He launched a renewed assault on his coalition partner as several opinion polls suggested the Tories had reaped an opinion poll bounce from the long-awaited policy.
Mr Cameron insists he wants to stay in the EU but pledged to claw back powers and offer voters a choice of new relationship or exit by the end of 2017 if the Conservatives are returned to power in 2015.
It has delighted eurosceptic backbenchers fearful of the challenge of the UK Independence Party which slipped back in the latest polls after a recent surge.
Mr Clegg dismissed the prospects of securing a significant renegotiation and suggested Mr Cameron should be concentrating on the economy - which risks slumping into a triple-dip recession.
"My priority will always remain a simple objective of building a stronger economy in a fairer society, enabling everybody to get on in life," the Liberal Democrat leader told BBC1's Andrew Marr Show.
"And I think that job is made more difficult if you have years and years of tying yourself up in knots having arcane debates about the precise terms of the membership of the European Union before we get to a referendum.
"It is not in the national interest when we have this fragile recovery, when we have a very open economy which is very dependent on investors in the car industry and the banking system and so on.
"You must always, when you are trying to piece together a recovery, foster those precarious conditions of greater confidence in the economy, you mustn't do anything to make that more difficult."
He claimed that "most businesses I speak to...are extremely concerned".
And he added: "Is it deliverable to in effect say to the rest of the European Union: we want to do all the bits that we like but can you keep all the stuff that we think is not good for the economy?
"That is not plausible."
He denied his party had done a U-turn by opposing a referendum - having argued strongly for an in/out vote in 2008 - saying that had been in the context of the approval of the Lisbon Treaty.
The coalition had legislated for a referendum if there was any further such transfer of powers.
"It is the Conservatives who have decided to completely reinvent the wheel and tie the country up in knots by redesigning and fiddling around with the terms...before the British people even get near a referendum."
Mr Clegg again declined to say whether he would form a coalition with the Tories if there was no clear winner at the 2015 general election.
Labour leader Ed Miliband defended his decision to oppose the referendum promised by the Prime Minister.
"I just don't think it's in the national interest. Right now it doesn't make sense to commit to a referendum years ahead."
"Has he changed his mind because he's changed his view about the national economic interest? Or has he changed his mind because there's pressure in the Conservative party and he's worried about UKIP?
"I contend it's the second, not the first. That's why I've stuck to the positioning we've always had," Mr Miliband said.