1.Determine the p K a of the underlined proton in methotrexate. pK a _____ 2.Is

Question

1.Determine the pKa of the underlined proton in methotrexate. pKa _____

2.Is the pKa of the underlined proton in -fluoromethotrexate lower or higher than

methotrexate? Explain your reasoning.

Fluorine is also used in pharmaceuticals to increase acidity of neighboring functional groups. For example, methotrexate is used for the treatment of rheumatoid arthritis. There are unwanted side effects that can occur from reactive carboxylate groups. _Fluoromethotrexate is less toxic than methotrexate because the carboxylate groups are more acidic, which prevents a reaction from occurring at the carboxylate. OH COOH F NH2 COOH NH2 COOH Me Me H2N Methotrexate y-Fluoromethotrexate Figure 1. Increased acidity of methotrexate via fluorination.

Explanation / Answer

1. Determine the pKa of the underlined proton in methotrexate.

Answer: pKa = 4.8 (4.7 is also reported)

Reference: http://www.pharmpress.com/files/docs/EssentialsPharmaceuticalChemistry_Sample(2).pdf (See Page 60 ).

https://pubchem.ncbi.nlm.nih.gov/compound/methotrexate#section=pKa

pKa is experimentally calculated value, there is no equation to find out.

2. Is the pKa of the underlined proton in -fluoromethotrexate lower or higher than methotrexate?

Answer:    lower

Reason:   acidity increases with decreasing in pKa value. Because the alpha carbon (in -fluoromethotrexate) has a highly electronegative atom fluorine. Fluorine withdraws electrons from adjacent atoms than any element in the periodic table. Hence the proton on carboxylic acid will easily lost and the formed carbanion is stabilized by resonance including electronegative character of adjacent fluorine atom.

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