Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

Whisler, Marna C.; MacNeil, Stephen L.; Snieckus, Victor; Beak, Peter

doi:10.1002/chin.200427232

Cited by 8 publications

(9 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We were also inspired in these endeavors by other areas outside of the realm of transition metal catalysis in which weak coordination has been successfully exploited to control the reactivity and selectivity of chemical transformations, including directed lithiation, Lewis acid catalysis, and organocatalysis. With respect to lithiation chemistry, Beak and Sniekus described the complex-induced proximity effect (CIPE), 30 the essence of which is controlling the selectivity of a reaction by positioning the reactive species in specified spatial orientations and driving the reaction through high effective molarity. This example reinforced our understanding that the key in our endeavors would not necessarily be the strength of coordination to the directing group but the distance and geometry between the metal and the target C–H bond.…”

Section: Early Inspiration and Motivation For Studying Weak Coordimentioning

confidence: 99%

Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions

et al. 2011

View full text Add to dashboard Cite

Conspectus Reactions that convert carbon–hydrogen (C–H) bonds into carbon–carbon (C–C) or carbon–heteroatom (C–Y) bonds are attractive tools for organic chemists, potentially expediting the synthesis of target molecules through new disconnections in retrosynthetic analysis. Despite extensive inorganic and organometallic study of the insertion of homogeneous metal species into unactivated C–H bonds, practical applications of this technology in organic chemistry are still rare. Only in the past decade have metal-catalyzed C–H functionalization reactions become more widely utilized in organic synthesis. Research in the area of homogeneous transition metal–catalyzed C–H functionalization can be broadly grouped into two subfields. They reflect different approaches and goals and thus have different challenges and opportunities. One approach involves reactions of completely unfunctionalized aromatic and aliphatic hydrocarbons, which we refer to as “first functionalization.” Here the substrates are nonpolar and hydrophobic and thus interact very weakly with polar metal species. To overcome this weak affinity and drive metal-mediated C–H cleavage, chemists often use hydrocarbon substrates in large excess (for example, as solvent). Because highly reactive metal species are needed in first functionalization, controlling the chemoselectivity to avoid over-functionalization is often difficult. Additionally, because both substrates and products are comparatively low-value chemicals, developing cost-effective catalysts with exceptionally high turnover numbers that are competitive with alternatives (including heterogeneous catalysts) is challenging. Although an exciting field, first functionalization is beyond the scope of this Account. The second subfield of C–H functionalization involves substrates containing one or more pre-existing functional groups, termed “further functionalization.” One advantage of this approach is that the existing functional group (or groups) can be used to chelate the metal catalyst and position it for selective C–H cleavage. Precoordination can overcome the paraffin nature of C–H bonds by increasing the effective concentration of the substrate so that it needn't be used as solvent. From a synthetic perspective, it is desirable to use a functional group that is an intrinsic part of the substrate so that extra steps for installation and removal of an external directing group can be avoided. In this way, dramatic increases in molecular complexity can be accomplished in a single stroke through stereo- and site-selective introduction of a new functional group. Although reactivity is a major challenge (as with first functionalization), the philosophy in further functionalization differs—the major challenge is developing reactions that work with predictable selectivity in intricately functionalized contexts on commonly occurring structural motifs. In this Account, we focus on an emergent theme within the further functionalization literature: the use of commonly occurring functional groups to direct C–H cle...

show abstract

Section: Early Inspiration and Motivation For Studying Weak Coordimentioning

confidence: 99%

Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Even though DoM reactions are remarkably powerful, 7 catalytic methods can exhibit complementary selectivities and functional group tolerance. 8 There are several examples of catalytic ortho functionalizations of aniline.…”

Section: Introductionmentioning

confidence: 99%

Achieving High Ortho Selectivity in Aniline C–H Borylations by Modifying Boron Substituents

et al. 2018

View full text Add to dashboard Cite

High ortho selectivity for Ir-catalyzed C–H borylations (CHBs) of anilines results when B2eg2 (eg = ethylene glycolate) is used as the borylating reagent in lieu of B2pin2, which is known to give isomeric mixtures with anilines lacking a blocking group at the 4-position. With this modification, high selectivities and good yields are now possible for various anilines, including those with groups at the 2- and 3-positions. Experiments indicate that ArylN(H)Beg species are generated prior to CHB and support the improved ortho selectivity relative to B2pin2 reactions arising from smaller Beg ligands on the Ir catalyst. The lowest-energy transition states (TSs) from density functional theory computational analyses have N–H···O hydrogen-bonding interactions between PhN(H)Beg and O atoms in Beg ligands. Ir-catalyzed CHB of PhN(H)Me with B2eg2 is also highly ortho-selective. 1H NMR experiments show that N-borylation fully generates PhN(Me)Beg prior to CHB. The TS with the lowest Gibbs energy was the ortho TS, in which the Beg unit is oriented anti to the bipyridine ligand.

show abstract

“… Directed C–H activation has emerged as a major approach for developing synthetically useful reactions, owing to the proximity-induced reactivity and selectivity enabled by coordinating functional groups 1–6 . In contrast, development of palladium-catalyzed non-directed C–H activation has faced significant challenges associated with the lack of sufficiently active palladium catalysts 7–8 .…”

mentioning

confidence: 99%

“…Typically, directing groups are employed to address these two problems simultaneously by exploiting a complex-induced proximity effect 1–6 . Extensive research on various directing group designs 1–6 and strategies 19–21 , as well as the development of ligands which accelerate C–H functionalization 22 , has significantly improved the practicality and utility of this approach. Ligand-acceleration has enabled palladium catalysts to functionalize remote C–H bonds of aromatic substrates by recognition of distance and geometry 23–24 .…”

mentioning

confidence: 99%

Ligand-accelerated non-directed C–H functionalization of arenes

Wang

Verma

Xia

et al. 2017

Nature

364

241

View full text Add to dashboard Cite

Directed C–H activation has emerged as a major approach for developing synthetically useful reactions, owing to the proximity-induced reactivity and selectivity enabled by coordinating functional groups1–6. In contrast, development of palladium-catalyzed non-directed C–H activation has faced significant challenges associated with the lack of sufficiently active palladium catalysts7–8. Current palladium catalysts are only reactive with electron-rich arenes unless an excess of arene is used9–18, which limits synthetic applications. Herein, we disclose a 2-pyridone ligand that significantly enhances the reactivity of a palladium catalyst, allowing for Pd(II)-catalyzed non-directed C–H activation of a broad range of aromatic substrates using the various arenes as the limiting reagent. The significance of this finding is demonstrated by the direct functionalization of advanced synthetic intermediates, drug molecules, and natural products that cannot be utilized in excessive quantities. The potential of this methodology to be expanded to a variety of transformations is indicated by the development of both C–H olefination and C–H carboxylation protocols. Furthermore, the site selectivity in this transformation is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C–H functionalization.

show abstract

Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

Abstract: Organic chemistryOrganic chemistry Z 0200 Beyond Thermodynamic Acidity: A Perspective on the Complex-Induced Proximity Effect (CIPE) in Deprotonation Reactions-[106 refs.]. -(WHISLER, M. C.; MACNEIL, S.; SNIECKUS, V.; BEAK, P.; Angew.

Cited by 8 publications

References 1 publication

Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions

Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions

Achieving High Ortho Selectivity in Aniline C–H Borylations by Modifying Boron Substituents

Ligand-accelerated non-directed C–H functionalization of arenes

Contact Info

Product

Resources

About

Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

Abstract: Organic chemistryOrganic chemistry Z 0200 Beyond Thermodynamic Acidity: A Perspective on the Complex-Induced Proximity Effect (CIPE) in Deprotonation Reactions-[106 refs.]. -(WHISLER, M. C.; MACNEIL, S.; SNIECKUS*, V.; BEAK*, P.; Angew.

Cited by 8 publications

References 1 publication

Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions

Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions

Achieving High Ortho Selectivity in Aniline C–H Borylations by Modifying Boron Substituents

Ligand-accelerated non-directed C–H functionalization of arenes

Contact Info

Product

Resources

About

Abstract: Organic chemistryOrganic chemistry Z 0200 Beyond Thermodynamic Acidity: A Perspective on the Complex-Induced Proximity Effect (CIPE) in Deprotonation Reactions-[106 refs.]. -(WHISLER, M. C.; MACNEIL, S.; SNIECKUS, V.; BEAK, P.; Angew.