagnesiation of a double bond in the synthesis of alkyhdenecyclopropanes (ACPs) has been reported by our research group [23]. As AGP derivatives have proved their high value in 

p-MeC6H4, o-BnOCeH4, p-BrC6H4, P-HOOCC6H4, 3,5-Br2C6H3, 3,4,5,-(MeO)3C6H2 

Ar= 1-naphthyl, 2-naphthyl, d-MeOCgHa, +F3CC6H4 R = C02Et, CH2CN, Ac, Bz, Ph, Me 

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Intramolecular reactions are faster and cleaner than intermolecular reactions. When we... 

Syntheses of alkenes with three or four bulky substituents cannot be achieved with an ylide or by a direct coupling reaction. Sterical hindrance of substituents presumably does not allow the direct contact of polar or radical carbon synthons in the transition state. A generally applicable principle formulated by A. Eschenmoser indicates a possible solution to this problem //an intermolecular reaction is complex or slow, it is advisable to change the educt in such a way. that the critical bond formation can occur intramolecularly (A. Eschenmoser, 1970). 

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

Unlike the intermolecular reaction, the intramolecular aminopalladation proceeds more easily[13,14,166], Methylindole (164) is obtained by the intramolecular exo amination of 2-allylaniline (163). If there is another olefinic bond in the same molecule, the aminopalladation product 165 undergoes intramolecular alkene insertion to give the tricyclic compound 166[178]. 2,2-Dimethyl-l,2-dihydroquinoline (168) is obtained by endo cyclization of 2-(3,3-dimethyiallyl)aniline (167). The oxidative amination proceeds smoothly... 

Intramolecular reactions with alkenes. While the intermolecular reaction is limited to unhindered alkenes, the intramolecular version permits the participation of even hindered substituted alkenes, and various cyclic compounds are prepared by the intramolecular Heck reaction. Particularly the... 

Self-Rephca.tingSystems. Recently, molecules have been synthesized that can catalyze covalent bond-making reactions by forming a noncovalently bonded superstmcture, a maneuver that converts an intermolecular reaction into an intramolecular one. In general, in such systems, two... 

High levels of asymmetric induction have been achieved in the hydroboration of 1,3-, 1,4-, and 1,5-dienes with thexylborane (482,483,489,490). The first chiral center is formed by an intermolecular reaction. In the second step, the organoborane intermediate undergoes an intramolecular hydroboration, creating the second chiral center with high diastereoselectivity. 

Chiral Lactones and Polyesters. Similar to intermolecular reactions described previously. Upases also catalyze intramolecular acylations of hydroxy acids the reactionsults in the formation of lactones. 

Intermolecular reactions with typical cycloaddition components are also possible. Phenyl isocyanate in ether converts triisopropyldiaziridinimine (182) to the 1,2,4-triazolidine under mild conditions. Labeling with a deuterated isopropyl group revealed that cycloaddition is not preceded by N—N cleavage, which should have resulted in deuterium randomization (77AG(E)109). 

Either UV-VIS or IR spectroscopy can be combined with the technique of matrix isolation to detect and identify highly unstable intermediates. In this method, the intomediate is trapped in a solid inert matrix, usually one of the inert gases, at very low temperatures. Because each molecule is surrounded by inert gas atoms, there is no possiblity for intermolecular reactions and the rates of intramolecular reactions are slowed by the low temperature. Matrix isolation is a very useful method for characterizing intermediates in photochemical reactions. The method can also be used for gas-phase reactions which can be conducted in such a way that the intermediates can be rapidly condensed into the matrix. 

Unreacted Starting Material S Intermolecular Reaction Product Keto Ester Product ... 

The mechanisms available to intramolecular reactions are the same as those of intermolecular reactions. The same problems of kinetic equivalence of rate terms may arise, and Table 6-3 shows some kinetically equivalent mechanisms for intramolecular reactions of the acyl function. The efficiency of intramolecular reactivity may be difficult to assess. One technique, described above as a method for the detection of an intramolecular reaction, is to make a comparison with an analog incapable of the intramolecular process. Thus p-nitrophenyl 5-nitrosalicylate, 17, hydrolyzes about 2500 times faster than p-nitrophenyl 2-methoxy-5-nitrobenzoate, 18. 

The currently popular approach is to compare the rate of the intramolecular reaction with the rate of an intermolecular reaction in which the reacting groups are closely similar. The intermolecular reaction will usually be overall second-order, in accordance with the rate equation... 

First-order and second-order rate constants have different dimensions and cannot be directly compared, so the following interpretation is made. The ratio intra/ inter has the units mole per liter and is the molar concentration of reagent Y in Eq. (7-72) that would be required for the intermolecular reaction to proceed (under pseudo-first-order conditions) as fast as the intramolecular reaction. This ratio is called the effective molarity (EM) thus EM = An example is the nu-... 

For this example EM = 1260 M. In ealculating EM it is necessary that the intermolecular reaction selected for the comparison possess the same mechanism as the intramolecular reaction. 

The proximity effect. This is the simple idea that in an intramolecular reaction the substrate function may be exposed to a larger local concentration of the reagent than in an intermolecular reaction, because the two functions are covalently constrained to occupy adjacent space. This effect has been called the approximation or propinquity effect. The proximity effect certainly seems physically reasonable and is likely to make some contribution to intramolecular reactivity, but it cannot be a major contributor when EM is large, because EM is itself a measure of a presumed local concentration, and the observed large EM values are physically impossible concentrations. The magnitude of rate enhancement achievable by prox-... 

Ring closure of 2-chloro-l-phenethylpyridinium ion (247) (prepared in situ) to l,2-dihydro-3,4-benzoquinolizium ion involves intramolecular nucleophilic displacement of the chloro group by the phenyl 77-electrons. A related intermolecular reaction involving a more activated pyridine ring and more nucleophilic 7r-electrons is the formation of 4-( -dimethylaminophenyl)pyridine (and benzaldehyde) from dimethylaniline and 1-benzoylpyridinium chloride (cf. Section III,B,4,c). 

The rhodium-catalyzed tandem carbonyl ylide formation/l,3-dipolar cycloaddition is an exciting new area that has evolved during the past 3 years and high se-lectivities of >90% ee was obtained for both intra- and intermolecular reactions with low loadings of the chiral catalyst. 

With a radical-scavenging compound present in the reaction mixture, an alkyl radical species like 5 can be trapped, thus suggesting a fast conversion of the alkoxy radical 3 by intramolecular hydrogen abstraction, followed by a slow intermolecular reaction with nitrous oxide. 

The Barton reaction is usually carried out by irradiation of a nitrite ester 1 dissolved in a hydroxyl-free solvent under nitrogen atmosphere. Possible side-reactions can be decomposition reactions and intermolecular reactions sometimes the disproportionation may even predominate ... 

A domino reaction,in this case consisting of an inter- and an intramolecular Diels-Alder reaction, is a key step in the synthesis of the hydrocarbon pago-dane 30, reported by Prinzbach et al When the bis-diQnQ 27 is treated with maleic anhydride 4, an initial intermolecular reaction leads to the intermediate product 28, which cannot be isolated, but rather reacts intramolecularly to give the pagodane precursor 29 ... 

The ene reaction as a reaction principle has been first recognized and systematically investigated by Alder It is a thermal addition reaction of a double bond species 2—the enophile—and an alkene 1—the ene—that has at least one allylic hydrogen. The intramolecular variant is of greater synthetic importance than is the intermolecular reaction. 

Acyclic diene molecules are capable of undergoing intramolecular and intermolec-ular reactions in the presence of certain transition metal catalysts molybdenum alkylidene and ruthenium carbene complexes, for example [50, 51]. The intramolecular reaction, called ring-closing olefin metathesis (RCM), affords cyclic compounds, while the intermolecular reaction, called acyclic diene metathesis (ADMET) polymerization, provides oligomers and polymers. Alteration of the dilution of the reaction mixture can to some extent control the intrinsic competition between RCM and ADMET. 

Whereas the production of arylnitrenes by the deoxygenation of nitrosobenzenes or nitro-benzenes by trivalent phosphorus reagents and their subsequent intramolecular ring expansion to 3//-azepines are well-known processes, the corresponding intermolecular reactions to form 1//-azepines have been exploited only on rare occasions and appear to be of little preparative value. For example, the highly electrophilic pentafluorophenylnitrene, obtained by deoxygenation of pentafluoronitrosobenzene with triethyl phosphite in benzene solution, produced a low yield (2-10%) of l-(pentafluorophenyl)-l//-azepine, which was isolated as its [4 + 2] cycloadduct with ethenetetracarbonitrile.169 With anisole as the substrate l-(pentafluorophenyl)-l//-azepin-2(3//)-one (16% bp 128 —130 C/0.4 Torr) was obtained. 

The stereoselectivity of these intermolecular reactions between 1-alkoxyallylstannanes and aldehydes induced by boron trifluoride-diethyl ether complex is consistent with an open-chain, antiperiplanar transition state. However, for intramolecular reactions, this transition state is inaccessible, and either (Z)-.yyn-products are formed, possibly from a synclinal process105, or 1,3-isomerization competes113. Remote substituents can influence the stereoselectivity of the intramolecular reaction114. 

Intermolecular reaction of the mannose-derived 2,3-0-isopropylideiie-a-D-/y.vc>-pentodialdo-l,4-furanoside 13 affords a diastereomeric mixture of nitroalcohols 14. Upon fluoride-catalyzed desilylation, a stereoisomerically pure nitrocyclitol 15 was obtained from a successive intramolecular nitroaldol reaction as a consequence of the reversibility of the nitroaldol reaction which, in this case, allows the equilibration of isomers through open-chain intermediates33. 

Asymmetric Bond Formation with Simple Diastereoselection 1.4.5.3.1. Intermolecular Reactions... 

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