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Uncovering the importance of proton donors in TmI2-promoted electron transfer: facile C-N bond cleavage in unactivated amides.

Szostak M, Spain M, Procter DJ - Angew. Chem. Int. Ed. Engl. (2013)

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK. michal.szostak@manchester.ac.uk

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To date, the majority of strategies to functionalize amide bonds have focused on activation of the carbonyl group towards nucleophilic addition, however only few examples of the selective activation of σ C–N bonds in amides have been reported... In this regard, the seminal discovery of Kagan and co-workers that SmI2 acts as a strong electron donor has resulted in one of the most important single-electron transfer reagents in organic chemistry., However, the inherent limitation of SmI2 is its relatively low redox potential (E° (Ln)=−1.5 V vs... NHE), especially when compared with the extremely powerful, albeit less chemoselective, alkali metals in liquid ammonia (i.e. Birch-type reductants)... In addition, two acyclic amides were similarly cleaved, thus demonstrating that the cyclic structure of amides is not necessary for the scission... Importantly, secondary n-alkyl and n-aryl amides did not undergo the cleavage reaction (see the Supporting Information), thus indicating complete selectivity of the reducing system for these tertiary amides... On the basis of this experiment and the known propensity of nonclassical LnI2 to cleave C−O bonds in ethers, we propose that the mechanism of the TmI2-mediated cleavage involves a direct insertion of Tm into the C−N amide bond; however, a mechanism involving fragmentation of an initially-formed ketyl-type radical seems also to be operating in some cases as suggested by the correlation of the reaction efficiency with thermochemical stabilization energies (SE) of the fragmenting radical in the series: tBu (71 %, SE=4.35 kcal mol)>iPr (29 %, SE=2.57 kcal mol)>Me (<2 %, SE=−1.65 kcal mol)... Moreover, it strongly suggests that the reactivity of nonclassical lanthanides(II) extends beyond being the reagents that simply close the energy gap between SmI2 and the Birch-type reductants., Having established that TmI2−ROH is capable of an efficient electron transfer to the amide carbonyl group but not their reduction, the reagent system was applied to the generation of ketyl radicals from esters (Table 2)... To gain a preliminary mechanistic insight into the key effect of protic additives on the properties of the TmI2 reagent (note that in both cases no reaction was observed with TmI2 alone, see the Supporting Information), we examined the reactivity of TmI2 with a set of aromatic hydrocarbons with gradually increasing redox potentials in the presence of MeOH (Table 3)... In this study, the TmI2−MeOH complex was found to reduce aromatic hydrocarbons with redox potentials up to −2.6 V (vs... SCE); however, benzene was inert under the reaction conditions... These results suggest that the addition of MeOH to TmI2 results in an increase of the reduction potential of TmI2 by approximately 0.6 V... Furthermore, deuterium incorporation and kinetic isotope effect studies in the reduction of stilbene, a reaction that is known to proceed through an outer-sphere electron-transfer mechanism, using TmI2−ROH ([D4]methanol, 96.5 % D2 incorporation, kH/kD=1.13±0.1; D2O, 98.0 % D2 incorporation, kH/kD=1.27±0.1), suggest that the increase in reduction potential of the reagent results from complexation between the proton donor and TmI2... A detailed examination of different proton donors in the model system (see the Supporting Information) revealed that a much lower concentration of alcohols (10 equiv) is required to enhance the redox potential of TmI2 in comparison with SmI2 (100 equiv)... In summary, the highly unusual cleavage of unactivated σ C−N bonds in amides in the presence of TmI2, the first nonclassical lanthanide(II) iodide in the series (TmI2, DyI2, NdI2), has been achieved.

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Cleavage of unactivated σ C−N bonds in amides in the presence of TmI2(ROH)n at 23 °C.
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fig02: Cleavage of unactivated σ C−N bonds in amides in the presence of TmI2(ROH)n at 23 °C.

Mentions: With the optimized conditions in hand, a series of amides was subjected to the reaction to provide an initial examination of the scope of this transformation (Scheme 1). The C−N bond scission occurred for both unhindered and sterically encumbered pyrrolidinyl amides (1 a–1 c). Moreover, the reaction of the azetidinyl amide 1 d demonstrated that the reaction is applicable to other cyclic amides. In addition, two acyclic amides (1 e–1 f) were similarly cleaved, thus demonstrating that the cyclic structure of amides is not necessary for the scission. Importantly, secondary n-alkyl and n-aryl amides did not undergo the cleavage reaction (see the Supporting Information), thus indicating complete selectivity of the reducing system for these tertiary amides. To gain a preliminary mechanistic insight, we subjected a sterically biased aziridinyl amide 1 g to the reaction conditions. The reaction afforded an approximately 1.6:1.0 ratio of regioisomeric amides, with the predominant product resulting from cleavage at the less substituted carbon center. On the basis of this experiment and the known propensity of nonclassical LnI2 to cleave C−O bonds in ethers,15 we propose that the mechanism of the TmI2-mediated cleavage involves a direct insertion of TmII into the C−N amide bond; however, a mechanism involving fragmentation of an initially-formed ketyl-type radical seems also to be operating in some cases as suggested by the correlation of the reaction efficiency with thermochemical stabilization energies (SE) of the fragmenting radical in the series: tBu (71 %, SE=4.35 kcal mol−1)>iPr (29 %, SE=2.57 kcal mol−1)>Me (<2 %, SE=−1.65 kcal mol−1).16


Uncovering the importance of proton donors in TmI2-promoted electron transfer: facile C-N bond cleavage in unactivated amides.

Szostak M, Spain M, Procter DJ - Angew. Chem. Int. Ed. Engl. (2013)

Cleavage of unactivated σ C−N bonds in amides in the presence of TmI2(ROH)n at 23 °C.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265963&req=5

fig02: Cleavage of unactivated σ C−N bonds in amides in the presence of TmI2(ROH)n at 23 °C.
Mentions: With the optimized conditions in hand, a series of amides was subjected to the reaction to provide an initial examination of the scope of this transformation (Scheme 1). The C−N bond scission occurred for both unhindered and sterically encumbered pyrrolidinyl amides (1 a–1 c). Moreover, the reaction of the azetidinyl amide 1 d demonstrated that the reaction is applicable to other cyclic amides. In addition, two acyclic amides (1 e–1 f) were similarly cleaved, thus demonstrating that the cyclic structure of amides is not necessary for the scission. Importantly, secondary n-alkyl and n-aryl amides did not undergo the cleavage reaction (see the Supporting Information), thus indicating complete selectivity of the reducing system for these tertiary amides. To gain a preliminary mechanistic insight, we subjected a sterically biased aziridinyl amide 1 g to the reaction conditions. The reaction afforded an approximately 1.6:1.0 ratio of regioisomeric amides, with the predominant product resulting from cleavage at the less substituted carbon center. On the basis of this experiment and the known propensity of nonclassical LnI2 to cleave C−O bonds in ethers,15 we propose that the mechanism of the TmI2-mediated cleavage involves a direct insertion of TmII into the C−N amide bond; however, a mechanism involving fragmentation of an initially-formed ketyl-type radical seems also to be operating in some cases as suggested by the correlation of the reaction efficiency with thermochemical stabilization energies (SE) of the fragmenting radical in the series: tBu (71 %, SE=4.35 kcal mol−1)>iPr (29 %, SE=2.57 kcal mol−1)>Me (<2 %, SE=−1.65 kcal mol−1).16

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK. michal.szostak@manchester.ac.uk

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

To date, the majority of strategies to functionalize amide bonds have focused on activation of the carbonyl group towards nucleophilic addition, however only few examples of the selective activation of σ C–N bonds in amides have been reported... In this regard, the seminal discovery of Kagan and co-workers that SmI2 acts as a strong electron donor has resulted in one of the most important single-electron transfer reagents in organic chemistry., However, the inherent limitation of SmI2 is its relatively low redox potential (E° (Ln)=−1.5 V vs... NHE), especially when compared with the extremely powerful, albeit less chemoselective, alkali metals in liquid ammonia (i.e. Birch-type reductants)... In addition, two acyclic amides were similarly cleaved, thus demonstrating that the cyclic structure of amides is not necessary for the scission... Importantly, secondary n-alkyl and n-aryl amides did not undergo the cleavage reaction (see the Supporting Information), thus indicating complete selectivity of the reducing system for these tertiary amides... On the basis of this experiment and the known propensity of nonclassical LnI2 to cleave C−O bonds in ethers, we propose that the mechanism of the TmI2-mediated cleavage involves a direct insertion of Tm into the C−N amide bond; however, a mechanism involving fragmentation of an initially-formed ketyl-type radical seems also to be operating in some cases as suggested by the correlation of the reaction efficiency with thermochemical stabilization energies (SE) of the fragmenting radical in the series: tBu (71 %, SE=4.35 kcal mol)>iPr (29 %, SE=2.57 kcal mol)>Me (<2 %, SE=−1.65 kcal mol)... Moreover, it strongly suggests that the reactivity of nonclassical lanthanides(II) extends beyond being the reagents that simply close the energy gap between SmI2 and the Birch-type reductants., Having established that TmI2−ROH is capable of an efficient electron transfer to the amide carbonyl group but not their reduction, the reagent system was applied to the generation of ketyl radicals from esters (Table 2)... To gain a preliminary mechanistic insight into the key effect of protic additives on the properties of the TmI2 reagent (note that in both cases no reaction was observed with TmI2 alone, see the Supporting Information), we examined the reactivity of TmI2 with a set of aromatic hydrocarbons with gradually increasing redox potentials in the presence of MeOH (Table 3)... In this study, the TmI2−MeOH complex was found to reduce aromatic hydrocarbons with redox potentials up to −2.6 V (vs... SCE); however, benzene was inert under the reaction conditions... These results suggest that the addition of MeOH to TmI2 results in an increase of the reduction potential of TmI2 by approximately 0.6 V... Furthermore, deuterium incorporation and kinetic isotope effect studies in the reduction of stilbene, a reaction that is known to proceed through an outer-sphere electron-transfer mechanism, using TmI2−ROH ([D4]methanol, 96.5 % D2 incorporation, kH/kD=1.13±0.1; D2O, 98.0 % D2 incorporation, kH/kD=1.27±0.1), suggest that the increase in reduction potential of the reagent results from complexation between the proton donor and TmI2... A detailed examination of different proton donors in the model system (see the Supporting Information) revealed that a much lower concentration of alcohols (10 equiv) is required to enhance the redox potential of TmI2 in comparison with SmI2 (100 equiv)... In summary, the highly unusual cleavage of unactivated σ C−N bonds in amides in the presence of TmI2, the first nonclassical lanthanide(II) iodide in the series (TmI2, DyI2, NdI2), has been achieved.

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