The connection is being dropped by the relay during the exchange and the message is delayed when sending to multiple recipients.
You also receive the following error message:
451 4.4.0 Primary target IP address responded with: "421 4.4.2 Connection dropped." Attempted failover to alternate host, but that did not succeed. Either there are no alternate hosts, or delivery failed to all alternate hosts."
The issue happens because the relay severs of HES have set the recipient limit to 1,000:
To resolve the issue, you need to configure your mail server's outbound mail configuration to follow this limit. If you need assistance in configuring your outbound mail settings, contact the technical support of the Mail Transfer Agent (MTA) you are using.
You may also refer to the following Microsoft KB articles: