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By 1613, the Dutch were settled in various points upon the coast between the Orinoco and the Amazon. In that year the Spaniards surprised and destroyed a Dutch post on the Corentyne River. In a report announcing this achievement, the Spanish commander stated: "It would be well to free our coasts of them entirely, for from the River of Maranon (Amazon) to the Orinoco, there are three or four more of their settlements, and their plantations are very considerable. They have possessed themselves of the mouths of these two rivers and are making themselves masters of the produce and possessions of the natives."

The Spanish parish priest and vicar of Trinidad in a letter of the 30 June 1614 stated that he had been informed that from the river called Guayapoco as far as the Orinoco, a distance of 200 leagues, there were four Flemish settlements.

In 1614, the Dutch, supported by the Caribs, besieged Trinidad. Reinforcement ammunition were later sent from Spain with a view to protecting that island which was in imminent danger.

Towards the end of that year, a Dutchman named Claessen, who had founded a settlement on the Wiapoco, petitioned the States-General of the Netherlands to establish a new colony in the ports of the West Indies. In 1615, the King of Spain was presented with a report and a map showing the places between the Amazon and the Island of Margarita, where it was believed that the Dutch intended to settle. From this report, he learned that the Dutch had navigated the Orinoco as far as its junction with the Caroni River, and the Waipoco as far as its third fall. The report also mentioned that the Dutch were spending large sums of money in colonial enterprises and that they wanted to put the commerce of Guyana directly under the control of the States-General.

In a description of Guyana made about 1669, Major John Scott stated that in 1616 the Dutch Captain, Adrian Groenewegen (Scott reported the name as Groenewegel), with a small fleet that sailed to Guyana, settled the Essequibo and built Fort Kykoveral "on a small island 30 leagues up the River Disseekeeb (Essequibo), which looked into two branches of that famous river". According to this description, it was Groenewegen who first opened up the interior of Guiana to trade and settlement, and he and his settlers lived on friendly terms both with the natives and with the foreigners, especially English traders, in the West Indies.

Groenewegen was actually sent by the Anglo-Dutch firm of Courteen and Company to establish a settlement in Essequibo. He was particularly interested in exploration and trade and, in the company of a Captain Mattheson, he travelled to the south of the country in search of Manoa del Dorado. It is believed that they reached as far as the Takutu River, and even the Rio Branco. On two occasions, Groenewegen destroyed the town of Santo Thomé when he led raids against the Spaniards there.

The origin of the Essequibo colony is still unclear. There apparently were two parallel administrations, one headed by Groenewegen, and the other by Adrian van der Goes, an appointee of the Dutch West India Company. Groenewegen's settlers were more enterprising and prosperous than those on the Company's settlement. The Company so badly neglected its colony that in 1632, van der Goes and his settlers abandoned their colony and returned to Amsterdam.

The following year, new Dutch settlers came from Tobago, but they joined Groenewegen's settlement since the other was completely abandoned. It is believed that they brought the first African slaves with them to Kykoveral. The Company's settlement and investment there were saved by the Zeeland Chamber which helped to fund resources and eventually sent van der Goes and another group of colonists in late 1632 back to Essequibo.

Groenewegen was very friendly with John Powell who had settled Barbados for the English in the 1620s. When the English colonists faced starvation in 1627, Powell sailed to Essequibo for help and Groenewegen assisted him with a cargo of cassava and other food supplies. He also sent a small group of Amerindians to teach the English to plant cassava and other root crops on the island.

At this period, the Spaniards were definitely excluded from the coast east of the Orinoco. They probably visited that area of coast for trading purposes at the close of the sixteenth century; but after the first arrival of the English in 1595 and the Dutch in 1598 and in succeeding years, it became more and more off-limits to them. The English and the Dutch allied themselves with the Caribs against the Spaniards; and after the sacking of Santo Thomé by Raleigh in 1618, the Arawaks, until then the friends of the Spaniards, also turned against them.

As a result of these reverses against the Spaniards, the settlement of Santo Thomé was in 1619 on the point of being abandoned altogether. This was only prevented by the arrival of the new Governor with some small reinforcements. Representations were at once made as to the defenceless state of the settlement which was to far away from any areas settled by the Spaniards. The nearest province was that of "Venezuela" about "120 leagues" away. No discovery or settlement, it was urged, could be carried out until the town was prepared to defend itself from attacks.

In 1619, Geronimo de Grados was sent from Santo Thomé to Guyana to force the Arawaks to obedience. However, he met with six ships of the English and Dutch in the Essequibo, and he was taken prisoner. This was the last of the early Spanish voyages to the east of the Orinoco. Those who made them did not appear to have explored the country or done more than visit the mouths of the rivers.