The primary outcome of a synthesis experiment is the formation of an organic product from a set of starting materials and a reagent. The important steps involved in performing a synthesis can be divided into 8 steps. Listed after each step is the section where details explaining each procedure are contained.

  1. Selecting the correct starting materials. Stockroom
  2. Selecting the correct solvent. Stockroom
  3. Setting up the correct reaction conditions. Building an Apparatus
  4. Adding the correct reagent. Reagents
  5. Monitoring the reaction using thin layer chromatography. TLC
  6. Quenching the reaction and working up the reaction mixture. Workup
  7. Purifying the product. Distillation, Recrystallization
  8. Characterizing the product using NMR, FTIR, Mass Spec, and melting points. NMR, FTIR, Mass Spec, Melting Point

Here are some important points to remember. (a) What is being tested here is the ability to think about what you want to do and why you want to do it. The simulation will respond with the appropriate outcome based on your decisions. (b) In a real laboratory, the apparatus is set up first in the hood, dried, and the solvent and reagents are added to it. In the simulation, the emphasis is on the thinking behind the synthesis and trying to reinforce the 8 steps described above. (c) The chalkboard will show the contents of the various solutions and serve to reinforce the interpretation of the analytical techniques. (d) The spectra library can be a useful tool to verify products. (e) Many of the reactions will proceed through a series of steps involving observable intermediates. It is important to remember this when determining the end of a reaction and when working up the reaction mixture. (f) The only way to verify that the correct steps in the synthesis were taken is by recording a complete set of notes in the lab book. This includes saving TLC plates, NMR spectra, FTIR spectra, and Mass Spec.


Building an Apparatus

After the starting materials and solvent have been added to the flask in the stockroom, the flask is brought to the lab bench and placed on the stir plate. At this point a reagent can be added or an apparatus can be assembled for the selected reaction conditions. The possible apparatus pieces include:

  1. A heating mantle (located on the lab bench)
  2. An ice bath (use the ice cooler in the stockroom)
  3. A condenser (located on the lab rack)
  4. N2 gas (located on the lab bench)

The separate apparatus parts are added to the reaction setup by dragging the part to the apparatus. An apparatus part can be removed by dragging it to the disposal bucket. Each apparatus part can be added in any order or combination except for the heating mantle and ice bath, which are mutually exclusive.


Here are a few things to remember. (a) The apparatus has a septum cap and is a closed system. N2 gas is required when heating (the return gas bubbler is not shown); otherwise, the apparatus will explode. (b) When heating without a condenser but with N2 gas, the reaction mixture will boil away. (c) There is no adjustment for the heating mantle. It is assumed that enough heat is applied to reflux the reaction mixture. (d) Heating a reaction mixture for excessive time periods may cause the mixture to turn to tar.


Reagents

On the back of the lab bench are 15 reagents, only one of which can be added to a flask containing any starting material/solvent solution brought from the stockroom. The reagent can be added at any time before the reaction is started, however, it is not necessary to add a reagent. Mousing over the reagent bottles displays the name and structure of the reagent on the chalkboard. Given below is a short description for each of the 15 reagents. Unless otherwise indicated, reagents are added in stoichiometric quantities.

  1. m-Chloro-Perbenzoic Acid (MCPBA). Solid meta-chloro-perbenzoic acid.
  2. Aluminum Trichloride. Solid AlCl3.
  3. Sodium Borohydride. Solid NaBH4.
  4. Pyridinium Chlorochromate (PCC). Solid pyridinium chlorochromate.
  5. Sulfuric Acid. Concentrated H2SO4 added in catalytic amounts (two to three drops).
  6. Hydrochloric Acid. Concentrated 37% HCl.
  7. Borane-THF/Peroxide. This reagent is actually a two-step process. The first step consists of the stoichiometric addition of Borane-THF followed by the addition of concentrated 30% H2O2 solution after the reaction is stopped. The peroxide cleaves the new borane resulting in boric acid and the finished alcohol product. If the borane does not react with the starting materials the peroxide cleavage is ignored.
  8. Bromine. Liquid Br2.
  9. Osmium Tetroxide. A sufficient quantity of 2.5% osmium tetroxide/tert-butanol solution is added to achieve stoichiometric amounts of OsO4. In a real lab, a stoichiometric oxidant is added to catalytic OsO4.
  10. Potassium Hydroxide. Concentrated KOH.
  11. Lithium Diisopropyl Amide (LDA). A sufficient quantity of 2.0 M diethyl ether/LDA solution is added to accomplish all relevant proton transfers. In an actual laboratory, LDA is generated from diisopropylamine and butyllithium.
  12. Nitric Acid/Sulfuric Acid. A mixture of 68% HNO3 and 98% H2SO4. For nitration reactions, an amount necessary to facilitate all possible nitrations is added.
  13. Thionyl Chloride (SOCl2). A sufficient quantity of 2.0 M thionyl chloride/methylene chloride solution is added to achieve stoichiometric amounts of thionyl chloride.
  14. Sodium Methoxide. A sufficient quantity of 0.5 M sodium methoxide/methanol solution is added to achieve stoichiometric amounts of methoxide ion.
  15. Chromic Acid. A sufficient quantity of chromium (VI) oxide/concentrated sulfuric acid/water solution is added to achieve stoichiometric amounts of chromic acid.

Here are some things to remember. (a) Some reagents are incompatible with one or two of the solvents, and some unexpected outcomes will result. (b) Some reagents will produce products that are explosive with corresponding consequences.


Workup

Once a reaction has reached completion it is quenched by adding an appropriate aqueous reagent. In the simulation, the reaction is stopped by selecting the separatory funnel from the lab rack and dragging the funnel to the reaction apparatus. This returns the various apparatus parts back to where they came from and places the reaction mixture in the funnel on the lab bench. The three aqueous reagents, H2O, 0.1 M NaOH, and 0.1 M HCl, are now active and can be added to the funnel by clicking and dragging a small bottle to the funnel. At this point, diethyl ether is also added to the funnel, there is assumed to be a shaking procedure (not shown in the simulation), and the compounds in the reaction mixture are partitioned into the appropriate organic and aqueous layers. Volatile compounds are lost in the workup process. Be aware that some explosions may occur during the shaking and partitioning procedure due to unstable compounds.


After the aqueous reagent has been added, the NMR, FTIR, and Mass spectra are now available in addition to the TLC, which is always available. Either layer in the funnel can be extracted by clicking on the layer and dragging it to the stir plate, the cork ring, or the disposal bucket. If the layer is placed on the stir plate, the separatory funnel is automatically emptied and placed back on the rack. If the organic layer is removed there is assumed to be a rotovap step (not shown in the simulation) which removes the ether from the organic layer. Extracting the aqueous layer does not remove the water.


The only exception to this process is for acid chloride reactions where an aqueous workup is not appropriate. If an acid chloride reaction is chosen, then adding an aqueous reagent is not necessary before removing the reaction mixture from the funnel and taking an NMR or IR spectra. In all other circumstances, an aqueous reagent must be added before the NMR or IR spectra are available and before a solution can be removed from the funnel.


At this point in the simulation, the student is now free to perform a counter-current extraction, characterize a solution with a TLC, NMR, FTIR, or Mass Spec, or purify a solution by distillation or recrystallization. This can be done by several means, but in short a student is allowed to remove the remaining layer from the funnel, have a flask on the stir plate and/or on the cork ring, add a solution back to an empty funnel, or add another aqueous reagent to a solution in the funnel.


Distillation

After working up a reaction mixture and extracting a layer from the separatory funnel, a solution can be purified by distillation. Use the following steps to perform a distillation: (1) The flask containing a solution (or possibly low melting point solids) must be placed on the stir plate. (2) The distillation apparatus is selected by clicking and dragging the apparatus from the rack to the flask. (3) N2 gas is necessary, otherwise, there is a closed system and the apparatus will explode. (4) Pressing the Stir button starts the distillation with a 10-minute induction time to bring the solution to boiling. (5) Mousing over the thermometer will pop up an estimate of the temperature of the vapor. (6) Fractions come over in approximately 30-minute intervals, but some may come over more quickly depending on the concentration of the components in the mixture. Use the TLC, NMR, FTIR, or Mass Spec to determine the status of the distillation. (7) The collection flask can be removed at any time and placed on the cork ring or in the disposal bucket. Any characterizations of a fraction (NMR, FTIR, Mass Spec,and TLC) must take place before the next fraction is ready to come off. (8) The distillation can be stopped at any time by clicking and dragging the distillation apparatus to the disposal bucket leaving the flask (and its contents) on the stir plate. (9) Remember that some compounds have high boiling points or are unstable and will decompose upon heating.


Recrystallization

After working up a reaction mixture and extracting a layer from the separatory funnel, a solution or a solid mixture resulting from the rotovap step can be purified by recrystallization. In general terms, a recrystallization is achieved by placing a solution containing the products (dissolved in a low boiling point solvent if necessary) in a crystallization dish and allowing all of the volatile components to evaporate slowly. In the simulation, a recrystallization is performed by dragging the solution that will be recrystallized from the funnel, stir plate, or from the cork ring to the crystallization dish. Any components in the solution that have a melting point above room temperature or are not sufficiently volatile will remain in the dish as crystals or as oils. A melting point measurement can be taken on any mixture in the recrystallization dish.


Again, it is important to remember that at any point in a purification process the NMR, FTIR, Mass Spec, and TLC analytical techniques are available.