A Conservative MEP will warn the people of Spain that Scottish independence "would trigger a wave of secessionist movements across the EU".
Scotland and Catalonia remain "better together" with the UK and Spain, Struan Stevenson will say in a speech in Barcelona on Monday.
Spain "played a historic role in the Act of Union" between Scotland and England when "Spanish soldiers finally drove a starving and exhausted band of Scottish colonists from Panama in 1699" ending the ill-fated Darien Scheme, according to the retiring Tory MEP.
Bankrupt aristocrats surrendered Scotland's independence in exchange for repayment and turned "disaster" into "a great success story", he will say in an address to support the re-election of Catalan Spanish unionist MEP Alejo Vidal Quadras.
Mr Stevenson will say: "This disastrous episode bankrupted Scotland and when it was suggested that all shareholders who had lost money in the scheme would be repaid in full if they signed up to the 1707 Act of Union between Scotland and England, the Scottish aristocracy readily consented and almost overnight, Scotland's independence was gone.
"In retrospect I think the Act of Union between Scotland and England was a great and fundamentally significant historic step, so ironically we have the Darien disaster and Spain to thank for the creation of the United Kingdom, which has been a great success story for more than 300 years."
Mr Stevenson will argue that a Yes vote in Scotland "would trigger a wave of secessionist movements across the EU, which would be bad for Britain, bad for Spain and bad for Europe".
"I agree with Artur Mas, leader of the Catalan nationalists, who acknowledges that an independent Catalonia would have to apply for membership of the EU," he will add.
"Sadly he does not seem to have convinced his good friend Alex Salmond about this, as the Scottish First Minister remains very confused over Scotland's position in Europe following a Yes vote.
"Secessionism flies in the face of our modern European and global environment. Sharing a common history, culture and language and yet being open to external solidarity with people from different backgrounds is surely what 'united in diversity' is all about? Seeking political disintegration would seem to me to be a betrayal of those core values of solidarity and human integration."
"I am proud to be Scottish, but I am also proud to be British and proud to be a European. I believe we are better together and I hope we will stay that way. Europe needs a united Britain and a united Spain. Let's work together for a better future."
Mr Vidal Quadras is an arch-critic of European secessionist movements, previously arguing that France and Spain would not accept an independent Scotland and insisting that the police would prevent an "unconstitutional" referendum on Catalan independence from taking place.
An SNP spokeswoman said: "It is ironic that Struan Stevenson talks about his proud European identity while his party is threatening to drag Scotland and UK out of the EU.
"Scotland is an immensely wealthy country and if we were independent, we would be wealthier per head than France, Italy, Japan and the UK. Our human and natural resources mean Scotland is as important to the EU as the EU is to Scotland.
"With independence, Scotland will enjoy full representation in Europe. At present, a land-locked country such as Luxembourg has more of a say on European fisheries policy than the Scottish Government. After a Yes vote, we will be able to sit at the top table alongside our friends and neighbours across Europe."
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