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You have to run update.php when updating from 2.1 (even if there seem to be no updates) or clear caches by other means to regain access to the module settings page.
Note #2
Unless Libraries API has a stable release, the 3.x branch of PHPMailer module will not become the recommended release. Module version 6.x-2.2 is otherwise feature identical to 6.x-3.0 and the 2.x branch will still be maintained in the future.
The 3.x branch of PHPMailer module now relies on Libraries API, otherwise it is feature identical to 6.x-2.2 (which will still be maintained in the future). However, the 3.x branch will not become the recommended release until Libraries API has a stable release.