The axioms of stereoelectronic theory constitute an atlas to navigate the contours of molecular space. All too rarely lauded, the advent and development of stereoelectronic theory has been one of organic chemistry’s greatest triumphs. Inevitably, however, in the absence of a comprehensive treatise, many of the field’s pioneers do not receive the veneration that they merit. Rather their legacies are the stereoelectronic pillars that persist in teaching and research. This ubiquity continues to afford practitioners of organic chemistry with an abundance of opportunities for creative endeavor in reaction design, in conceiving novel activation modes, in preorganizing intermediates, or in stabilizing productive transition states and products. Antipodal to steric governance, which mitigates destabilizing nonbonding interactions, stereoelectronic control allows well-defined, often complementary, conformations to be populated. Indeed, the prevalence of stabilizing hyperconjugative interactions in biosynthetic processes renders this approach to molecular preorganization decidedly biomimetic and, by extension, expansive. In this Account, the evolution and application of a simple donor–acceptor model based on the fluorine gauche effect is delineated. Founded on reinforcing hyperconjugative interactions involving C(sp³)–H bonding orbitals and C(sp³)–X antibonding orbitals [σ_C–H → σ_C–X*], this general stratagem has been used in conjunction with an array of secondary noncovalent interactions to achieve acyclic conformational control (ACC) in structures of interest. These secondary effects range from 1,3-allylic strain (A^1,3) through to electrostatic charge-dipole and cation−π interactions. Synergy between these interactions ensures that rotation about strategic C(sp³)–C(sp³) bonds is subject to the stereoelectronic requirement for antiperiplanarity (180°). Logically, in a generic [X–CH₂–CH₂–Y] system (X, Y = electron withdrawing groups) conformations in which the two C(sp³)–X bonds are synclinal (i.e., gauche) are significantly populated. As such, simple donor–acceptor models are didactically and predictively powerful in achieving topological preorganization. In the case of the gauche effect, the low steric demand of fluorine ensures that the remaining substituents at the C(sp³) hybridized center are placed in a predictable area of molecular space: An exit vector analogy is thus appropriate. Furthermore, the intrinsic chemical stability of the C–F bond is advantageous, thus it may be considered as an inert conformational steering group: This juxtaposition of size and electronegativity renders fluorinated organic molecules unique among the organo-halogen series. Cognizant that the replacement of one fluorine atom in the difluoroethylene motif by another electron withdrawing group preserves the gauche conformation, it was reasoned that β-fluoroamines would be intriguing candidates for investigation. The burgeoning field of Lewis base catalysis, particularly via iminium ion activation, provided a timely platform from which to explore a postulated fluorine–iminium ion gauche effect. Necessarily, activation of this stereoelectronic effect requires a process of intramolecularization to generate the electron deficient neighboring group: Examples include protonation, condensation to generate iminium salts, or acylation. This process, akin to substrate binding, has obvious parallels with enzymatic catalysis, since it perturbs the conformational dynamics of the system [synclinal-endo, antiperiplanar, synclinal-exo]. This Account details the development of conformationally predictable small molecules based on the [X–C_α–C_β–F] motif through a logical process of molecular design and illustrates their synthetic value in enantioselective catalysis.

中文翻译：

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通知分子设计的立体电子理论：氟左岸影响催化

立体电子理论的公理构成导航分子空间轮廓的图集。很少有人称赞，立体电子理论的出现和发展一直是有机化学最伟大的成就之一。然而，不可避免地，在缺乏全面论述的情况下，该领域的许多先驱者并没有受到他们应得的崇敬。相反，他们的遗产是在教学和研究中始终存在的立体声电子支柱。这种普遍存在继续为有机化学从业者提供大量的机会来进行反应设计，构想新的活化方式，预组织中间体或稳定生产过渡态和产物的创新性尝试。对位治理的反对，它减轻了不稳定的非键相互作用的影响，立体声电子控制允许填充定义明确的（通常是互补的）构象。确实，在生物合成过程中稳定高共轭相互作用的普遍性使这种分子预组织的方法可以肯定地是仿生的，并且因此是可扩展的。在这个帐户中，基于氟的简单供体-受体模型的发展和应用描述了薄纱效果。建立在增强涉及C（sp ³）–H键轨道和C（sp ³）–X反键轨道[σC _–H →σC _–X *]的超共轭相互作用的基础上，此一般策略已与一系列次要非共价相互作用，以实现目标结构中的无环构象控制（ACC）。这些次级影响的范围从1,3-烯丙基应变（A ^1,3）一直到静电荷-偶极子和阳离子-π相互作用。这些相互作用之间的协同作用可确保围绕战略C（sp ³）–C（sp ³）键的旋转受到反平面性的立体电子要求（180°）。逻辑上，在一个通用的[X–CH ₂ –CH ₂ –Y]系统（X，Y =吸电子基团）中，两个C（sp ³）–X键是向斜的（即gauche）构型。因此，简单的供体-受体模型在实现拓扑预组织方面在理论上和预测上都很有效。在树胶效应的情况下，氟的低空间需求量可确保C（sp ³）将杂交中心放置在分子空间的可预测区域中：因此，以出口向量类比是合适的。此外，CF键的内在化学稳定性是有利的，因此可以将其视为惰性构象控制基团：大小和电负性的并列使得氟化有机分子在有机卤素系列中独树一帜。认识到二氟乙烯基序中的一个氟原子被另一个吸电子基团所取代，可以保留该gauche构象，有理由认为，β-氟胺将是有趣的研究对象。刘易斯碱催化的蓬勃发展领域，特别是通过亚胺离子的活化，提供了一个及时的平台，可以从中探索一种假定的条件。氟-亚胺离子纱布效应。必要的是，要激活此立体电子效应，需要进行分子内化过程以生成电子不足的邻近基团：例子包括质子化，缩合以生成亚胺盐或酰化反应。该过程类似于底物的结合，与酶催化具有明显的相似之处，因为它扰乱了系统的构象动力学[向斜内-，反周平面，向外-外]。此帐户详情基于所述[X-C构象预测的小分子的发展_α -C _β–F]基序通过分子设计的逻辑过程进行说明，并说明了它们在对映选择性催化中的合成价值。