Wow, changes between 2.x and 4.x would be a very long list. It really depends on what features of the product you are leveraging.
Here are the big architectural changes:
* Share user interface, which I think is a big improvement over the Explorer interface in 2.x
* CMIS APIs
* Records Management (released in 3.2, and will be available in 4.x as 4.1)
* Solr search, which should be more reliable and performent
* IMAP interface
* SharePoint protocol support
* Tagging (I don't think this was available in 2.x, but I could be wrong)
* Support for more transformations and more metadata extraction (EXIF, geotag, etc)
* Replication between multiple Alfresco repositories
* Better integration with WCM solutions using Web QuickStart
* Social features
* Automatic email notifications on activities and events
* Publishing content to Twitter, Youtube, Facebook, etc
* Doclib portlet
In general, it is a huge jump in architecture and functionality.