Question

Following is a retrosynthetic analysis for ibutilide, a drug used to treat cardiac arrhythmia. In this scheme, Hept is an abbreviation for the 1-heptyl group. (a) Propose a synthesis for ibutilide starting with aniline, methanesulfonyl chloride, succinic anhydride, and \(N\)-ethyl-1-heptanamine. (b) Is isobutilide chiral? If so, which of the possible stereoisomers are formed in this synthesis?

Short answer

Question: Propose a synthesis for ibutilide using the given starting materials, and determine if ibutilide is chiral and which stereoisomers are formed in the synthesis. Answer: To synthesize ibutilide from the given starting materials: aniline reacts with methanesulfonyl chloride, forming anilinium methanesulfonate. This intermediate reacts with succinic anhydride to form a succinimide derivative. Finally, the succinimide derivative undergoes an S_N2 reaction with N-ethyl-1-heptanamine to form ibutilide. Ibutilide is chiral because it has one stereocenter at the carbon atom connected to the nitrogen from the N-ethyl-1-heptanamine moiety. This leads to the formation of two stereoisomers (enantiomers): R-ibutilide and S-ibutilide. The S_N2 reaction proceeds with an inversion of configuration, leading to the formation of only one enantiomer (either R- or S-ibutilide). To identify the specific enantiomer synthesized, further analysis of the stereochemistry of the starting materials and intermediates is necessary.

Step-by-step solution

Synthesis of ibutilide from starting materials

First, write the structures of the given starting materials: aniline, methanesulfonyl chloride, succinic anhydride, and N-ethyl-1-heptanamine. Then, design a synthetic pathway that connects these starting materials, leading to the formation of ibutilide. Aniline can be reacted with methanesulfonyl chloride to form anilinium methanesulfonate. This intermediate can then be reacted with succinic anhydride to form a succinimide derivative. Finally, the succinimide derivative can undergo an S_N2 reaction with N-ethyl-1-heptanamine to yield ibutilide.

Determine if ibutilide is chiral

Examine the structure of ibutilide to identify if it has any stereocenters. A molecule is chiral if it has a non-superimposable mirror image (enantiomer). Ibutilide has one stereocenter at the carbon atom that is connected to the nitrogen from the N-ethyl-1-heptanamine moiety. This carbon is also connected to two different groups: one is a part of the succinimide ring, and the other is the heptyl group. Since there is a stereocenter, isobutilide is indeed chiral.

Identify possible stereoisomers formed in the synthesis

Since ibutilide has one stereocenter, it can give rise to two stereoisomers (enantiomers): R-ibutilide and S-ibutilide. The S_N2 reaction between the succinimide derivative and N-ethyl-1-heptanamine proceeds with inversion of configuration. Considering the stereocenter configuration in the starting materials, the reaction will lead to the formation of only one of the enantiomers (either R- or S-ibutilide). To identify which enantiomer is formed, assign the stereochemistry of the starting materials and the intermediates leading to the formation of ibutilide. Based on the reaction outcome, we can determine the specific enantiomer synthesized in this pathway.

Key concepts

Organic Synthesis

Organic synthesis is the process of constructing organic molecules using a series of chemical reactions. It's akin to building with molecular lego blocks, carefully arranging them to design complex structures. The process involves creativity and systematic planning, akin to solving a puzzle backward—a strategy known in chemistry as retrosynthetic analysis.

For instance, in the case of ibutilide synthesis, aniline, methanesulfonyl chloride, succinic anhydride, and N-ethyl-1-heptanamine serve as our initial molecular pieces. By connecting these pieces in a specific sequence, chemists are able to construct ibutilide systematically. This systematic construction is essential, as it allows scientists to produce pharmaceutical drugs in a laboratory setting, ensuring that medications like ibutilide are available for treating conditions such as cardiac arrhythmia. Here, understanding and recognizing functional groups and how they react is crucial, as it determines the construction sequence and ultimately the success of the synthesis.

Chirality and Stereoisomers

Chirality is a geometric property where a molecule exists in two forms (known as enantiomers) that are mirror images of each other but cannot be superimposed on one another. Imagine your hands as an analogy; they are similar but not identical—this is chirality in a nutshell. Stereoisomers are compounds with the same molecular formula and sequence of bonded atoms (constitution), but they differ in the three-dimensional orientations of their atoms in space.

In the context of ibutilide, chirality plays a fundamental role in its biological activity. The presence of a stereocenter gives rise to two different enantiomers of the drug, entitled R-ibutilide and S-ibutilide. In biological systems, these enantiomers can exhibit significantly different effects, which makes understanding chirality crucial when synthesizing pharmaceuticals. Often, only one enantiomer is therapeutically active or safe, so the ability to control the stereochemistry during synthesis is a valuable skill in organic chemistry.

SN2 Reaction

The S_N2 reaction stands for 'substitution nucleophilic bimolecular.' It's a fundamental type of reaction in organic chemistry where a nucleophile (an electron-rich species) replaces a leaving group (electron withdrawing) attached to a carbon atom. This reaction is characterized by its 'backside attack' mechanism, where the nucleophile approaches the carbon from the opposite side of the leaving group, leading to an inversion of configuration at the carbon atom.

In the synthesis of ibutilide, the S_N2 reaction is the decisive step that helps introduce the N-ethyl-1-heptanamine moiety into the molecule, ultimately furnishing the chiral center necessary for its activity. This step highlights the importance of understanding reaction mechanisms to predict the outcome of organic synthesis. The ability to anticipate the configuration of the product from an S_N2 reaction is essential, especially when the product is a chiral molecule and only one enantiomer is desired, such as in the production of ibutilide for medical use.