Scaling Reactions
CHEM 231 Lab
Technique Primer
Scaling Reactions The synthetic chemist is often faced with the task of adapting existing reaction conditions (as reported in the literature, for example) for a specific purpose. Perhaps one would like to synthesize a product that is similar, but not identical, to the existing example— or one wants to run a much larger (or smaller) reaction. An understanding of how organic chemists think of putting reactions together will be helpful in your own experimental design. Consider the reaction of benzyl bromide with sodium methoxide in methanol to produce methoxymethylbenzene (Scheme 1). The synthesis is described in the following narrative experimental passage: “Sodium methoxide (194 mg) is dissolved in methanol (4.0 mL). To this solution is added benzyl bromide (357 L). The mixture is heated to 40°C and stirred for 2 h.”
Scheme 1. Synthesis of (methoxymethyl)benzene. In order to examine these conditions in more detail, it is useful to calculate the molar quantities of all reagents involved. This requires a few basic physical constants, such as density and molecular weight. A great resource for this information is the Aldrich catalog (http://www.sigmaaldrich.com/catalog/). A table can thus be generated, as follows: reagent
d (g/mL)
MW
mL
mg
mmol
1.438
171.0
0.357
513
3.00
sodium methoxide
--
54.02
--
194
3.59
methanol
--
--
4.0
--
--
benzyl bromide
red = from Aldrich; black = from experimental; blue = calculated
The reaction scale is usually defined by the number of moles (or millimoles) of the limiting reagent. In this example, we would say the reaction was run on a 3.0-mmol scale, or it was a “3 mmol reaction”. It is also often useful to have an estimate of the total reaction volume (VT). For the purposes of this very rough calculation, the density of solids is assumed to be 1 g/mL. Thus, 194 mg of sodium methoxide is assumed to have a volume of 194 L. The total reaction volume (VT) would then be approximately 4.6 mL (4.0 + 0.357 + 0.194).
With this value in hand, we can calculate the reaction concentration, which is usually based on the limiting reagent (here, benzyl bromide). In this example, the reaction concentration would be approximately: 3.00 mmol 4.6 mL = 0.65 M One final concept to develop is the idea of reagent equivalency, which is the molar ratio of one reagent to another. The limiting reagent is usually defined as one equivalent, and everything else is compared to it. Therefore, the equivalents of sodium methoxide would be defined as: 3.59 mmol 3.00 mmol = 1.2 eq This vocabulary is frequently used when organic chemists communicate with one another. For example, the reaction in Scheme 1 might be described as follows: “Benzyl bromide was reacted with 1.2 eq of sodium methoxide in methanol for 2 h at 40°C. The reaction was run on a 3-mmol scale at a concentration of 0.65 M.” Even though this description looks very different, it actually encodes the same information as the previous passage. The reason the latter description is useful is that it focuses on the parameters that one can vary in a reaction. To be precise, these variable parameters are:
temperature time reaction scale reaction concentration reagent equivalencies reagent identities
In theory, changing the reaction scale is not expected to change the outcome of the reaction, but modifying the other parameters can (and usually does) have an impact. Very often, these parameters are varied intentionally in a series of experiments, a process known as reaction optimization. Usually the goal of any optimization is to achieve the highest yield of product in the highest purity in the least amount of time and with minimum cost.
Technique Primer
Scaling Reactions The synthetic chemist is often faced with the task of adapting existing reaction conditions (as reported in the literature, for example) for a specific purpose. Perhaps one would like to synthesize a product that is similar, but not identical, to the existing example— or one wants to run a much larger (or smaller) reaction. An understanding of how organic chemists think of putting reactions together will be helpful in your own experimental design. Consider the reaction of benzyl bromide with sodium methoxide in methanol to produce methoxymethylbenzene (Scheme 1). The synthesis is described in the following narrative experimental passage: “Sodium methoxide (194 mg) is dissolved in methanol (4.0 mL). To this solution is added benzyl bromide (357 L). The mixture is heated to 40°C and stirred for 2 h.”
Scheme 1. Synthesis of (methoxymethyl)benzene. In order to examine these conditions in more detail, it is useful to calculate the molar quantities of all reagents involved. This requires a few basic physical constants, such as density and molecular weight. A great resource for this information is the Aldrich catalog (http://www.sigmaaldrich.com/catalog/). A table can thus be generated, as follows: reagent
d (g/mL)
MW
mL
mg
mmol
1.438
171.0
0.357
513
3.00
sodium methoxide
--
54.02
--
194
3.59
methanol
--
--
4.0
--
--
benzyl bromide
red = from Aldrich; black = from experimental; blue = calculated
The reaction scale is usually defined by the number of moles (or millimoles) of the limiting reagent. In this example, we would say the reaction was run on a 3.0-mmol scale, or it was a “3 mmol reaction”. It is also often useful to have an estimate of the total reaction volume (VT). For the purposes of this very rough calculation, the density of solids is assumed to be 1 g/mL. Thus, 194 mg of sodium methoxide is assumed to have a volume of 194 L. The total reaction volume (VT) would then be approximately 4.6 mL (4.0 + 0.357 + 0.194).
With this value in hand, we can calculate the reaction concentration, which is usually based on the limiting reagent (here, benzyl bromide). In this example, the reaction concentration would be approximately: 3.00 mmol 4.6 mL = 0.65 M One final concept to develop is the idea of reagent equivalency, which is the molar ratio of one reagent to another. The limiting reagent is usually defined as one equivalent, and everything else is compared to it. Therefore, the equivalents of sodium methoxide would be defined as: 3.59 mmol 3.00 mmol = 1.2 eq This vocabulary is frequently used when organic chemists communicate with one another. For example, the reaction in Scheme 1 might be described as follows: “Benzyl bromide was reacted with 1.2 eq of sodium methoxide in methanol for 2 h at 40°C. The reaction was run on a 3-mmol scale at a concentration of 0.65 M.” Even though this description looks very different, it actually encodes the same information as the previous passage. The reason the latter description is useful is that it focuses on the parameters that one can vary in a reaction. To be precise, these variable parameters are:
temperature time reaction scale reaction concentration reagent equivalencies reagent identities
In theory, changing the reaction scale is not expected to change the outcome of the reaction, but modifying the other parameters can (and usually does) have an impact. Very often, these parameters are varied intentionally in a series of experiments, a process known as reaction optimization. Usually the goal of any optimization is to achieve the highest yield of product in the highest purity in the least amount of time and with minimum cost.
