📚 4. Synthetic Routes in Organic Chemistry (HL) | 有机合成路线（高级水平）
In IB Chemistry Higher Level, Topic 20.2 "Synthetic Routes" challenges students to design multi-step reaction sequences that convert simple starting materials into complex target molecules. This skill goes beyond memorising individual reactions; it requires a deep understanding of functional group interconversions, selectivity, protecting-group strategies, and retrosynthetic analysis. Mastery of synthetic routes not only prepares you for examination success but also gives a taste of real‑world organic synthesis in pharmaceutical and materials chemistry.
在 IB 化学高级课程中，专题 20.2“合成路线”要求学生设计多步反应序列，将简单原料转化为结构复杂的产物。这一技能远不只是背诵孤立反应，它需要深刻理解官能团转化、选择性、保护基策略以及逆合成分析。掌握合成路线不仅能帮助你在考试中脱颖而出，也让你初步体验制药和材料化学中真实有机合成的思维方式。
1. Introduction to Synthetic Routes | 合成路线简介
A synthetic route is a planned sequence of chemical reactions used to construct a target molecule from available starting materials. In HL, you must deduce feasible routes given specified reagents and conditions, often under constraints of efficiency and selectivity.
合成路线是一系列计划好的化学反应序列，用于从易得的原料构建目标分子。在高级水平中，你需要根据给定试剂和条件推断可行的合成路线，同时要考虑效率和选择性。
Key factors governing the design of a route include overall yield (which drops quickly with each extra step), atom economy, number of synthetic steps, chemo‑ and regioselectivity, and control of stereochemistry.
设计路线的关键因素包括总产率（每多一步骤产率就会急剧下降）、原子经济性、合成步骤数、化学选择性与区域选择性以及立体化学控制。
Most synthetic transformations fall into three categories: functional group interconversions (FGI), carbon–carbon bond-forming reactions, and oxidation–reduction processes.
大多数合成转化可分为三类：官能团相互转化（FGI）、碳‑碳键形成反应以及氧化‑还原过程。
2. Retrosynthetic Analysis: Thinking Backwards | 逆合成分析：倒推思维
Retrosynthesis is the process of deconstructing a target molecule into progressively simpler precursors by “disconnecting” bonds. This is symbolised by a retrosynthetic arrow (⇒).
逆合成分析是将目标分子通过“切断”化学键逐步拆解为更简单的前体，用逆合成箭头（⇒）表示。
Each disconnection suggests a corresponding forward reaction, most importantly a C–C bond-forming step such as a Grignard addition to a carbonyl, a Friedel–Crafts alkylation, or a nitrile alkylation.
每一次切断都对应着一个正向反应，最重要的是碳‑碳键形成步骤，例如格氏试剂对羰基的加成、弗瑞德‑克来福特烷基化或腈的烷基化。
Recognising functional group patterns, symmetry, and heteroatom positions in the target helps you identify strategic disconnections. For instance, an alcohol can be disconnected to a carbonyl compound plus a Grignard reagent.
识别目标分子中的官能团模式、对称性和杂原子位置有助于确定关键的切断位置。例如，醇可以被切断为羰基化合物加一分子格氏试剂。
Always check that the forward reaction is reliable and that the synthons correspond to stable, available reagents.
始终要检查正向反应是否可靠，以及合成子是否对应稳定、可得的试剂。
3. Functional Group Interconversion Toolkit | 官能团相互转化工具箱
A solid grasp of interconversions between functional groups is essential. The table below summarises common transformations and typical reagents used at HL.
牢固掌握官能团之间的相互转化至关重要。下表总结了常见转化和高级水平中使用的典型试剂。
- Alcohol → Aldehyde (1°): ₇ / H⁺, distil off aldehyde. Primary alcohol → carboxylic acid: excess KMnO₄ / H⁺, reflux.
醇 → 醛（伯醇）：K₂Cr₂O₇ / H⁺，蒸馏出醛。伯醇 → 羧酸：过量 KMnO₄ / H⁺，回流。 - Alcohol → Ketone (2°): K₂Cr₂O₇ / H⁺, reflux. No further oxidation under careful control.
醇 → 酮（仲醇）：K₂Cr₂O₇ / H⁺，回流。在严格控制下不会继续氧化。 - Aldehyde/Ketone → Alcohol: NaBH₄ in water or ethanol; LiAlH₄ in dry ether for more reactive substrates.
醛/酮 → 醇：NaBH₄ 在水或乙醇中；更活泼的底物用 LiAlH₄ 在干醚中。 - Carboxylic acid → Primary alcohol: LiAlH₄, then dilute acid work‑up.
羧酸 → 伯醇：LiAlH₄，然后稀酸处理。 - Alkene → Alkane: H₂ / Pt or Pd catalyst, room temperature and pressure.
烯烃 → 烷烃：H₂ / Pt 或 Pd 催化，常温常压。 - Halogenoalkane → Alcohol: NaOH(aq) warm, nucleophilic substitution.
卤代烷 → 醇：NaOH(aq) 温热，亲核取代。 - Halogenoalkane → Nitrile → Carboxylic acid / Amine: KCN in ethanol, then H⁺/H₂O hydrolysis for acid, or LiAlH₄ reduction for amine.
卤代烷 → 腈 → 羧酸/胺：乙醇中 KCN，然后 H⁺/H₂O 水解得酸，或 LiAlH₄ 还原得胺。 - Nitro → Amine: Sn / conc. HCl, then NaOH; or H₂ / Pd.
硝基 → 氨基：Sn/浓 HCl，然后 NaOH；或 H₂/Pd。
4. Carbon–Carbon Bond Formation: Building the Skeleton | 碳‑碳键形成：构建骨架
Creating new C–C bonds is the heart of organic synthesis. At HL, you are expected to use Grignard reagents, Friedel–Crafts reactions, and nitrile chemistry to extend the carbon framework.
形成新的碳‑碳键是有机合成的核心。在高级水平中，你应当会用格氏试剂、弗瑞德‑克来福特反应和腈化学来延伸碳骨架。
- Grignard + formaldehyde → primary alcohol; + aldehyde → secondary alcohol; + ketone → tertiary alcohol. Reactivity: RMgX + C=O.
格氏试剂 + 甲醛 → 伯醇；+ 醛 → 仲醇；+ 酮 → 叔醇。反应式为 RMgX + C=O。 - Grignard + CO₂ → carboxylic acid (after acidic work‑up). A useful way to add one carbon atom as –COOH.
格氏试剂 + CO₂ → 羧酸（酸性后处理）。这是一个增加一个碳原子并引入羧基的实用方法。 - Friedel–Crafts alkylation: enzene + RCl, AlCl₃ → alkylbenzene. Risk of polyalkylation and carbocation rearrangements.
弗瑞德‑克来福特烷基化：苯 + RCl，AlCl₃ → 烷基苯。有多烷基化和碳正离子重排的风险。 - Friedel–Crafts acylation: ryl ketone. No rearrangement, and can be followed by Clemmensen reduction to alkylbenzene.
弗瑞德‑克来福特酰基化：苯 + RCOCl，AlCl₃ → 芳基酮。不会发生重排，可随后用 Clemmensen 还原得到烷基苯。 - Nitrile alkylation: R–Br + KCN → R–CN, which can be hydrolysed to R–COOH or reduced to R–CH₂NH₂.
腈的烷基化：R–Br + KCN → R–CN，可水解为 R–COOH 或还原为 R–CH₂NH₂。
5. Oxidation and Reduction in Organic Synthesis | 有机合成中的氧化与还原
Controlling the oxidation state of carbon atoms allows you to switch between functional groups smoothly. Selective oxidising and reducing agents are chosen to avoid over‑reaction.
控制碳原子的氧化态可以让你在官能团之间顺畅切换。选择性的氧化剂和还原剂可避免过度反应。
Oxidising agents: ot alkaline KMnO₄ cleaves C=C bonds, while acidic KMnO₄ oxidises side chains completely to –COOH.
氧化剂：酸化的 K₂Cr₂O₇ 将伯醇氧化为醛（蒸馏）或羧酸（回流过量）；仲醇生成酮。热碱性 KMnO₄ 可断裂 C=C 键，而酸性 KMnO₄ 可将侧链完全氧化为 –COOH。
Reducing agents: on of C=C and reduction of NO₂ to NH₂. Sn/conc. HCl is a classic system for nitro → amine.
还原剂：NaBH₄ 选择性还原醛和酮，在质子溶剂中不攻击酯或羧酸。LiAlH₄ 强大得多，可将羧酸、酯、酰胺和腈还原为相应的醇或胺。H₂/Pd‑C 用于 C=C 加氢和 NO₂ → NH₂。Sn/浓 HCl 是硝基 → 氨基的经典体系。
6. Protecting Groups: When and How to Use Them | 保护基团：何时以及如何使用
In a multi‑step synthesis, a functional group that would interfere with a planned reaction must be temporarily masked. A protecting group is introduced, the desired reaction carried out, and then the protecting group is removed.
在多步合成中，如果某个官能团会干扰预期反应，就必须被暂时掩蔽。首先引入保护基团，进行所需的反应，然后脱除保护基团。
An excellent illustrative example is the synthesis of 4‑aminophenol from phenol. The –OH group is an ortho/para‑directing activator; if unprotected, nitration would occur on the ring, but subsequent reduction of –NO₂ without protection could have side reactions. Instead, we protect –OH as an ester.
一个绝佳的示例是由苯酚合成对氨基苯酚。–OH 是一个邻/对位活化定位基；若不保护，硝化会在环上发生，但后续还原 –NO₂ 时若无保护可能发生副反应。因此我们将 –OH 保护为酯。
Steps:
① Phenol + (CH₃CO)₂O → phenyl acetate (ester protection).
② Nitration with HNO₃/H₂SO₄ gives 4‑nitrophenyl acetate.
③ Base‑catalysed hydrolysis removes the acetyl protecting group, yielding 4‑nitrophenol.
④ Reduction with H₂/Pd or Sn/HCl then reduces –NO₂ to –NH₂, giving 4‑aminophenol.
中文：① 苯酚 + (CH₃CO)₂O → 乙酸苯酯（酯保护）。② 用 HNO₃/H₂SO₄ 硝化得到 4‑硝基乙酸苯酯。③ 碱催化水解脱除乙酰基保护，得到 4‑硝基苯酚。④ 用 H₂/Pd 或 Sn/HCl 将 –NO₂ 还原为 –NH₂，得到对氨基苯酚。
Other common protecting groups: amines can be protected as amides (e.g. acetylation), and carbonyls as cyclic acetals. The key is that the protecting group must survive the intended reaction conditions and be removable selectively.
其他常见的保护基团：氨基可保护为酰胺（如乙酰化），羰基可保护为环状缩醛。关键在于保护基必须在目标反应条件下稳定，并能被选择性脱除。
7. Stereochemical Control in Multi‑Step Synthesis | 多步合成中的立体化学控制
When a synthesis generates new chiral centres, the absolute configuration or E/Z geometry may need to be controlled. Although HL requires mainly awareness, certain reactions inherently give specific stereochemical outcomes.
当合成产生新的手性中心时，可能需要控制绝对构型或 E/Z 几何异构。尽管高级水平主要要求认识，但某些反应本身具有特定的立体化学结果。
For example, catalytic hydrogenation of an alkene with H₂/Pd gives syn addition (both hydrogens added to the same face), while bromination followed by elimination can be used to install a defined E‑alkene stereochemistry.
例如，用 H₂/Pd 对烯烃进行催化加氢给出顺式
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