Addition of Lactides to PEG

Note: it is very important to keep this reaction as dry as possible. I usually dry all glassware in the 80C oven before starting.

The following procedure is for addition of 2 lactide molecules per side of poly(ethylene glycol) of molecular weight 3400 (PEG3400):

1) Place 10 g PEG into a 25-50 ml round bottom flask. Add a stir bar.

2) Add D,L-lactides (Polysciences). Depending upon PEG molecular weight used and degree of substitution desired, the amount is calculated using the following formula:

Amt. of lactides = (10 g PEG)/(3400 g/mol)*(4 mol lactides/mol PEG)*(144 g/mol lactides)

For placing one lactide group on each end of PEG3400, this amount is 1.694 g.

3) Purge the round bottom flask with argon or nitrogen for 5-10 minutes (make sure the flask is vented with a vent needle), then add stannous octoate (1:200 mass ratio to PEG), which acts as a catalyst for the reaction. Stannous octoate has a density of 1.25 g/ml and is also known as 2-ethylhexanoate. For our case, the calculation is shown below:

Amt. stann. oct. = (1/200)*(10 g PEG) = 50 mg stannous octoate (40 μl)

4) Heat the reaction to 140C using a temperature-controlled hot plate and an oil bath. It is very important that the top of the round bottom flask remains submerged in oil, so try to use the smallest flask possible. When heated, the lactides will vaporize to some extent and condense/crystallize on the top of the round bottom flask if the top is not submerged in oil.

5) Allow the reaction to proceed for 4 hours at 140C, then place the reaction in a refrigerator until it is needed.

6) The product must now be purified. If it is to be acrylated or methacrylated, it is very important that all stannous octoate is removed. Any remaining stannous octoate will inhibit the acrylation/methacrylation steps. PEG-LA can be purified by dissolving in a minimum amount of methylene chloride (25 ml for our case) and precipitating (either dripping from a separatory funnel or dropwise using a glass pipet) into ice-cold ethyl ether (10:1 ether:product by volume). The product is then filtered through Whatman paper using a ceramic filter and dried in a vacuum oven at 50C anywhere from several hours to overnight (depending upon purity desired). This dried product can be re-dissolved in a minimum amount of methylene chloride and re-precipitated in ethyl ether to further purify the product and separate out the stannous octoate. For best purification, the product should be precipitated a total of 3 times.

*Note: before precipitating and/or re-precipitating the entire product, it is advisable to purify a small sample and analyze using NMR to make sure substitution is okay. Ethyl ether is expensive and it’s important to minimize generation of hazardous wastes.

**If the PEG-LA product is to be acrylated or methacrylated, the procedure for acrylating/methacrylating PEG can be used with a few small adjustments. Mainly, the calculations must be altered because now the molecular weight of the PEG molecules has changed slightly (e.g., for PEG3400-DA with two lactide molecules per side the molecular weight has changed from 3400 to 3400+144*4 = 3976 g/mol). The rest of the procedure is the same, though.

7) Clean up your mess.