Name: a two-step protocol for umpolung functionalization of ketones via enolonium species
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一项由爱丽大学提供的创业补助金和一份独立研究补助金 (1914/15) 给 AMS 的致谢。

1. Enolonium 种的制备
注意: 在执行该协议之前, 请查阅所有试剂和溶剂的 MSDS。
注: 所有新试剂均使用从商业来源收到。如果已经储存了三氟化硼乙醚, 在使用前先蒸馏。
<ol><li>在一个干燥的圆底烧瓶, 装有隔膜和磁铁搅拌, 添加科泽的试剂 (1.5 equiv), 并冲洗瓶与氮气或氩气。</li>
	<li>添加干二氯甲烷, 使悬浮0.234 摩尔/L 正式浓度。</li>
	<li>使用干冰/丙酮浴或冷指仪器/丙酮浴冷却悬浮到-78 °c。</li>
	<li>加整齐的 BF3氨基酸2 (1.5 equiv) 慢慢地。</li>
	<li>将异质混合物加热到室温, 直至形成黄溶液。通常情况下, 这发生在5分钟以内。</li>
	<li>冷却溶液到-78 摄氏度。</li>
	<li>对冷却溶液, 加入三甲基硅 enolether (1 equiv, 0.313 摩尔/升) 在干二氯甲烷滴状超过2-10 分钟 (取决于鳞片)。硅烯醇式醚的加入完成后, enolonium 种的形成是完整的。 注: enolonium 物种的溶液可在-78 摄氏度左右, 至少30分钟, 产量不变。enolonium 的物种在这段时间是稳定的, 如报告的核磁共振研究6所示。</li>
</ol>2. Enolonium 种的功能化
<ol><li>氯化阴离子
	<ol>
<li>对 enolonium 种的制备溶液, 在干二氯甲烷中加入苄基甲基 decylammonium 氯 (2.0 equiv, 1.25 摩尔/升), 以降明智的方式。按速率添加此解决方案, 使温度保持在摄氏-55 摄氏度以下。在 0.5-2 毫摩尔规模, 增加超过5分钟是令人满意的。</li>
		<li>将反应混合物保持在-78 摄氏度, 5 分钟。</li>
		<li>除去冷却液, 使反应混合物达到室温。</li>
		<li>将反应在室温下保持20分钟。</li>
		<li>将水添加到反应混合物中 (用于制备 enolonium 种的二氯甲烷体积的一半)。</li>
		<li>二氯甲烷三次萃取。通常, 使用2-3 倍的反应量在每次提取在 0.5-2 毫摩尔小规模。</li>
		<li>用盐水冲洗两次组合的有机层。通常, 使用相同的盐水量作为联合反应量。</li>
		<li>用无水硫酸钠干燥30分钟。</li>
		<li>过滤掉硫酸硫酸钠 (例如, 通过硅藻土插头)。</li>
		<li>在减压和40摄氏度的旋转蒸发器上去除溶剂。</li>
		<li>用己烷和醋酸乙酯 eluents 在硅胶上的柱层析法提纯原油, 在溶剂去除后, 叠氮基酮的纯对应。 注: 在0.5 毫摩尔到2毫摩尔的三甲基硅烯醇负离子的鳞片上, 在2厘米直径的玻璃柱上进行柱层析, 使用标准硅胶60在高度 (长度) 15 厘米。该卷将需要不同的规模。</li>
	</ol></li>
	<li>Azidation-叠氮化物 注意: 叠氮化合物一般都是爆炸性的, 应注意处理和准备产品。叠氮化物是有毒的。使用前请咨询 MSDS。<ol>
<li>在-78 摄氏度的 enolonium 物种的制备溶液中, 添加整齐的 azidotrimethylsilane (2.5 equiv) 以滴状的方式。以速率添加此解决方案, 以使温度保持在-55 摄氏度以下。在 0.5-2 毫摩尔规模, 增加超过2-3 分钟是令人满意的。</li>
		<li>搅拌反应混合物15分钟, 在-78 摄氏度。</li>
		<li>加热反应混合物到-55 °c 并且离开在这个温度为2到 3 h。</li>
		<li>将水添加到反应混合物中 (用于制备 enolonium 种的二氯甲烷体积的一半)。</li>
		<li>二氯甲烷三次萃取。通常, 使用2-3 倍的反应量在每次提取在 0.5-2 毫摩尔小规模。</li>
		<li>用盐水冲洗两次组合的有机层。通常, 使用相同的盐水量作为联合反应量。</li>
		<li>用无水硫酸钠干燥萃取物30分钟。</li>
		<li>过滤掉硫酸钠。</li>
		<li>在减压和40摄氏度的旋转蒸发器上去除溶剂。</li>
		<li>用己烷和醋酸乙酯 eluents 在硅胶上的柱层析法提纯原油, 在溶剂去除后, 叠氮基酮的纯对应。</li>
	</ol></li>
	<li>反应与唑类药物
	<ol>
<li>在-78 摄氏度的 enolonium 物种的制备溶液中, 加入唑 (4 至 5 equiv, 1 摩尔/升), 以滴状方式溶解在5毫升的二氯甲烷中。在 0.5-2 毫摩尔规模, 增加超过5分钟是令人满意的。 注: 在不溶性唑类药物如 tetrazoles 的情况下, 使用乙腈浓度为0.5 摩尔/升而不是二氯甲烷。以速率添加此解决方案, 以使温度保持在-55 摄氏度以下。</li>
		<li>搅拌反应混合物15分钟, 在-78 摄氏度。</li>
		<li>加热反应混合物到-55 °c 并且离开在这个温度为4到 8 h。</li>
		<li>将水添加到反应混合物中 (用于制备 enolonium 种的有机溶剂的一半)。</li>
		<li>二氯甲烷三次萃取。通常, 使用2-3 倍的反应量在每次提取在 0.5-2 毫摩尔小规模。</li>
		<li>用盐水冲洗两次组合的有机层。通常, 使用相同的盐水量作为联合反应量。</li>
		<li>用无水硫酸钠干燥萃取物30分钟。</li>
		<li>过滤掉硫酸钠。</li>
		<li>在减压和40摄氏度的旋转蒸发器上去除溶剂。</li>
		<li>用己烷和醋酸乙酯 eluents 在硅胶上的柱层析法提纯原油, 在溶剂去除后, 唑酮的纯对应。</li>
	</ol></li>
	<li>烯丙基、crotylation、cinnamylation 和 prenylation 使用烯丙基烷
	<ol>
<li>添加整齐的烯丙基,-, crotyl, 肉桂, 或梨醇 trimethylsilane (2 equiv) 缓慢在-78 摄氏度。以速率添加此解决方案, 以使温度保持在-55 摄氏度以下。在 0.5-2 毫摩尔规模, 增加超过2-3 分钟是令人满意的。</li>
		<li>搅拌反应混合物10分钟, 在-78 摄氏度。</li>
		<li>通过去除冷却浴, 让反应混合物慢慢地温暖到室温。将反应在室温下保持20分钟。</li>
		<li>将水添加到反应混合物中 (用于制备 enolonium 种的二氯甲烷体积的一半)。</li>
		<li>二氯甲烷三次萃取。通常, 使用2-3 倍的反应量在每次提取在 0.5-2 毫摩尔小规模。</li>
		<li>用盐水冲洗两次组合的有机层。通常, 使用相同的盐水量作为联合反应量。</li>
		<li>用无水硫酸钠干燥萃取物30分钟。</li>
		<li>过滤掉硫酸钠。</li>
		<li>在减压和40摄氏度的旋转蒸发器上去除溶剂。</li>
		<li>用己烷和醋酸乙酯 eluents 在硅胶上的柱层析法提纯粗品, 在溶剂去除后, 得到纯对应的α烯丙基产物。</li>
	</ol></li>
	<li>Arylation 注: 对于 arylation, 在 enolonium 物种的制备过程中, 使用3当量的 BF3氨基酸2 , 以避免 enolonium 物种 tosylation 为主要的副反应。一般而言, 只有1.6 当量的芳香基板是需要的。然而, 如果芳香基板是 pyrane, 噻吩, 或吡咯, 最好的结果是通过5当量的芳香基体。<ol>
<li>对制备的 enolonium 物种的解决方案, 在干二氯甲烷 (1.6 equiv, 0.5 摩尔/升) 中添加芳香基的溶液, 以滴状方式。以速率添加此解决方案, 以使温度保持在-55 摄氏度以下。在 0.5-2 毫摩尔规模, 增加超过5-10 分钟是令人满意的。</li>
		<li>在芳香基体的加法完成之后, 增加混合物的温度到-55 °c 并且离开混合物在这个温度为20分钟。</li>
		<li>将水添加到反应混合物中 (用于制备 enolonium 种的二氯甲烷体积的一半)。</li>
		<li>二氯甲烷三次萃取。通常, 使用2-3 倍的反应量在每次提取在 0.5-2 毫摩尔小规模。</li>
		<li>用盐水冲洗两次组合的有机层。通常, 使用相同的盐水量作为联合反应量。</li>
		<li>用无水硫酸钠干燥萃取物30分钟。</li>
		<li>过滤掉硫酸钠。</li>
		<li>在减压和40摄氏度的旋转蒸发器上去除溶剂。</li>
		<li>用己烷和醋酸乙酯 eluents 在硅胶上的柱层析法提纯原油, 在溶剂去除后, arylated 酮的纯对应。</li>
	</ol></li>
</ol>

<ol>
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V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Carbon-carbon+bond+formation+in+reactions+of+PhIO&#183;HBF4-silyl+enol+ether+adduct+with+alkenes+or+silyl+enol+ethers.">Carbon-carbon bond formation in reactions of PhIO&#183;HBF4-silyl enol ether adduct with alkenes or silyl enol ethers.</a> Journal of Organic Chemistry. 54 (11), 2605-2608 (1989).</li><li>Maksymenko, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transition-metal-free+intermolecular+&#945;-arylation+of+ketones+via+enolonium+species.">Transition-metal-free intermolecular &#945;-arylation of ketones via enolonium species.</a> Organic Letters. 19 (23), 6312-6315 (2017).</li><li>Vita, M. 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我们没有什么可透露的。

从 TMS-enolates 成功地制备 enolonium 物种取决于许多因素。在制备步骤中的主要副反应是由形成的 enolonium 分子与烯醇负离子分子的反应产生的起始材料的人偶联。因此, 反应条件的要求是避免这种二聚化通过确保快速反应的刘易斯酸活化高价碘试剂与增加 TMS 烯醇负离子相对于二聚化率。这是在协议中通过活化和溶解科泽试剂使用化学计量 BF3。许多高价碘试剂包括科泽试剂在标准有机溶剂中...

Enolates 是经典的碳亲核试剂在有机化学和其中最广泛使用。极性转换 enolates 创造亲 enolonium 物种允许有价值的替代方法, 以产生α功能性酮, 并使新的反应不可能通过经典的烯醇负离子化学。Enolonium 种在许多反应中被建议为中间体, 特别是涉及高价碘试剂的反应。这些反应包括α卤化, 氧合和胺化1以及其他反应2,3,4,5。
然而, 这些反应的范围总是受到反应 enolonium 物种瞬态性质的限制。这顷刻要求在反应混合物中存在任何亲核试剂在羰基 enolates 反应期间与强氧化高价碘试剂。因此, 任何亲核试剂易氧化, 如电子丰富的芳香化合物 (杂环化合物) 和烯烃, 不能使用。
在过去的一年里, 我们通过发展条件来克服这些限制, enolonium 物种在一个步骤中形成一个离散的中间, 然后在第二步加入亲核试剂。该协议不仅允许经典类型的功能化, 如氯化6, 而且使用氧化碳亲核试剂, 如 allylsilanes6,8, enolates1,6, 7、和电子丰富的芳香化合物9, 导致碳-碳键形成。烯丙基方法适合于第四纪和第三纪中心的形成。酮 arylation 法构成芳香化合物的正式 C H 功能化, 不需要指导组9。最近, 我们报告增加了唑类药物和叠氮化合物10以及11。该议定书的详细表述可望有助于将这些方法引入合成有机化学家的日常工具箱中。

<table><tbody><tr><td>Chlorotrimethylsilane, 98+%</td><td>Alfa Aesar</td><td>A13651</td><td>TMS-Cl</td></tr><tr><td>Boron trifluoride diethyl etherate, 98+%</td><td>Alfa Aesar</td><td>A15275</td><td>BF3*Et2O</td></tr><tr><td>2-Methylindole, 98+%</td><td>Alfa Aesar</td><td>A10764</td><td>2-Me-indole</td></tr><tr><td>Hydroxy(tosyloxy) iodobenzene, 97%</td><td>Alfa Aesar</td><td>L15701</td><td>Koser&#039;s reagent</td></tr><tr><td>Acetophenone, &gt;98%</td><td>Merck</td><td>800028</td><td></td></tr><tr><td>n-Butyllithium solution 1.6M in hexanes</td><td>Aldrich</td><td>186171</td><td>nBuLi</td></tr><tr><td>BIS(ISOPROPYL)AMINE</td><td>Apollo</td><td>OR1090</td><td>DIPA</td></tr><tr><td>Trimethylsilyl azide, 94%</td><td>Alfa Aesar</td><td>L00173</td><td>TMS-N3</td></tr></tbody></table>

a two-step protocol for umpolung functionalization of ketones via enolonium species

高价碘试剂 enolates 极性转换酮的α功能化是合成有机化学的一个重要概念。最近, 我们已经制定了两个步骤的战略, 酮烯醇负离子极性转换, 这使得发展的方法, 氯化, azidation 和胺化使用唑类药物。此外, 我们还开发了 c-bond–forming arylation 和烯丙基反应。这些方法的核心是在添加反应性亲核试剂之前制备中间和高活性 enolonium 种。这一策略使人联想到在古典合成化学中金属 enolates 的制备和使用。这种策略允许使用亲核试剂, 否则将与强烈氧化高价碘试剂不相容。本文提出了氯化、azidation、n-heteroarylation、arylation 和烯丙基的详细协议。产品包括在药用活性产品中流行的图案。本文将极大地帮助其他人使用这些方法。

图 1给出了根据该议定书取得的代表性成果, 并在讨论部分进行了讨论。值得注意的是, 很大范围的不同的酮可以成功地用于反应, 使产品的良好的产量, 可以看到的 azidation11。在酮α位置引入唑类药物反应的范围包括大多数常见的单循环和笼含杂环化合物氮。烯丙基过程的范围包括烯丙基、crotyl 和梨醇-trimethylsilane6?...

Watch this Scientific Journal Video about A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species at JoVE.com

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

本文介绍了极性转换酮 enolates 到 enolonium 种的两步单锅协议, 并对α位亲核试剂的添加进行了描述。亲核试剂包括氯、叠氮化物、唑类药物、烯丙基烷和芳香化合物。

Enolonium 种极性转换酮功能化的两步协议

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. ...

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Organic Chemistry

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Aldehydes and Ketones

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9.9K 次观看.  Ariel University. 本文介绍了极性转换酮 enolates 到 enolonium 种的两步单锅协议, 并对α位亲核试剂的添加进行了描述。亲核试剂包括氯、叠氮化物、唑类药物、烯丙基烷和芳香化合物。

视频: A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

功能化单有机硼化合物共轭法高效合成全碳第四纪中心

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

科研

化学

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products and notably to generate chiral carbon centers. The crucial first step consists in the selective double hydroboration of CO2 catalyzed by an iron hydride complex. The product obtained with this 4 e- reduction is a rare bis(boryl)acetal, compound 1, which is subjected in situ to three different reactions in a second step. The first reaction concerns a condensation reaction with (diisopropyl)phenylamine affording the corresponding imine 2. In the second and third reaction, intermediate 1 reacts with triazol-5-ylidene (Enders&#39; carbene) to afford compounds 3 or 4, depending on the reaction conditions. In both compounds, C-C bonds are formed, and chiral centers are generated from CO2 as the only source of carbon. Compound 4 exhibits two chiral centers obtained in a diastereoselective manner in a formose-type mechanism. We proved that the remaining boryl fragment plays a key role in this unprecedented stereocontrol. The interest of the method stands on the reactive and versatile nature of 1, giving rise to various complex molecules from a single intermediate. The complexity of a two-step method is compensated by the overall short reaction time (2 h for the larger reaction time), and mild reaction conditions (25 &#176;C to 80 &#176;C and 1 to 3 atm of CO2).

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations are conducted in a one-pot two-step procedure for the synthesis of complex molecules. The selective 4 e- reduction of CO2 with a hydroborane reductant affords a reactive and versatile bis(boryl)acetal intermediate which is subsequently involved in condensation reaction or carbene-mediated C-C coupling generation.

多功能 CO2转化为复杂产品:单罐两步战略

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products ...

A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis

Heteroarylation introduces heteroaryl fragments to organic molecules. Despite the numerous available reactions reported for arylation via transition metal catalysis, the literature on direct heteroarylation is scarce. The presence of heteroatoms such as nitrogen, sulfur and oxygen often make heteroarylation a challenging research field due to catalyst poisoning, product decomposition and the rest. This protocol details a highly efficient direct &#945;-C(sp3) heteroarylation of ketones under microwave irradiation. Key factors for successful heteroarylation include the use of XPhos Palladacycle Gen. 4 Catalyst, excess base to suppress side reactions and the high temperature and pressure achieved in a sealed reaction vial under microwave irradiation. The heteroarylation compounds prepared by this method were fully characterized by proton nuclear magnetic resonance spectroscopy (1H NMR), carbon nuclear magnetic resonance spectroscopy (13C NMR) and high-resolution mass spectrometry (HRMS). This methodology has several advantages over literature precedents including broad substrate scope, rapid reaction time, greener procedure and operational simplicity by eliminating the preparation of intermediates such as silyl enol ether. Possible applications for this protocol include, but are not limited to, diversity-oriented synthesis for the discovery of biologically active small molecules, domino synthesis for the preparation of natural products and ligand development for new transition metal catalytic systems.

Heteroaryl compounds are important molecules utilized in organic synthesis, medicinal and biological chemistry. A microwave-assisted heteroarylation using palladium catalysis provides a rapid and efficient method to attach heteroaryl moieties directly to ketone substrates.

利用过渡金属催化的酮的微波辅助直接异化

Heteroarylation introduces heteroaryl fragments to organic molecules. Despite the numerous available reactions reported for arylation via transition metal ...

Reactivity of Enols

Enols are a class of compounds where a hydroxyl group is attached to a carbon&#8211;carbon double bond, which implies that it is a vinyl alcohol. A carbonyl compound with an &#945; hydrogen undergoes keto&#8211;enol tautomerism and remains in equilibrium with its tautomer, the enol form. Usually, the keto tautomer is present in a higher concentration than the enol tautomer due to the higher bond energy of C=O compared to C=C. Moreover, the direction of the keto&#8211;enol equilibrium is governed by factors like conjugation, intramolecular hydrogen bonding, and aromatic energy. Recall that tautomers are constitutional isomers with distinct atomic arrangements, while resonance forms are different representations of one molecule. This tautomerization is reversibly catalyzed by both acids and bases involving protonation and deprotonation steps. While protonation precedes deprotonation in presence of an acid leading to enols, the reverse order is followed in base-catalyzed enolization that yields enolates.
Enols are electron-rich and hence nucleophilic in nature, like other compounds containing carbon&#8211;carbon double bonds. Due to the strong electron-donating resonance effect of the hydroxyl group, a second resonance structure of the enol can be drawn where the negative charge is on the &#945; carbon. Consequently, this carbon atom is especially nucleophilic and reacts with electrophiles (E+) to form a new C&#8211;E bond. Loss of a proton in the next step leads to a neutral product. The net result amounts to the substitution of hydrogen by an electrophile on the &#945; carbon. Therefore, carbonyl compounds are halogenated at the &#945; position by halogens, such as bromine, in both acidic and basic solutions. This results in the formation of different products under various reaction conditions.
When a carbonyl compound with at least one &#945; hydrogen is dissolved in D2O, to which DCl or NaOD are added, the &#945; hydrogens are gradually replaced by deuterium (D) atoms via enol formation. If this carbonyl compound is chiral owing to a stereogenic center at the &#945; carbon, its chirality is destroyed by rapid interconversion between keto and enol forms through a planar, achiral enol intermediate. The spontaneous racemization prevents the synthesis of chiral &#42933;-keto esters whose only stereogenic center lies in between the two keto groups.

烯醇的反应性

Enols are a class of compounds where a hydroxyl group is attached to a carbon&#8211;carbon double bond, which implies that it is a vinyl alcohol. A ...

教育

有机化学

&alpha;-Carbon Chemistry: Enols, Enolates, and Enamines

关键术语与概念

Reactivity of Enolate Ions

Enolate ions are formed by the acid&#8211;base reaction of a carbonyl compound with a base. This leads to deprotonation of the &alpha; hydrogen atom, leading to a resonance-stabilized enolate ion where one of the contributing structures is an oxyanion, which imparts additional stability. Therefore, the proton on the &alpha; carbon is more acidic in nature than that of other sp3-hybridized C&#8211;H bonds but less acidic than those in O&#8211;H bonds where the negative charge in the conjugate base is localized on the oxygen atom. This is reflected in their trend of pKa values. For example, acetic acid, ethanol, acetone, 1-propene, and ethane have pKa values of 4.8, 16, 19.2, 43, and 50, respectively.
The enolate ion is an example of an ambident nucleophile&#8212;i.e., a nucleophile with two reactive sites. The contributing structures of enolate ions show that both carbon and oxygen atoms can bear the negative charge. Hence, the enolate ion is the conjugate base of both keto and enol forms. In theory, it can react with a particular electrophile to form two different products by bond formation at the two different sites. However, an enolate ion usually reacts at the carbon end, as this is more nucleophilic than the oxygen site.
As enolate ions are Br&#248;nsted bases, they react with Br&#248;nsted acids, like protons. This leads to hydrogen exchange at the &alpha; position of carbonyl compounds with that of solvent, leading to isotope exchange in the presence of D2O and an aqueous base. An optically active aldehyde or ketone undergoes racemization if there is an asymmetric &alpha; carbon in the molecule. The loss in stereogenicity owes to the formation of an achiral enolate intermediate where all three atoms are trigonal planar due to sp2 hybridization and conjugation through p-orbital overlap. Since the pKa of an &alpha; hydrogen is very high in the case of esters, the various consequences of enolate ion formation is observed specifically for aldehydes and ketones.
Enolate ions also react as Lewis bases, where they act as nucleophiles. Therefore, they can undergo two types of reaction leading to the formation of new bonds at the &alpha; carbon:
<ol>
	<li>Substitution reactions with electrophiles to yield halogenated and alkylated products with molecular halogen (X2) in the presence of an acid or base and an alkyl halide (RX) or sulfonate ester (RSO3&#8722;), respectively.</li>
	<li>Addition reactions with carbonyl groups at the electrophilic carbon center followed by nucleophilic acyl substitution reactions depending on the structure of the carbonyl group.</li>
</ol>

烯醇化根离子的反应性

Enolate ions are formed by the acid&#8211;base reaction of a carbonyl compound with a base. This leads to deprotonation of the &alpha; hydrogen atom, ...

Regioselective Formation of Enolates

As depicted in the figure below, the unsymmetrical ketones can form two possible enolates:&#160; less substituted or more substituted enolates. Usually, the thermodynamic enolates are formed from the more substituted &#945;-carbon atom, while the kinetic enolates are formed faster by deprotonation from the less substituted position. The thermodynamic enolates have lower energy, so they are&#160; more stable. But the energy required to form kinetic enolates is less.
<img alt="Figure1" src="/files/ftp_upload/12381/12381_PT_Figure_1.svg" style="text-align: center; height: 172px;" />
This regioselectivity in enolate formation is essentially an acid-base reaction and is controlled by various factors such as solvent, base, cation, and temperature. Protic solvents and weaker bases favor the formation of thermodynamic enolates, while aprotic solvents and stronger bases favor the kinetic enolates. Thermodynamic enolates are formed at higher temperatures and have longer reaction times because of the higher energy barrier. On the other hand, kinetic enolates are formed at lower temperatures with short reaction times. The conditions favoring thermodynamic enolates encourage a reversible reaction which is not the case with conditions involved for kinetic enolates intermediate.

烯醇酸盐的区域选择性形成

As depicted in the figure below, the unsymmetrical ketones can form two possible enolates:&#160; less substituted or more substituted enolates. Usually, ...

Acid-Catalyzed &alpha;-Halogenation of Aldehydes and Ketones

By replacing an α-hydrogen with a halogen, acid-catalyzed α-halogenation of aldehydes or ketones yields a monohalogenated product
In the first step of the mechanism, the acid protonates the carbonyl oxygen resulting in a resonance-stabilized cation, which subsequently loses an α-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the –OH group. Consequently, the double bond attacks an electrophilic halogen to form a monohalogenated carbocation. In the final step, deprotonation of the carbocation yields the α-halo aldehydes or ketones.
Note that the enol formation is the rate-determining step of the reaction, and the halogen is not involved in the rate-limiting step. Therefore, the initial rates of the α-halogenation are independent of the type and concentration of halogen. Overall, the reaction follows second-order kinetics, wherein the rates depend on the concentration of the carbonyl and the acid.
The addition of a second halogen is unfavorable as the carbocation intermediate formed by the reaction of a monohalogenated enol with halogens is highly destabilized by the electron-withdrawing polar effect of two halogen atoms. Interestingly, the acid formed as a by-product of this reaction can ultimately catalyze the first step of enolization, thus turning the reaction autocatalytic. The unsymmetrical ketones undergo α-halogenation at the more substituted carbon by the preferential formation of a thermodynamic enol. As shown below, the acid-catalyzed α-halogenation reaction also works well to convert ketones to α,β‒unsaturated ketones via E2 elimination reactions forming a new π bond.
<img alt="Cyclohexanone to 2-cyclohexenone synthesis, equations, chemical process diagram, organic chemistry." src="/files/ftp_upload/12382/12382_PT_Figure_1.svg" style="text-align: center; height: 110px;" data-altupdatedat="1747908711000" data-alt="Figure1">

Acid-Catalyzed &#945;-Halogenation of Aldehydes and Ketones

醛和酮的酸催化 α-卤化反应

By replacing an &#945;-hydrogen with a halogen, acid-catalyzed &#945;-halogenation of aldehydes or ketones yields a monohalogenated product
In the first ...

Dehydration of Aldols to Enones: Acid-Catalyzed Aldol Condensation

As shown in Figure 1, under acidic conditions, the β-hydroxy ketone undergoes dehydration via an E1 elimination reaction to form an enone.
<img alt="Organic reaction mechanism, dehydration of alcohol to ketone, formula with HCl and H2O." src="/files/ftp_upload/13063/13063-PT_Figure1.svg" style="text-align: center; height: 85px;" data-altupdatedat="1747908711000" data-alt="Figure1">
Figure 1. The dehydration reaction of a β-hydroxy ketone.
Figure 2 depicts the sequential processes involved in the mechanism of the reaction. Here, the acid protonates the hydroxyl group in the β-hydroxy ketone to form a hydrated hydroxyl group, which then departs to form a tertiary carbocation intermediate. Subsequently, the loss of the hydrogen atom from the α carbon yields an enone as the final product.
<img alt="Ketone formation via alcohol dehydration; chemical reaction diagramc; acid-catalyzed mechanism." src="/files/ftp_upload/13063/13063-PT_Figure2.svg" style="text-align: center; height: 95px;" data-altupdatedat="1747908711000" data-alt="Figure2">
Figure 2. The mechanism of the dehydration reaction of a β-hydroxy ketone.

羟醛脱水为烯酮:酸催化羟醛缩合

As shown in Figure 1, under acidic conditions, the &#946;-hydroxy ketone undergoes dehydration via an E1 elimination reaction to form an enone.

Figure 1. ...

Aldehydes and Ketones with Amines: Enamine Formation Mechanism

Enamine formation involves the addition of carbonyl compounds to a secondary amine through a series of reactions. The mechanism begins with the generation of carbinolamine, a nucleophilic attack followed by several proton transfer reactions. The hydroxyl group of the carbinolamine is converted into water to make a better leaving group that can push the reaction forward by eliminating a water molecule. In enamine formation, the last step involves the abstraction of a proton from the α carbon to form a C=C bond in the enamine. This differs from the last step of imine formation, where the N–H proton was abstracted to give the imine.
Enamines are formed under mildly acidic conditions. A pH of 4.5 is ideal for the reaction.
If the pH is low or the solution is too acidic, the reaction slows down in the first step—when the lone pair on the nitrogen atom of the amine attacks the carbonyl carbon of the substrate. A low pH indicates a high concentration of the protonated form of amine. The protonated amine cannot function as a nucleophile, slowing down this step’s rate.
If the pH is high or the solution is too basic, the fourth step of the reaction mechanism is affected. This is when the hydroxyl group of the carbinolamine is protonated to generate the leaving group, water. Highly basic conditions inhibit the process of water elimination by making the protonated amine, the proton donor in this step, less available for the reaction.
<img alt="Amide hydrolysis mechanism; chemical reaction diagram illustrating the step-by-step process." src="/files/ftp_upload/13216/13216_Figure_1.svg" style="text-align: center; height: 275px;" data-altupdatedat="1747908711000" data-alt="Figure1">

醛和酮与胺:烯胺形成机制

Enamine formation involves the addition of carbonyl compounds to a secondary amine through a series of reactions. The mechanism begins with the generation ...

&alpha;-Alkylation of Ketones via Enolate Ions

Ketones with &#945; protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by resonance, and its hybrid structure exhibits negative charges on the carbonyl oxygen and the &#945; carbon. This ambident nucleophile can attack an electrophile via two possible sites: the carbonyl oxygen, known as O-attack, or the &#945;&nbsp;carbon, known as C-attack. The nucleophilic attack via the carbanionic site is preferred. This is due to the strong interaction of the positive counterpart of the base with the anionic oxygen, which restricts the approaching electrophile, making the reaction less favorable. Also, the product obtained through C-attack is more stable than that obtained through O-attack, as the stronger C=O &#960; bond is retained in the former, whereas a weaker C=C &#960; bond is preserved in the latter.
A subsequent reaction of the enolate with electrophiles such as alkyl halides produces an &#945;-alkylated ketone via the SN2 pathway. The &#945;-alkylation of ketones is achieved with the halides of primary alkyl, benzyl, and allylic groups. With secondary and tertiary alkyl halides, elimination predominates over substitution.

Enolonium 种极性转换酮功能化的两步协议

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