Alicyclic Ring Structure: Conformational Influence of the CF2 Group in Cyclododecanes
Alicyclic Ring Structure: Conformational Influence of the CF2 Group in Cyclododecanes
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DOI：
10.1002/anie.201105060
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发表时间：
2011-01-01
影响因子：
16.6
通讯作者：
O'Hagan, David
中科院分区：
文献类型：
--
作者：
Skibinski, Maciej;Wang, Yi;O'Hagan, David
氟原子的选择性掺入是一种被证实的有效的方法，用于调节有机化合物的性质以开发性能分子。[1]例如，由于C？F键的小尺寸和高极性，选择性地引入氟作为氢或羟基的替代可以在药物化学产品的开发中赋予更好的性能[2]，[3]将C/O/S-CF3基团结合到分子骨架上已被广泛采用，作为药物化学[4]和农用化学工业中调节药代动力学性质的策略。[5]此外，与C？F键及其低粘度模数相关的偶极矩使含氟有机物成为有机材料如液晶中的重要实体。[6]尽管选择性氟化和CF3并入已被广泛探索，但CF2基团尽管具有作为官能团的独特性质，但受到的关注相对较少。例如，相对于H3CF(1.87D)或HCF3(1.65D)，H_2CF2具有最高的偶极矩(1.97D)，沿着从甲烷到四氟甲烷的氟甲烷系列进行。[8]在这里，我们重点研究了CF2基团作为CH2取代的作用，并选择脂环环，环十二烷(1)作为分子骨架来探讨其空间和结构的影响。首先，对剑桥晶体数据中心保存的包含∼CH2CF2CH2∼基序的所有结构进行了筛选，以评估FCF角和CC(F2)-C键角的趋势。[9]搜索发现，从满足这一标准的23个化合物和38个基序中，平均C-CF2-C角为1188，平均FCF角为1048(图1)，分别显著地宽和窄。这些几何变化可以用中心碳原子的价壳电子对排斥理论[3，11]来解释。[3，11]这表明二氟甲基将松弛应变脂环，因为它可以容纳比CC(H2)-C更宽的CC(F2)-C角。环十二烷(1)的熔点(MP)为648℃，是第一个在室温下为固体的脂环。在1960年的一篇里程碑式的论文中，Dunitz和Sheeller[12]用单晶X射线衍射法解决了环十二烷的结构，尽管这种分子是高度无序的，具有很大的热学参数。他们的最佳解决方案得出结论，在固态下，1基本上是一个方形的[3333][13]结构，四个碳链的边缘以反之字形的方式排列，如图2a所示。随后的理论[14]和电子衍射[15]研究支持这种D4结构。Anet等人。测定了环十二烷环相互转化的实验(核磁共振)构象能垒为7.3kcalmo1。[14，16]这比例如环己烷(10.5kcalmo1)[13b]低几个kcalmo1，这表明了显著的构象灵活性，并与用X射线衍射法解析固体结构的困难一致。根据[3333]的结构，有八个内切氢原子指向分子，四个在环的平面上，四个在环的平面下，每个四重态排列成一个正方形。1，4-H，H跨环接触位于van der Waals附近(2.10-2.25)，是增加环应变的重要特征。此外，[3333]结构清楚地区分了边缘和角亚甲基(CH2)基团。该环在…中提供了一个有趣的框架
Selective incorporation of fluorine atoms is a proven and powerful method for modulating the properties of organic compounds for the development of performance molecules.[1] For example the selective introduction of fluorine as a replacement for hydrogen or an hydroxy group can confer improved properties in the development of medicinal chemistry products [2] due to the small size and high polarity of the CÀ F bond,[3] and incorporation of the C/O/S-CF3 group onto molecular frameworks has been widely adopted as a strategy for modulating pharmacokinetic properties within the medicinal chemistry [4] and agrochemistry industries.[5] Also the dipole moment associated with the CÀF bond and its low viscosity modulus has rendered fluoroorganics important entities in organic materials such as liquid crystals.[6] Although selective fluorination and CF3 incorporation have been widely explored, the CF2 group has received relatively limited attention despite having unique properties as a functional group.[3, 7] For example H2CF2 has the highest dipole moment (1.97 D) relative to H3CF (1.87 D) or HCF3 (1.65 D) progressing along the fluoromethane series from methane to tetrafluoromethane.[8] Here we have focused on the role of the CF2 group as a CH2 replacement, and as a case study have selected the alicyclic ring, cyclododecane (1) as a molecular framework to explore its steric and structural influence. At the outset a screen of all structures deposited in the Cambridge Crystallographic Data Centre (CCDC) containing the∼ CH2CF2CH2∼ motif were explored to assess trends in the FCF and CC (F2)-C bond angles.[9] The search revealed that from 23 compounds and 38 motifs, satisfying this criterion, the average C-CF2-C angle was 1188 and the average FCF angle was 1048 (Figure 1), significantly wider and narrower, respectively, than the tetrahedral angle and consistent with the earlier predictions from Wiberg s theory analyses.[10] These geometric changes can be rationalized by valence shell electron pair repulsion theory (VSEPR) analysis of the central carbon atom.[3, 11] To a first approximation this indicates that the difluoromethyl group will relax strained alicyclic rings as it can accommodate a much wider CC (F2)-C angle relative to CC (H2)-C.Cyclododecane (1) has a melting point (mp) of 648C and is the first of the alicyclic rings which is a solid at room temperature. In a landmark paper in 1960 Dunitz and Shearer [12] solved the structure of cyclododecane by singlecrystal X-ray diffraction, although the molecule was highly disordered with large thermal parameters. Their best solution concluded that in the solid state, 1 is essentially a square [3333][13] structure with the four-carbon chain edges arranged in an anti zig-zag manner, as shown in Figure 2a. Subsequent theory [14] and electron diffraction [15] studies supported this D4 structure. Anet et al. determined an experimental (NMR) conformational energy barrier of 7.3 kcalmolÀ1 for the cyclododecane ring interconversion.[14, 16] This is several kcalmolÀ1 lower than eg cyclohexane (10.5 kcalmolÀ1)[13b] indicative of significant conformational flexibility and consistent with the difficulty of resolving the solid-state structure by X-ray diffraction. It follows from the [3333] structure that there are eight endo hydrogen atoms pointing into the molecule, four above and four below the plane of the ring, each quartet arranged in a square. The 1, 4-H, H transannular contacts are at van der Waals proximities (2.10–2.25), and are a significant feature adding to the ring strain. Also the [3333] structure clearly distinguishes edge and corner methylene (CH2) groups. The ring offers an interesting framework in …