{"id":11963,"date":"2018-10-15T06:00:00","date_gmt":"2018-10-15T10:00:00","guid":{"rendered":"https:\/\/www.masterorganicchemistry.com\/?p=11963"},"modified":"2026-04-22T10:06:09","modified_gmt":"2026-04-22T15:06:09","slug":"aromatic-synthesis-1-order-of-operations","status":"publish","type":"post","link":"https:\/\/www.masterorganicchemistry.com\/2018\/10\/15\/aromatic-synthesis-1-order-of-operations\/","title":{"rendered":"Aromatic Synthesis (1) – “Order Of Operations”"},"content":{"rendered":"

Planning An Aromatic Synthesis:\u00a0 Putting Reactions In The Right Order<\/strong><\/p>\n

When planning a synthesis of simple aromatic compounds, it’s not enough to pick the right reactions. You also have to put them in the right order! If you’re not careful, you may end up making a\u00a0para<\/em>– product when you meant to make a\u00a0meta-\u00a0<\/em>, or vice versa!<\/p>\n

\"importance-of-order-of-operations-in-the-synthesis-of-aromatic-molecules\"<\/a><\/p>\n

Table of Contents<\/strong><\/p>\n

    \n
  1. Synthesis of Aromatic Compounds: “Order of Operations” Matters<\/a><\/li>\n
  2. Example #1: Synthesis of\u00a0m<\/em>-Bromonitrobenzene From Benzene<\/a><\/li>\n
  3. Example #2:Synthesis of\u00a0p<\/em>-Ethylacetophenone From Benzene<\/a><\/li>\n
  4. Summary:\u00a0 To\u00a0 Obtain The\u00a0Para-\u00a0<\/em>Product, Install the\u00a0Ortho-,Para- <\/em>Director First; To Obtain the Meta- <\/em>Product, Install the Meta- <\/em>Director First<\/a><\/li>\n
  5. Practice Questions<\/a><\/li>\n
  6. Notes<\/a><\/li>\n
  7. Quiz Yourself!<\/a><\/li>\n<\/ol>\n
    \n

    <\/a>1. Synthesis of Aromatic Compounds: “Order Of Operations” Matters<\/strong><\/h2>\n

    Up to now, we’ve covered electrophilic aromatic substitution\u00a0[6 key reactions<\/a>] [mechanism<\/a>] [ortho-para-meta<\/a>] and then the reactions of aromatic substituents [bromination & oxidation<\/a>] [carbonyl reduction<\/a>] [nitro reduction & Baeyer-Villiger<\/a>].<\/p>\n

    So what?!<\/em> All we’ve done is\u00a0assemble a workshop full of gleaming new tools. We haven’t actually\u00a0used<\/em> them for anything yet!<\/p>\n

    So let’s start putting these reactions together in sequences with the goal of building specific molecules.<\/p>\n

    We’ll begin with a key principle for planning the synthesis of disubstituted aromatic molecules.<\/p>\n

    In planning a synthesis, the order in which reactions are done can have a crucial impact on the outcome!<\/strong><\/p>\n

    <\/a>2. Example #1: m<\/em>-Bromonitrobenzene From Benzene<\/h2>\n

    Say you want to make this compound,\u00a0m<\/em>-bromonitrobenzene, from benzene:<\/p>\n

    \"quiz<\/p>\n

    When faced with a synthesis question that has a defined starting point like this,\u00a0 my first question is always:<\/p>\n

    “What’s different? What bonds need to form and break going from the starting material to the product?<\/strong>”\u00a0<\/em><\/p><\/blockquote>\n

    In this example, the bonds that form are C\u2013NO2<\/sub> and C\u2013Br , and the bonds that break are C\u2013H and C\u2013H.<\/p>\n

    The second question I always ask is:<\/p>\n

    “What reactions<\/strong> do I know that form and break these bonds?<\/em>“.<\/p><\/blockquote>\n

    In this case, the required reactions should be pretty straightforward : bromination<\/strong> (Br2<\/sub>, FeBr3<\/sub>) and nitration<\/strong> (HNO3<\/sub>, H2<\/sub>SO4<\/sub>)<\/p>\n

    \"plan<\/p>\n

    So is that all there is to it? Almost.<\/em><\/p>\n

    This is where “order of operations” rears its potentially ugly head.<\/p>\n

    If we just barrel along, doing bromination first and nitration second, what happens?<\/p>\n

    \"plan<\/p>\n

    Since the first reaction (bromination) installs an\u00a0ortho-, para-\u00a0<\/em>director, the second reaction (nitration) will result in the\u00a0undesired\u00a0<\/strong>para-<\/em> and\u00a0ortho-<\/em> products.<\/p>\n

    Since we want the\u00a0meta<\/em> product,\u00a0 the first step should be installation of a\u00a0meta<\/em>– director (nitration) followed by bromination.<\/p>\n

    \"synthesis<\/p>\n

    The bottom line is that\u00a0after<\/em> you have determined the bonds that need to form\/break, and after<\/em> you have a list of some of the reactions needed to form\/break these bonds, you need to ask a third question<\/strong>\u00a0when planning a synthesis:<\/p>\n

    “In what\u00a0order\u00a0<\/strong>do we run these reactions?”<\/p>\n

    (This doesn’t just apply to the synthesis of aromatic compounds – this is important for synthesis in general. )<\/em><\/span><\/p>\n

    <\/a>3. Example: para<\/em>-Ethyl\u00a0 Acetophenone<\/strong><\/h2>\n

    Another example. Say we want to synthesize para<\/em>-ethyl acetophenone (below):<\/p>\n

    \"example<\/p>\n

    The bonds that form here are two carbon-carbon bonds: C-CH2<\/sub>CH3<\/sub> and C-C(O)CH3\u00a0<\/sub>, and the bonds that break are two C\u2013H bonds.<\/p>\n

    Two reactions which could form and break these bonds are:<\/p>\n